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The Journal of Neuroscience, February 11, 2015 • 35(6):i • i
This Week in The Journal
Size-Based Sorting Enhances
Antigen Presentation by Microglia
Cong Chen, Hui-Quan Li, Yi-jun Liu,
Zhi-fei Guo, Hang-jun Wu, et al.
(see pages 2674 –2688)
Most cells continuously take up extracellular
solutes via pinocytosis, a form of endocytosis
inwhichtheplasmamembranenonselectively
engulfs extracellular fluid and encapsulates it
in small endocytic vesicles called pinosomes.
Antigen-presenting immune cells—including
microglia that have been activated by CNS injury or disease—use pinocytosis to ingest soluble proteins, which they degrade to peptide
fragments. The fragments are then bound
to major histocompatibility complex II
(MHCII) molecules and returned to the
plasma membrane, where they can be
recognized by T cells to trigger an immune
response. In multiple sclerosis (MS), a
T-cell-mediated demyelinating disease, activated microglia present myelin-derived
antigens, thus stimulating the activity of
myelin-targeting T cells and exacerbating
the disease. Understanding the steps that occur between pinocytosis and antigen presentation in microglia might therefore yield
insights into potential treatments for MS.
To better understand these steps, Chen et
al. studied the movement of fluorescently labeled proteins and polysaccharides in cultured
rat microglia. Pinocytosed molecules were initially colocalized in single pinosomes. Newly
formed pinosomes quickly acidified and were
surroundedbyMHCII-containinglysosomes.
Within 15 min, pinocytosed proteins were
broken down by proteinases in the acidified
compartments, and the peptide fragments
moved from the pinosome to lysosomes, leavinglargerpolysaccharidesbehind.Whensmall
polysaccharides were pinocytosed with proteins, the protein fragments and polysaccharides were both transferred to the same
lysosomal compartments, suggesting that the
transfer depended on the size of molecules,
rather than recognition of a specific sorting
signal.
Size-based sorting of pinocytosed molecules required ATP, GTP, proteins involved
in fusion between late endosomes and lysosomes, and dynamin (a protein involved in
membrane fission). Inhibiting dynamin disrupted size-based sorting by preventing the
transfer of some small molecules to lysosomes and permitting the transfer of some
large molecules. At the same time, inhibiting
dynamin reduced both secretion of
interferon-␥ and proliferation of T cells cocultured with microglia, indicating that it reduced the efficiency of antigen presentation by
microglia. Treatments that similarly interfere
with the size-based movement of molecules
from pinosomes to MHCII-containing lysosomes in microglia might therefore slow the
progression of MS.
Time-lapseimagesofamicroglialcellinducedtoundergopinocytosis
in the presence of large (green) and small (red) polysaccharides. Initially (top left), the polysaccharides were enclosed in the same pinosome(yellow),whichwassurroundedbylysosomes(blue).After8
min(topright),smallerpolysaccharidemoleculeshadbeguntomove
into lysosomes. More small polysaccharide molecules had exited the
pinosome 2 (bottom left) and 4 (bottom right) min later, leaving the
largerpolysaccharidesbehind.SeethearticlebyChenetal.fordetails.
Microglia Contribute to Rett
Syndrome by Secreting Glutamate
Lee-Way Jin, Makoto Horiuchi, Heike Wulff,
Xiao-Bo Liu, Gino A. Cortopassi, et al.
(see pages 2516 –2529)
Rett syndrome (RTT) is an X-linked neurodevelopmentaldisordercharacterizedbynormal
development in infancy followed by slowed
growth; deterioration of motor, mental, and
language skills; and the appearance of autistic
features. RTT is caused by mutations in
methyl-CpG-binding protein 2 (MeCP2), a
protein that regulates transcription by binding
to methylated CpG dinucleotides in DNA.
ThemostobviousneurologicalfeatureofRTT
is reduced brain size: neurons are smaller,
with less complex dendritic arbors and
fewer dendritic spines. Despite the role of
MeCP2 in transcriptional regulation, however, brain-wide gene expression is relatively
normal in MeCP2-deficient mice, suggesting that gene expression changes are subtle
or restricted to a small subset of cells.
MeCP2ishighlyexpressedinneurons,and
neuron-specific expression of MeCP2 can rescue RTT-like symptoms in otherwise MeCP2deficient mice. Expression of MeCP2 in glia is
much lower than in neurons, but recent evidence suggests that glia also contribute to RTT
neuropathology. For example, incubating cultured wild-type mouse neurons with medium
conditioned by MeCP2-null microglia damaged dendrites. The neurotoxicity stemmed
from increased production and release of glutamate by MeCP2-null microglia (Maezawa
and Jin 2010, J Neurosci 30:5346). This increase was attributed to increased expression
of glutaminase, which synthesizes glutamate
from glutamine, and connexin hemichannels,
through which microglia release glutamate.
New evidence suggests that glutamate
production in MeCP2-deficient microglia is
further enhanced by increased uptake of glutamine. Having previously identified the glutamine transporter SNAT1 as a target of
MeCP2-mediated transcriptional repression,
Jin et al. now report that SNAT1 levels were
elevated approximately threefold in MeCP2deficient microglia compared to wild-type.
Interestingly, however, SNAT1 was not upregulated in MeCP2-deficient neurons or
astrocytes, suggesting cell-type specific regulation by MeCP2. Inhibiting SNAT1 returned
glutamate production by MeCP2-deficient
microglia to control levels. Furthermore, conditioned medium from a microglial cell line
overexpressing SNAT1 caused dendritic damage in wild-type neurons, and the damage was
prevented by blocking NMDA receptors, suggesting it was mediated by glutamate toxicity.
Together with previous studies, these results suggest that MeCP2 represses several
genes involved in glutamate production and
release from glia. Inhibiting the proteins encoded by these genes may therefore reduce
glutamate-induced excitotoxicity, thus reducing dendritic loss in RTT.
This Week in The Journal is written by X Teresa Esch, Ph.D.
The Journal of Neuroscience
February 11, 2015 • Volume 35 Number 6 • www.jneurosci.org
i
This Week in The Journal
Journal Club
2323
Network Mechanisms Underlying the Initiation and Generation of
Sharp-Wave-Associated Ripple Oscillations
Jagdish Patel
2326
A Thalamic Origin to the Electrocortical Patterns Associated with Transitions into
Anesthetic-Induced Loss-of-Consciousness
Lia Mesbah-Oskui
Brief Communications
Cover legend: This image shows dye-filled,
genetically identified retinal ganglion cells (RGCs).
Some RGC types are more likely than others to
degenerate in the early stages of glaucoma, one of the
leading causes of blindness. RGCs whose dendrites
reside in the “Off” sublayer of the inner retina are
particular vulnerable. For more information, see the
article by El-Danaf and Huberman (pages
2329 –2343).
2417
Modulation of Microglial Process Convergence Toward Neuronal Dendrites by
Extracellular Calcium
Ukpong B. Eyo, Nan Gu, Srijisnu De, Hailong Dong, Jason R. Richardson,
and Long-Jun Wu
Articles
CELLULAR/MOLECULAR
2438
Aberrant Synaptic Integration in Adult Lamina I Projection Neurons Following
Neonatal Tissue Damage
Jie Li, Elizabeth Kritzer, Paige E. Craig, and Mark L. Baccei
2492
Phosphorylation of Synaptic Vesicle Protein 2A at Thr84 by Casein Kinase 1 Family
Kinases Controls the Specific Retrieval of Synaptotagmin-1
Ning Zhang, Sarah L. Gordon, Maximilian J. Fritsch, Noor Esoof, David G. Campbell,
Robert Gourlay, Srikannathasan Velupillai, Thomas Macartney, Mark Peggie,
Daan M.F. van Aalten, Michael A. Cousin, and Dario R. Alessi
2530
Functional Cooperation between the IP3 Receptor and Phospholipase C Secures the
High Sensitivity to Light of Drosophila Photoreceptors In Vivo
Elkana Kohn, Ben Katz, Bushra Yasin, Maximilian Peters, Elisheva Rhodes,
Rachel Zaguri, Shirley Weiss, and Baruch Minke
2559
Trip6 Promotes Dendritic Morphogenesis through Dephosphorylated
GRIP1-Dependent Myosin VI and F-Actin Organization
Kaosheng Lv (吕考升), Liang Chen (陈亮), Yuanjun Li (李圆君),
Zenglong Li (李曾龙), Pengli Zheng (郑鹏里), Yingying Liu (刘盈盈),
Jianguo Chen (陈建国), and Junlin Teng (滕俊琳)
2624
The Roles of Cdk5-Mediated Subcellular Localization of FOXO1 in Neuronal Death
Jiechao Zhou, Huifang Li, Xiaoping Li, Guanyun Zhang, Yaqiong Niu,
Zengqiang Yuan, Karl Herrup, Yun-Wu Zhang, Guojun Bu, Huaxi Xu,
and Jie Zhang
䊉
2646
Cooperative Roles of Hydrophilic Loop 1 and the C-Terminus of Presenilin 1 in the
Substrate-Gating Mechanism of ␥-Secretase
Shizuka Takagi-Niidome, Tomoki Sasaki, Satoko Osawa, Takeshi Sato,
Kanan Morishima, Tetsuo Cai, Takeshi Iwatsubo, and Taisuke Tomita
2674
A Novel Size-Based Sorting Mechanism of Pinocytic Luminal Cargoes in Microglia
Cong Chen, Hui-Quan Li, Yi-jun Liu, Zhi-fei Guo, Hang-jun Wu, Xia Li,
Hui-Fang Lou, Liya Zhu, Di Wang, Xiao-Ming Li, Li Yu, Xuetao Cao, Linrong Lu,
Zhihua Gao, and Shu-Min Duan
2731
Speed and Sensitivity of Phototransduction in Drosophila Depend on Degree of
Saturation of Membrane Phospholipids
Alex S. Randall, Che-Hsiung Liu, Brian Chu, Qifeng Zhang, Sidharta A. Dongre,
Mikko Juusola, Kristian Franze, Michael J.O. Wakelam, and Roger C. Hardie
2747
PKC Enhances the Capacity for Secretion by Rapidly Recruiting Covert Voltage-Gated
Ca2ⴙ Channels to the Membrane
Christopher J. Groten and Neil S. Magoski
2803
Spillover Transmission Is Mediated by the Excitatory GABA Receptor LGC-35 in C. elegans
Meghan A. Jobson, Chris M. Valdez, Jann Gardner, L. Rene Garcia,
Erik M. Jorgensen, and Asim A. Beg
DEVELOPMENT/PLASTICITY/REPAIR
2344
␣2-Chimaerin Is Required for Eph Receptor-Class-Specific Spinal Motor Axon
Guidance and Coordinate Activation of Antagonistic Muscles
Tzu-Jen Kao, Georgina C.B. Nicholl, Jamie A. Johansen, Artur Kania,
and Asim A. Beg
2432
Norepinephrine Is Necessary for Experience-Dependent Plasticity in the Developing
Mouse Auditory Cortex
Kathryn N. Shepard, L. Cameron Liles, David Weinshenker, and Robert C. Liu
2452
Secreted Ectodomain of Sialic Acid-Binding Ig-Like Lectin-9 and Monocyte
Chemoattractant Protein-1 Promote Recovery after Rat Spinal Cord Injury by
Altering Macrophage Polarity
Kohki Matsubara, Yoshihiro Matsushita, Kiyoshi Sakai, Fumiya Kano, Megumi Kondo,
Mariko Noda, Noboru Hashimoto, Shiro Imagama, Naoki Ishiguro, Akio Suzumura,
Minoru Ueda, Koichi Furukawa, and Akihito Yamamoto
2596
Control of Axon Guidance and Neurotransmitter Phenotype of dB1 Hindbrain
Interneurons by Lim-HD Code
Ayelet Kohl, Till Marquardt, Avihu Klar, and Dalit Sela-Donenfeld
2657
Sensory Deprivation Disrupts Homeostatic Regeneration of Newly Generated
Olfactory Sensory Neurons after Injury in Adult Mice
Shu Kikuta, Takashi Sakamoto, Shin Nagayama, Kaori Kanaya, Makoto Kinoshita,
Kenji Kondo, Koichi Tsunoda, Kensaku Mori, and Tatsuya Yamasoba
2817
The JAK/STAT3 Pathway Is a Common Inducer of Astrocyte Reactivity in Alzheimer’s
and Huntington’s Diseases
Lucile Ben Haim, Kelly Ceyze´riat, Maria Angeles Carrillo-de Sauvage,
Fabien Aubry, Gwennae¨lle Auregan, Martine Guillermier, Marta Ruiz,
Fanny Petit, Diane Houitte, Emilie Faivre, Matthias Vandesquille,
Romina Aron-Badin, Marc Dhenain, Nicole De´glon, Philippe Hantraye,
Emmanuel Brouillet, Gilles Bonvento, and Carole Escartin
SYSTEMS/CIRCUITS
2329
Characteristic Patterns of Dendritic Remodeling in Early-Stage Glaucoma:
Evidence from Genetically Identified Retinal Ganglion Cell Types
Rana N. El-Danaf and Andrew D. Huberman
2384
G-Protein-Coupled Estrogen Receptor 1 Is Anatomically Positioned to Modulate
Synaptic Plasticity in the Mouse Hippocampus
Elizabeth M. Waters, Louisa I. Thompson, Parth Patel, Andreina D. Gonzales,
Hector (Zhiyu) Ye, Edward J. Filardo, Deborah J. Clegg, Jolanta Gorecka,
Keith T. Akama, Bruce S. McEwen, and Teresa A. Milner
2398
Responses to Conflicting Stimuli in a Simple Stimulus–Response Pathway
Pieter Laurens Baljon and Daniel A. Wagenaar
2423
Photoreceptor Ablation Initiates the Immediate Loss of Glutamate Receptors in
Postsynaptic Bipolar Cells in Retina
Felice A. Dunn
2547
The Nucleus Prepositus Hypoglossi Contributes to Head Direction Cell Stability in
Rats
William N. Butler and Jeffrey S. Taube
2636
Behavioral Relevance Helps Untangle Natural Vocal Categories in a Specific Subset of
Core Auditory Cortical Pyramidal Neurons
Kathryn N. Shepard, Frank G. Lin, Charles L. Zhao, Kelly K. Chong,
and Robert C. Liu
2689
Gain Modulation of Synaptic Inputs by Network State in Auditory Cortex In Vivo
Ramon Reig, Yann Zerlaut, Ramiro Vergara, Alain Destexhe,
and Maria V. Sanchez-Vives
2717
Prospective Coding of Dorsal Raphe Reward Signals by the Orbitofrontal Cortex
Jingfeng Zhou, Chunying Jia, Qiru Feng, Junhong Bao, and Minmin Luo
2766
A Functional Link between MT Neurons and Depth Perception Based on Motion
Parallax
HyungGoo R. Kim, Dora E. Angelaki, and Gregory C. DeAngelis
2778
Adult Cortical Plasticity Studied with Chronically Implanted Electrode Arrays
Hiroshi Abe, Justin N.J. McManus, Nirmala Ramalingam, Wu Li, Sally A. Marik,
Stephan Meyer zum Alten Borgloh, and Charles D. Gilbert
BEHAVIORAL/COGNITIVE
2372
Loss of Cyclin-Dependent Kinase 5 from Parvalbumin Interneurons Leads to
Hyperinhibition, Decreased Anxiety, and Memory Impairment
Andrii Rudenko, Jinsoo Seo, Ji Hu, Susan C. Su, Froylan Calderon de Anda,
Omer Durak, Maria Ericsson, Marie Carle´n, and Li-Huei Tsai
2407
Reversal Learning and Dopamine: A Bayesian Perspective
Vincent D. Costa, Valery L. Tran, Janita Turchi, and Bruno B. Averbeck
2465
Memory Retrieval Requires Ongoing Protein Synthesis and NMDA Receptor
Activity-Mediated AMPA Receptor Trafficking
Joe¨lle Lopez, Karine Gamache, Rilla Schneider, and Karim Nader
2476
Revisiting the Evidence for Collapsing Boundaries and Urgency Signals in Perceptual
Decision-Making
Guy E. Hawkins, Birte U. Forstmann, Eric-Jan Wagenmakers, Roger Ratcliff,
and Scott D. Brown
2572
Circadian Modulation of Dopamine Levels and Dopaminergic Neuron Development
Contributes to Attention Deficiency and Hyperactive Behavior
Jian Huang, Zhaomin Zhong, Mingyong Wang, Xifeng Chen, Yicheng Tan,
Shuqing Zhang, Wei He, Xiong He, Guodong Huang, Haiping Lu, Ping Wu,
Yi Che, Yi-Lin Yan, John H. Postlethwait, Wenbiao Chen, and Han Wang
2588
Differential Magnetic Resonance Neurofeedback Modulations across Extrinsic
(Visual) and Intrinsic (Default-Mode) Nodes of the Human Cortex
Tal Harmelech, Doron Friedman, and Rafael Malach
2703
Basal Ganglia Outputs Map Instantaneous Position Coordinates during Behavior
Joseph W. Barter, Suellen Li, Tatyana Sukharnikova, Mark A. Rossi,
Ryan A. Bartholomew, and Henry H. Yin
2791
Single-Unit Recordings in the Macaque Face Patch System Reveal Limitations of fMRI
MVPA
Julien Dubois, Archy Otto de Berker, and Doris Ying Tsao
2830
Behavioral Oscillation in Priming: Competing Perceptual Predictions Conveyed in
Alternating Theta-Band Rhythms
Yan Huang, Lin Chen, and Huan Luo
NEUROBIOLOGY OF DISEASE
䊉
2358
Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP
Transgenic Mice
Dena B. Dubal, Lei Zhu, Pascal E. Sanchez, Kurtresha Worden, Lauren Broestl,
Erik Johnson, Kaitlyn Ho, Gui-Qiu Yu, Daniel Kim, Alexander Betourne,
Makoto Kuro-o, Eliezer Masliah, Carmela R. Abraham, and Lennart Mucke
2485
Inspiration Is the Major Regulator of Human CSF Flow
Steffi Dreha-Kulaczewski, Arun A. Joseph, Klaus-Dietmar Merboldt,
Hans-Christoph Ludwig, Jutta Ga¨rtner, and Jens Frahm
2508
Anatomical Changes at the Level of the Primary Synapse in Neuropathic Pain:
Evidence from the Spinal Trigeminal Nucleus
Sophie L. Wilcox, Sylvia M. Gustin, Paul M. Macey, Chris C. Peck,
Greg M. Murray, and Luke A. Henderson
2516
Dysregulation of Glutamine Transporter SNAT1 in Rett Syndrome Microglia:
A Mechanism for Mitochondrial Dysfunction and Neurotoxicity
Lee-Way Jin, Makoto Horiuchi, Heike Wulff, Xiao-Bo Liu, Gino A. Cortopassi,
Jeffrey D. Erickson, and Izumi Maezawa
2612
Posttraumatic Stress Disorder-Like Induction Elevates ␤-Amyloid Levels, Which Directly
Activates Corticotropin-Releasing Factor Neurons to Exacerbate Stress Responses
Nicholas J. Justice, Longwen Huang, Jin-Bin Tian, Allysa Cole, Melissa Pruski,
Albert J. Hunt, Jr., Rene Flores, Michael X. Zhu, Benjamin R. Arenkiel,
and Hui Zheng
2838
Retraction: The article “Induced Alpha Rhythms Track the Content and Quality of Visual
Working Memory Representations with High Temporal Precision”, by David E. Anderson,
John T. Serences, Edward K. Vogel, and Edward Awh, appeared on pages 7587–7599 of the
May 28, 2014 issue. A retraction for this article appears on page 2838.
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BRIEF COMMUNICATIONS
Modulation of Microglial Process Convergence Toward Neuronal Dendrites by Extracellular
Calcium
Ukpong B. Eyo,1 Nan Gu,1,2 Srijisnu De,1 Hailong Dong,2 Jason R. Richardson,3 and Long-Jun Wu1,4
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854, 2Department of Anesthesia, the Fourth Military Medical
University Xijing Hospital, Xi’an, China, 710032, 3Department of Environmental and Occupational Medicine, Rutgers University Robert Wood Johnson
Medical School, Piscataway, New Jersey 08854, and 4Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China,
230032
1
Extracellular calcium concentrations in the brain fluctuate during neuronal activities and may affect the behavior of brain cells. Microglia are highly dynamic immune cells
of the brain. However, the effects of extracellular calcium concentrations on microglial dynamics have not been investigated. Here, we addressed this question in mouse
brain slices and in vivo using two-photon microscopy. We serendipitously found that extracellular calcium reduction induced microglial processes to converge at distinct
sites, a phenomenon we termed microglial process convergence (MPCs). Our studies revealed that MPCs target neuronal dendrites independent of neuronal action potential
firing and is mediated by ATP release and microglial P2Y12 receptors. These results indicate that microglia monitor and interact with neurons during conditions of cerebral
calcium reduction in the normal and diseased brain.
The Journal of Neuroscience, February 11, 2015 • 35(6):2417–2422
Articles
CELLULAR/MOLECULAR
Aberrant Synaptic Integration in Adult Lamina I Projection Neurons Following Neonatal Tissue
Damage
Jie Li, Elizabeth Kritzer, Paige E. Craig, and Mark L. Baccei
Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, Ohio 45267
Mounting evidence suggests that neonatal tissue damage evokes alterations in spinal pain reflexes which persist into adulthood. However, less is known about potential
concomitant effects on the transmission of nociceptive information to the brain, as the degree to which early injury modulates synaptic integration and membrane
excitability in mature spinal projection neurons remains unclear. Here we demonstrate that neonatal surgical injury leads to a significant shift in the balance between
synaptic excitation and inhibition onto identified lamina I projection neurons of the adult mouse spinal cord. The strength of direct primary afferent input to mature
spino-parabrachial neurons was enhanced following neonatal tissue damage, whereas the efficacy of both GABAergic and glycinergic inhibition onto the same population
was compromised. This was accompanied by reorganization in the pattern of sensory input to adult projection neurons, which included a greater prevalence of monosynaptic input from low-threshold A-fibers when preceded by early tissue damage. In addition, neonatal incision resulted in greater primary afferent-evoked action potential
discharge in mature projection neurons. Overall, these results demonstrate that tissue damage during early life causes a long-term increase in the gain of spinal nociceptive
circuits, and suggest that the prolonged consequences of neonatal trauma may not be restricted to the spinal cord but rather include excessive ascending signaling to
supraspinal pain centers.
The Journal of Neuroscience, February 11, 2015 • 35(6):2438 –2451
Phosphorylation of Synaptic Vesicle Protein 2A at Thr84 by Casein Kinase 1 Family Kinases
Controls the Specific Retrieval of Synaptotagmin-1
Ning Zhang,1* Sarah L. Gordon,2* Maximilian J. Fritsch,1* Noor Esoof,1* David G. Campbell,1 Robert Gourlay,1
Srikannathasan Velupillai,1 Thomas Macartney,1 Mark Peggie,1 Daan M.F. van Aalten,1 Michael A. Cousin,2* and
Dario R. Alessi1*
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland,
United Kingdom, and 2Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, Scotland, United Kingdom
1
Synaptic vesicle protein 2A (SV2A) is a ubiquitous component of synaptic vesicles (SVs). It has roles in both SV trafficking and neurotransmitter release. We demonstrate
that Casein kinase 1 family members, including isoforms of Tau–tubulin protein kinases (TTBK1 and TTBK2), phosphorylate human SV2A at two constellations of
residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of
Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1. We show by crystallographic and other analyses that the
phosphorylated Thr84 residue binds to a pocket formed by three conserved Lys residues (Lys314, Lys326, and Lys328) on the surface of the synaptotagmin-1 C2B domain.
Finally, we observed dysfunctional synaptotagmin-1 retrieval during SV endocytosis by ablating its phospho-dependent interaction with SV2A, knockdown of SV2A, or
rescue with a phosphorylation-null Thr84 SV2A mutant in primary cultures of mouse neurons. This study reveals fundamental details of how phosphorylation of Thr84 on
SV2A controls its interaction with synaptotagmin-1 and implicates SV2A as a phospho-dependent chaperone required for the specific retrieval of synaptotagmin-1 during
SV endocytosis.
The Journal of Neuroscience, February 11, 2015 • 35(6):2492–2507
Functional Cooperation between the IP3 Receptor and Phospholipase C Secures the High
Sensitivity to Light of Drosophila Photoreceptors In Vivo
Elkana Kohn, Ben Katz, Bushra Yasin, Maximilian Peters, Elisheva Rhodes, Rachel Zaguri, Shirley Weiss, and
Baruch Minke
Departments of Medical Neurobiology, the Institute of Medical Research Israel-Canada, and the Edmond and Lily Safra Center for Brain Sciences, Faculty of
Medicine of the Hebrew University, Jerusalem 91120, Israel
Drosophila phototransduction is a model system for the ubiquitous phosphoinositide signaling. In complete darkness, spontaneous unitary current events (dark bumps)
are produced by spontaneous single Gq␣ activation, while single-photon responses (quantum bumps) arise from synchronous activation of several Gq␣ molecules. We have
recently shown that most of the spontaneous single Gq␣ activations do not produce dark bumps, because of a critical phospholipase C␤ (PLC␤) activity level required for
bump generation. Surpassing the threshold of channel activation depends on both PLC␤ activity and cellular [Ca 2⫹], which participates in light excitation via a still unclear
mechanism. We show here that in IP3 receptor (IP3R)-deficient photoreceptors, both light-activated Ca 2⫹ release from internal stores and light sensitivity were strongly
attenuated. This was further verified by Ca 2⫹ store depletion, linking Ca 2⫹ release to light excitation. In IP3R-deficient photoreceptors, dark bumps were virtually absent
and the quantum-bump rate was reduced, indicating that Ca 2⫹ release from internal stores is necessary to reach the critical level of PLC␤ catalytic activity and the cellular
[Ca 2⫹] required for excitation. Combination of IP3R knockdown with reduced PLC␤ catalytic activity resulted in highly suppressed light responses that were partially
rescued by cellular Ca 2⫹ elevation, showing a functional cooperation between IP3R and PLC␤ via released Ca 2⫹. These findings suggest that in contrast to the current
dogma that Ca 2⫹ release via IP3R does not participate in light excitation, we show that released Ca 2⫹ plays a critical role in light excitation. The positive feedback between
PLC␤ and IP3R found here may represent a common feature of the inositol-lipid signaling.
The Journal of Neuroscience, February 11, 2015 • 35(6):2530 –2546
Trip6 Promotes Dendritic Morphogenesis through Dephosphorylated GRIP1-Dependent
Myosin VI and F-Actin Organization
Kaosheng Lv (吕考升),1* Liang Chen (陈亮),1* Yuanjun Li (李圆君),1 Zenglong Li (李曾龙),1 Pengli Zheng (郑鹏里),1
Yingying Liu (刘盈盈),1 Jianguo Chen (陈建国),1,2 and Junlin Teng (滕俊琳)1
Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education and State Key Laboratory of Bio-Membrane and Membrane
Bio-Engineering, College of Life Sciences, and 2Center for Quantitative Biology, Peking University, Beijing 100871, China
1
Thyroid receptor-interacting protein 6 (Trip6), a multifunctional protein belonging to the zyxin family of LIM proteins, is involved in various physiological and pathological
processes, including cell migration and tumorigenesis. However, the role of Trip6 in neurons remains unknown. Here, we show that Trip6 is expressed in mouse
hippocampal neurons and promotes dendritic morphogenesis. Through interaction with the glutamate receptor-interacting protein 1 (GRIP1) and myosin VI, Trip6 is
crucial for the total dendritic length and the number of primary dendrites in cultured hippocampal neurons. Trip6 depletion reduces F-actin content and impairs dendritic
morphology, and this phenocopies GRIP1 or myosin VI knockdown. Furthermore, phosphorylation of GRIP1 956T by AKT1 inhibits the interaction between GRIP1 and
myosin VI, but facilitates GRIP1 binding to 14-3-3 protein, which is required for regulating F-actin organization and dendritic morphogenesis. Thus, the Trip6 –GRIP1–
myosin VI interaction and its regulation on F-actin network play a significant role in dendritic morphogenesis.
The Journal of Neuroscience, February 11, 2015 • 35(6):2559 –2571
The Roles of Cdk5-Mediated Subcellular Localization of FOXO1 in Neuronal Death
Jiechao Zhou,1* Huifang Li,1* Xiaoping Li,1 Guanyun Zhang,1 Yaqiong Niu,1 Zengqiang Yuan,2 Karl Herrup,3,4
Yun-Wu Zhang,1 Guojun Bu,1 Huaxi Xu,1 and Jie Zhang1
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University,
Xiamen, 361005, Fujian Province, China, 2Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing, 100101, China, 3Division of Life
Science and the State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Kowloon, Hong Kong, and
4Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854
1
Deficiency of cyclin-dependent kinase 5 (Cdk5) has been linked to the death of postmitotic cortical neurons during brain development. We now report that, in mouse
cortical neurons, Cdk5 is capable of phosphorylating the transcription factor FOXO1 at Ser249 in vitro and in vivo. Cellular stresses resulting from extracellular stimulation
by H2O2 or ␤-amyloid promote hyperactivation of Cdk5, FOXO1 nuclear export and inhibition of its downstream transcriptional activity. In contrast, a loss of Cdk5 leads
to FOXO1 translocation into the nucleus: a shift due to decreased AKT activity but independent of S249 phosphorylation. Nuclear FOXO1 upregulates transcription of the
proapoptotic gene, BIM, leading to neuronal death, which can be rescued when endogenous FOXO1 was replaced by the cytoplasmically localized form of FOXO1,
FOXO1-S249D. Cytoplasmic, but not nuclear, Cdk5 attenuates neuronal death by inhibiting FOXO1 transcriptional activity and BIM expression. Together, our findings
suggest that Cdk5 plays a novel and unexpected role in the degeneration of postmitotic neurons through modulation of the cellular location of FOXO1, which constitutes an
alternative pathway through which Cdk5 deficiency leads to neuronal death.
The Journal of Neuroscience, February 11, 2015 • 35(6):2624 –2635
Cooperative Roles of Hydrophilic Loop 1 and the C-Terminus of Presenilin 1 in the SubstrateGating Mechanism of ␥-Secretase
Shizuka Takagi-Niidome,1 Tomoki Sasaki,1 Satoko Osawa,1 Takeshi Sato,2 Kanan Morishima,3 Tetsuo Cai,3
Takeshi Iwatsubo,1,4 and Taisuke Tomita1
Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo
113-0033, Japan, 2Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan, 3Department of Neuropathology and Neuroscience,
Faculty of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, and 4Department of Neuropathology,
Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
1
␥-Secretase is a multisubunit protease complex that is responsible for generating amyloid-␤ peptides, which are associated with Alzheimer disease. The catalytic subunit
of ␥-secretase is presenilin 1 (PS1), which contains an initial substrate-binding site that is distinct from the catalytic site. Processive cleavage is suggested in the
intramembrane-cleaving mechanism of ␥-secretase. However, it largely remains unknown as to how ␥-secretase recognizes its substrate during proteolysis. Here, we
identified that the ␣-helical structural region of hydrophilic loop 1 (HL1) and the C-terminal region of human PS1 are distinct substrate-binding sites. Mutational analyses
revealed that substrate binding to the HL1 region is critical for both ␧- and ␥-cleavage, whereas binding to the C-terminal region hampers ␥-cleavage. Moreover, we propose
that substrate binding triggers conformational changes in PS1, rendering it suitable for catalysis. Our data provide new insights into the complicated catalytic mechanism
of PS1.
The Journal of Neuroscience, February 11, 2015 • 35(6):2646 –2656
A Novel Size-Based Sorting Mechanism of Pinocytic Luminal Cargoes in Microglia
Cong Chen,1* Hui-Quan Li,1* Yi-jun Liu,1 Zhi-fei Guo,1 Hang-jun Wu,1 Xia Li,1 Hui-Fang Lou,1 Liya Zhu,1 Di Wang,2
Xiao-Ming Li,1 Li Yu,3 Xuetao Cao,2,4 Linrong Lu,2 Zhihua Gao,1 and Shu-Min Duan1
Department of Neurobiology, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Key Laboratory of Neurobiology of Zhejiang
Province, and 2Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China, 3State Key Laboratory of Biomembrane and
Membrane Biotechnology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing
100084, China, and 4National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433,
China
1
Microglia are the resident immune cells in the CNS and play diverse roles in the maintenance of CNS homeostasis. Recent studies have shown that microglia continually
survey the CNS microenvironment and scavenge cell debris and aberrant proteins by phagocytosis and pinocytosis, and that reactive microglia are capable to present
antigens to T cells and initiate immune responses. However, how microglia process the endocytosed contents and evoke an immune response remain unclear. Here we
report that a size-dependent selective transport of small soluble contents from the pinosomal lumen into lysosomes is critical for the antigen processing in microglia. Using
fluorescent probes and water-soluble magnetic nanobeads of defined sizes, we showed in cultured rodent microglia, and in a cell-free reconstructed system that pinocytosed
proteins become degraded immediately following pinocytosis and the resulting peptides are selectively delivered to major histocompatibility complex class II (MHC-II)
containing lysosomes, whereas undegraded proteins are retained in the pinosomal lumen. This early size-based sorting of pinosomal contents relied on the formation of
transient tunnel between pinosomes and lysosomes in a Rab7- and dynamin II-dependent manner, which allowed the small contents to pass through but restricted large
ones. Inhibition of the size-based sorting markedly reduced proliferation and cytokine release of cocultured CD4 ⫹ T cells, indicating that the size-based sorting is required
for efficient antigen presentation by microglial cells. Together, these findings reveal a novel early sorting mechanism for pinosomal luminal contents in microglial cells,
which may explain how microglia efficiently process protein antigens and evoke an immune response.
The Journal of Neuroscience, February 11, 2015 • 35(6):2674 –2688
Speed and Sensitivity of Phototransduction in Drosophila Depend on Degree of Saturation of
Membrane Phospholipids
Alex S. Randall,1 Che-Hsiung Liu,1 Brian Chu,1 Qifeng Zhang,2 Sidharta A. Dongre,3 Mikko Juusola,3,4 Kristian Franze,1
Michael J.O. Wakelam,2 and Roger C. Hardie1
Department of Physiology Development and Neuroscience, Cambridge University, Cambridge CB2 3EG, United Kingdom, 2Babraham Institute, Babraham,
Cambridge CB22 3AT, United Kingdom, 3Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom, and 4National Key
Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing 100875, China
1
Drosophila phototransduction is mediated via a G-protein-coupled PLC cascade. Recent evidence, including the demonstration that light evokes rapid contractions of the
photoreceptors, suggested that the light-sensitive channels (TRP and TRPL) may be mechanically gated, together with protons released by PLC-mediated PIP2 hydrolysis.
If mechanical gating is involved we predicted that the response to light should be influenced by altering the physical properties of the membrane. To achieve this, we used
diet to manipulate the degree of saturation of membrane phospholipids. In flies reared on a yeast diet, lacking polyunsaturated fatty acids (PUFAs), mass spectrometry
showed that the proportion of polyunsaturated phospholipids was sevenfold reduced (from 38 to ⬃5%) but rescued by adding a single species of PUFA (linolenic or linoleic
acid) to the diet. Photoreceptors from yeast-reared flies showed a 2- to 3-fold increase in latency and time to peak of the light response, without affecting quantum bump
waveform. In the absence of Ca 2⫹ influx or in trp mutants expressing only TRPL channels, sensitivity to light was reduced up to ⬃10-fold by the yeast diet, and essentially
abolished in hypomorphic G-protein mutants (G␣q). PLC activity appeared little affected by the yeast diet; however, light-induced contractions measured by atomic force
microscopy or the activation of ectopic mechanosensitive gramicidin channels were also slowed ⬃2-fold. The results are consistent with mechanosensitive gating and
provide a striking example of how dietary fatty acids can profoundly influence sensory performance in a classical G-protein-coupled signaling cascade.
The Journal of Neuroscience, February 11, 2015 • 35(6):2731–2746
PKC Enhances the Capacity for Secretion by Rapidly Recruiting Covert Voltage-Gated Ca2⫹
Channels to the Membrane
Christopher J. Groten and Neil S. Magoski
Department of Biomedical and Molecular Sciences, Physiology Graduate Program, Queen’s University, Kingston, Ontario K7L3N6, Canada
It is unknown whether neurons can dynamically control the capacity for secretion by promptly changing the number of plasma membrane voltage-gated Ca 2⫹ channels. To
address this, we studied peptide release from the bag cell neurons of Aplysia californica, which initiate reproduction by secreting hormone during an afterdischarge. This
burst engages protein kinase C (PKC) to trigger the insertion of a covert Ca 2⫹ channel, Apl Cav2, alongside a basal channel, Apl Cav1. The significance of Apl Cav2
recruitment to secretion remains undetermined; therefore, we used capacitance tracking to assay secretion, along with Ca 2⫹ imaging and Ca 2⫹ current measurements,
from cultured bag cell neurons under whole-cell voltage-clamp. Activating PKC with the phorbol ester, PMA, enhanced Ca 2⫹ entry, and potentiated stimulus-evoked
secretion. This relied on channel insertion, as it was occluded by preventing Apl Cav2 engagement with prior whole-cell dialysis or the cytoskeletal toxin, latrunculin B.
Channel insertion reduced the stimulus duration and/or frequency required to initiate secretion and strengthened excitation-secretion coupling, indicating that Apl Cav2
accesses peptide release more readily than Apl Cav1. The coupling of Apl Cav2 to secretion also changed with behavioral state, as Apl Cav2 failed to evoke secretion in silent
neurons from reproductively inactive animals. Finally, PKC also acted secondarily to enhance prolonged exocytosis triggered by mitochondrial Ca 2⫹ release. Collectively,
our results suggest that bag cell neurons dynamically elevate Ca 2⫹ channel abundance in the membrane to ensure adequate secretion during the afterdischarge.
The Journal of Neuroscience, February 11, 2015 • 35(6):2747–2765
Spillover Transmission Is Mediated by the Excitatory GABA Receptor LGC-35 in C. elegans
Meghan A. Jobson,3,4* Chris M. Valdez,1,2* Jann Gardner,4 L. Rene Garcia,5,7 Erik M. Jorgensen,3,4,6 and Asim A. Beg1,2
1Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, 2Neuroscience Program, University of Michigan, Ann Arbor, Michigan
48109, 3Program in Neuroscience, University of Utah School of Medicine, Salt Lake City, Utah 84132, 4Department of Biology, University of Utah, Salt Lake
City, Utah 84132, 5Department of Biology, Texas A&M University, College Station, Texas 77843, 6Howard Hughes Medical Institute, University of Utah, Salt
Lake City, Utah 84132, and 7Howard Hughes Medical Institute, Texas A&M University, College Station, Texas 77843
Under most circumstances, GABA activates chloride-selective channels and thereby inhibits neuronal activity. Here, we identify a GABA receptor in the nematode
Caenorhabditis elegans that conducts cations and is therefore excitatory. Expression in Xenopus oocytes demonstrates that LGC-35 is a homopentameric cation-selective
receptor of the cys-loop family exclusively activated by GABA. Phylogenetic analysis suggests that LGC-35 evolved from GABA-A receptors, but the pore-forming domain
contains novel molecular determinants that confer cation selectivity. LGC-35 is expressed in muscles and directly mediates sphincter muscle contraction in the defecation
cycle in hermaphrodites, and spicule eversion during mating in the male. In the locomotory circuit, GABA release directly activates chloride channels on the muscle to cause
muscle relaxation. However, GABA spillover at these synapses activates LGC-35 on acetylcholine motor neurons, which in turn cause muscles to contract, presumably to
drive wave propagation along the body. These studies demonstrate that both direct and indirect excitatory GABA signaling plays important roles in regulating neuronal
circuit function and behavior in C. elegans.
The Journal of Neuroscience, February 11, 2015 • 35(6):2803–2816
DEVELOPMENT/PLASTICITY/REPAIR
␣2-Chimaerin Is Required for Eph Receptor-Class-Specific Spinal Motor Axon Guidance and
Coordinate Activation of Antagonistic Muscles
Tzu-Jen Kao,3,5,6* Georgina C.B. Nicholl,1* Jamie A. Johansen,7 Artur Kania,3,4 and Asim A. Beg1,2
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, 2Neuroscience Program, University of Michigan, Ann
Arbor MI 48109, 3Institut de Recherches Cliniques de Montre´al, Montre´al, QC H2W 1R7 Canada, 4Departments of Anatomy and Cell Biology and Biology,
Division of Experimental Medicine, McGill University Montre´al, Quebec H3A 2B2, Canada, and Faculte´ de Me´decine, Universite´ de Montre´al, Montre´al,
Quebec H3C 3J7, Canada, 5Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology and 6Center for Neurotrauma
and Neuroregeneration, Taipei Medical University, Taipei, Taiwan, and 7College of Medicine, Central Michigan University, Mount Pleasant, Michigan
48859
1
Axonal guidance involves extrinsic molecular cues that bind growth cone receptors and signal to the cytoskeleton through divergent pathways. Some signaling intermediates are deployed downstream of molecularly distinct axon guidance receptor families, but the scope of this overlap is unclear, as is the impact of embryonic axon
guidance fidelity on adult nervous system function. Here, we demonstrate that the Rho-GTPase-activating protein ␣2-chimaerin is specifically required for EphA and not
EphB receptor signaling in mouse and chick spinal motor axons. Reflecting this specificity, the loss of ␣2-chimaerin function disrupts the limb trajectory of extensormuscle-innervating motor axons the guidance of which depends on EphA signaling. These embryonic defects affect coordinated contraction of antagonistic flexor-extensor
muscles in the adult, indicating that accurate embryonic motor axon guidance is critical for optimal neuromuscular function. Together, our observations provide the first
functional evidence of an Eph receptor-class-specific intracellular signaling protein that is required for appropriate neuromuscular connectivity.
The Journal of Neuroscience, February 11, 2015 • 35(6):2344 –2357
Norepinephrine Is Necessary for Experience-Dependent Plasticity in the Developing Mouse
Auditory Cortex
Kathryn N. Shepard,1,2 L. Cameron Liles,3 David Weinshenker,1,3 and Robert C. Liu1,2
1
Graduate Program in Neuroscience, 2Department of Biology, and 3Department of Human Genetics, Emory University, Atlanta, Georgia 30322
Critical periods are developmental windows during which the stimuli an animal encounters can reshape response properties in the affected system to a profound degree.
Despite this window’s importance, the neural mechanisms that regulate it are not completely understood. Pioneering studies in visual cortex initially indicated that
norepinephrine (NE) permits ocular dominance column plasticity during the critical period, but later research has suggested otherwise. More recent work implicating NE
in experience-dependent plasticity in the adult auditory cortex led us to re-examine the role of NE in critical period plasticity. Here, we exposed dopamine ␤-hydroxylase
knock-out (Dbh ⫺/⫺) mice, which lack NE completely from birth, to a biased acoustic environment during the auditory cortical critical period. This manipulation led to a
redistribution of best frequencies (BFs) across auditory cortex in our control mice, consistent with prior work. By contrast, Dbh ⫺/⫺ mice failed to exhibit the expected
redistribution of BFs, even though NE-deficient and NE-competent mice showed comparable auditory cortical organization when reared in a quiet colony environment.
These data suggest that while intrinsic tonotopic patterning of auditory cortical circuitry occurs independently from NE, NE is required for critical period plasticity in
auditory cortex.
The Journal of Neuroscience, February 11, 2015 • 35(6):2432–2437
Secreted Ectodomain of Sialic Acid-Binding Ig-Like Lectin-9 and Monocyte Chemoattractant
Protein-1 Promote Recovery after Rat Spinal Cord Injury by Altering Macrophage Polarity
Kohki Matsubara,1 Yoshihiro Matsushita,1 Kiyoshi Sakai,1 Fumiya Kano,1 Megumi Kondo,1 Mariko Noda,4
Noboru Hashimoto,3 Shiro Imagama,2 Naoki Ishiguro,2 Akio Suzumura,4 Minoru Ueda,1 Koichi Furukawa,3 and
Akihito Yamamoto1
Department of Oral and Maxillofacial Surgery, 2Orthopedic Surgery, and 3Biochemistry II, Nagoya University Graduate School of Medicine, Showa-ku,
Nagoya 466-8550, Japan, and 4Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Chikusa-ku, Nagoya
464-8601, Japan
1
Engrafted mesenchymal stem cells from human deciduous dental pulp (SHEDs) support recovery from neural insults via paracrine mechanisms that are poorly understood.
Here we show that the conditioned serum-free medium (CM) from SHEDs, administered intrathecally into rat injured spinal cord during the acute postinjury period, caused
remarkable functional recovery. The ability of SHED-CM to induce recovery was associated with an immunoregulatory activity that induced anti-inflammatory M2-like
macrophages. Secretome analysis of the SHED-CM revealed a previously unrecognized set of inducers for anti-inflammatory M2-like macrophages: monocyte chemoattractant protein-1 (MCP-1) and the secreted ectodomain of sialic acid-binding Ig-like lectin-9 (ED-Siglec-9). Depleting MCP-1 and ED-Siglec-9 from the SHED-CM
prominently reduced its ability to induce M2-like macrophages and to promote functional recovery after spinal cord injury (SCI). The combination of MCP-1 and
ED-Siglec-9 synergistically promoted the M2-like differentiation of bone marrow-derived macrophages in vitro, and this effect was abolished by a selective antagonist for
CC chemokine receptor 2 (CCR2) or by the genetic knock-out of CCR2. Furthermore, MCP-1 and ED-Siglec-9 administration into the injured spinal cord induced M2-like
macrophages and led to a marked recovery of hindlimb locomotor function after SCI. The inhibition of this M2 induction through the inactivation of CCR2 function
abolished the therapeutic effects of both SHED-CM and MCP-1/ED-Siglec-9. Macrophages activated by MCP-1 and ED-Siglec-9 extended neurite and suppressed apoptosis
of primary cerebellar granule neurons against the neurotoxic effects of chondroitin sulfate proteoglycans. Our data suggest that the unique combination of MCP-1 and
ED-Siglec-9 repairs the SCI through anti-inflammatory M2-like macrophage induction.
The Journal of Neuroscience, February 11, 2015 • 35(6):2452–2464
Control of Axon Guidance and Neurotransmitter Phenotype of dB1 Hindbrain Interneurons by
Lim-HD Code
Ayelet Kohl,1 Till Marquardt,2 Avihu Klar,3 and Dalit Sela-Donenfeld1
Koret School of Veterinary Medicine, Robert H. Smith Faculty of Agriculture, Food and Environment, Hebrew University of Jerusalem, Rehovot 76100,
Israel, 2Developmental Neurobiology Laboratory, European Neuroscience Institute, Go¨ttingen 37077, Germany, and 3Department of Medical Neurobiology
IMRIC, Hebrew University Medical School, Jerusalem, 91120, Israel
1
Hindbrain dorsal interneurons (HDIs) are implicated in receiving, processing, integrating, and transmitting sensory inputs from the periphery and spinal cord, including
the vestibular, auditory, and proprioceptive systems. During development, multiple molecularly defined HDI types are set in columns along the dorsoventral axis, before
migrating along well-defined trajectories to generate various brainstem nuclei. Major brainstem functions rely on the precise assembly of different interneuron groups and
higher brain domains into common circuitries. Yet, knowledge regarding interneuron axonal patterns, synaptic targets, and the transcriptional control that govern their
connectivity is sparse. The dB1 class of HDIs is formed in a district dorsomedial position along the hindbrain and gives rise to the inferior olive nuclei, dorsal cochlear nuclei,
and vestibular nuclei. dB1 interneurons express various transcription factors (TFs): the pancreatic transcription factor 1a (Ptf1a), the homeobox TF-Lbx1 and the
Lim-homeodomain (Lim-HD), and TF Lhx1 and Lhx5. To decipher the axonal and synaptic connectivity of dB1 cells, we have used advanced enhancer tools combined with
conditional expression systems and the PiggyBac-mediated DNA transposition system in avian embryos. Multiple ipsilateral and contralateral axonal projections were
identified ascending toward higher brain centers, where they formed synapses in the Purkinje cerebellar layer as well as at discrete midbrain auditory and vestibular
centers. Decoding the mechanisms that instruct dB1 circuit formation revealed a fundamental role for Lim-HD proteins in regulating their axonal patterns, synaptic targets,
and neurotransmitter choice. Together, this study provides new insights into the assembly and heterogeneity of HDIs connectivity and its establishment through the central
action of Lim-HD governed programs.
The Journal of Neuroscience, February 11, 2015 • 35(6):2596 –2611
Sensory Deprivation Disrupts Homeostatic Regeneration of Newly Generated Olfactory Sensory
Neurons after Injury in Adult Mice
Shu Kikuta,1,2 Takashi Sakamoto,1 Shin Nagayama,3 Kaori Kanaya,1 Makoto Kinoshita,1 Kenji Kondo,1
Koichi Tsunoda,4 Kensaku Mori,2 and Tatsuya Yamasoba1
Department of Otolaryngology and 2Department of Physiology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo
113-0033, Japan, 3Department of Neurobiology and Anatomy, University of Texas Medical School at Houston, Houston, Texas 77030, and 4Department of
Artificial Organs and Medical Device Creation, National Institute of Sensory Organs, Tokyo Medical Center, National Hospital Organization, Meguro-ku,
Tokyo 152-8902, Japan
1
Although it is well known that injury induces the generation of a substantial number of new olfactory sensory neurons (OSNs) in the adult olfactory epithelium (OE), it is
not well understood whether olfactory sensory input influences the survival and maturation of these injury-induced OSNs in adults. Here, we investigated whether olfactory
sensory deprivation affected the dynamic incorporation of newly generated OSNs 3, 7, 14, and 28 d after injury in adult mice. Mice were unilaterally deprived of olfactory
sensory input by inserting a silicone tube into their nostrils. Methimazole, an olfactotoxic drug, was also injected intraperitoneally to bilaterally ablate OSNs. The OE was
restored to its preinjury condition with new OSNs by day 28. No significant differences in the numbers of olfactory marker protein-positive mature OSNs or apoptotic OSNs
were observed between the deprived and nondeprived sides 0 –7 d after injury. However, between days 7 and 28, the sensory-deprived side showed markedly fewer OSNs and
mature OSNs, but more apoptotic OSNs, than the nondeprived side. Intrinsic functional imaging of the dorsal surface of the olfactory bulb at day 28 revealed that responses
to odor stimulation were weaker in the deprived side compared with those in the nondeprived side. Furthermore, prevention of cell death in new neurons 7–14 d after injury
promoted the recovery of the OE. These results indicate that, in the adult OE, sensory deprivation disrupts compensatory OSN regeneration after injury and that newly
generated OSNs have a critical time window for sensory-input-dependent survival 7–14 d after injury.
The Journal of Neuroscience, February 11, 2015 • 35(6):2657–2673
The JAK/STAT3 Pathway Is a Common Inducer of Astrocyte Reactivity in Alzheimer’s and
Huntington’s Diseases
Lucile Ben Haim,1,2 Kelly Ceyze´riat,1,2 Maria Angeles Carrillo-de Sauvage,1,2 Fabien Aubry,1,2 Gwennae¨lle Auregan,1,2
Martine Guillermier,1,2 Marta Ruiz,1,2 Fanny Petit,1,2 Diane Houitte,1,2 Emilie Faivre,1,2 Matthias Vandesquille,1,2
Romina Aron-Badin,1,2 Marc Dhenain,1,2 Nicole De´glon,1,2 Philippe Hantraye,1,2 Emmanuel Brouillet,1,2
Gilles Bonvento,1,2 and Carole Escartin1,2
Commissariat a` l’Energie Atomique et aux Energies Alternatives (CEA), De´partement des Sciences du Vivant (DSV), Institut d’Imagerie Biome´dicale
(I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and 2Centre National de la Recherche Scientifique (CNRS),
Universite´ Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France
1
Astrocyte reactivity is a hallmark of neurodegenerative diseases (ND), but its effects on disease outcomes remain highly debated. Elucidation of the signaling cascades
inducing reactivity in astrocytes during ND would help characterize the function of these cells and identify novel molecular targets to modulate disease progression. The
Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway is associated with reactive astrocytes in models of acute injury, but it is unknown
whether this pathway is directly responsible for astrocyte reactivity in progressive pathological conditions such as ND. In this study, we examined whether the JAK/STAT3
pathway promotes astrocyte reactivity in several animal models of ND. The JAK/STAT3 pathway was activated in reactive astrocytes in two transgenic mouse models of
Alzheimer’s disease and in a mouse and a nonhuman primate lentiviral vector-based model of Huntington’s disease (HD). To determine whether this cascade was
instrumental for astrocyte reactivity, we used a lentiviral vector that specifically targets astrocytes in vivo to overexpress the endogenous inhibitor of the JAK/STAT3
pathway [suppressor of cytokine signaling 3 (SOCS3)]. SOCS3 significantly inhibited this pathway in astrocytes, prevented astrocyte reactivity, and decreased microglial
activation in models of both diseases. Inhibition of the JAK/STAT3 pathway within reactive astrocytes also increased the number of huntingtin aggregates, a neuropathological hallmark of HD, but did not influence neuronal death. Our data demonstrate that the JAK/STAT3 pathway is a common mediator of astrocyte reactivity that is highly
conserved between disease states, species, and brain regions. This universal signaling cascade represents a potent target to study the role of reactive astrocytes in ND.
The Journal of Neuroscience, February 11, 2015 • 35(6):2817–2829
SYSTEMS/CIRCUITS
Characteristic Patterns of Dendritic Remodeling in Early-Stage Glaucoma: Evidence from
Genetically Identified Retinal Ganglion Cell Types
Rana N. El-Danaf1,2,3 and Andrew D. Huberman1,2,3,4
Department of Neurosciences, 2Neurobiology Section in the Division of Biological Sciences, and 3Department of Ophthalmology, University of California,
San Diego, La Jolla, California 92093, and 4Salk Institute for Biological Studies, La Jolla, California 92093
1
Retinal ganglion cell (RGC) loss is a hallmark of glaucoma and the second leading cause of blindness worldwide. The type and timing of cellular changes leading to RGC loss
in glaucoma remain incompletely understood, including whether specific RGC subtypes are preferentially impacted at early stages of this disease. Here we applied the
microbead occlusion model of glaucoma to different transgenic mouse lines, each expressing green fluorescent protein in 1–2 specific RGC subtypes. Targeted filling,
reconstruction, and subsequent comparison of the genetically identified RGCs in control and bead-injected eyes revealed that some subtypes undergo significant dendritic
rearrangements as early as 7 d following induction of elevated intraocular pressure (IOP). By comparing specific On-type, On-Off-type and Off-type RGCs, we found that
RGCs that target the majority of their dendritic arbors to the scleral half or “Off” sublamina of the inner plexiform layer (IPL) undergo the greatest changes, whereas RGCs
with the majority of their dendrites in the On sublamina did not alter their structure at this time point. Moreover, M1 intrinsically photosensitive RGCs, which functionally
are On RGCs but structurally stratify their dendrites in the Off sublamina of the IPL, also underwent significant changes in dendritic structure 1 week after elevated IOP.
Thus, our findings reveal that certain RGC subtypes manifest significant changes in dendritic structure after very brief exposure to elevated IOP. The observation that RGCs
stratifying most of their dendrites in the Off sublamina are first to alter their structure may inform the development of new strategies to detect, monitor, and treat glaucoma
in humans.
The Journal of Neuroscience, February 11, 2015 • 35(6):2329 –2343
G-Protein-Coupled Estrogen Receptor 1 Is Anatomically Positioned to Modulate Synaptic
Plasticity in the Mouse Hippocampus
Elizabeth M. Waters,1 Louisa I. Thompson,1,2 Parth Patel,2 Andreina D. Gonzales,2 Hector (Zhiyu) Ye,2
Edward J. Filardo,3 Deborah J. Clegg,4 Jolanta Gorecka,1 Keith T. Akama,1 Bruce S. McEwen,1* and Teresa A. Milner1,2*
Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10065, 2Brain and Mind
Research Institute, Weill Cornell Medical College, New York, New York 10065, 3Department of Medicine, Brown University, Providence, Rhode Island
02903, and 4Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390
1
Both estrous cycle and sex affect the numbers and types of neuronal and glial profiles containing the classical estrogen receptors ␣ and ␤, and synaptic levels in the rodent
dorsal hippocampus. Here, we examined whether the membrane estrogen receptor, G-protein-coupled estrogen receptor 1 (GPER1), is anatomically positioned in the
dorsal hippocampus of mice to regulate synaptic plasticity. By light microscopy, GPER1-immunoreactivity (IR) was most noticeable in the pyramidal cell layer and
interspersed interneurons, especially those in the hilus of the dentate gyrus. Diffuse GPER1-IR was found in all lamina but was most dense in stratum lucidum of CA3.
Ultrastructural analysis revealed discrete extranuclear GPER1-IR affiliated with the plasma membrane and endoplasmic reticulum of neuronal perikarya and dendritic
shafts, synaptic specializations in dendritic spines, and clusters of vesicles in axon terminals. Moreover, GPER1-IR was found in unmyelinated axons and glial profiles.
Overall, the types and amounts of GPER1-labeled profiles were similar between males and females; however, in females elevated estrogen levels generally increased axonal
labeling. Some estradiol-induced changes observed in previous studies were replicated by the GPER agonist G1: G1 increased PSD95-IR in strata oriens, lucidum, and
radiatum of CA3 in ovariectomized mice 6 h after administration. In contrast, estradiol but not G1 increased Akt phosphorylation levels. Instead, GPER1 actions in the
synapse may be due to interactions with synaptic scaffolding proteins, such as SAP97. These results suggest that although estrogen’s actions via GPER1 may converge on the
same synaptic elements, different pathways are used to achieve these actions.
The Journal of Neuroscience, February 11, 2015 • 35(6):2384 –2397
Responses to Conflicting Stimuli in a Simple Stimulus–Response Pathway
Pieter Laurens Baljon1 and Daniel A. Wagenaar1,2
California Institute of Technology, Division of Biology, Pasadena, California 91125, and 2University of Cincinnati, Department of Biological Sciences,
Cincinnati, Ohio 45221
1
The “local bend response” of the medicinal leech (Hirudo verbana) is a stimulus–response pathway that enables the animal to bend away from a pressure stimulus applied
anywhere along its body. The neuronal circuitry that supports this behavior has been well described, and its responses to individual stimuli are understood in quantitative
detail. We probed the local bend system with pairs of electrical stimuli to sensory neurons that could not logically be interpreted as a single touch to the body wall and used
multiple suction electrodes to record simultaneously the responses in large numbers of motor neurons. In all cases, responses lasted much longer than the stimuli that
triggered them, implying the presence of some form of positive feedback loop to sustain the response. When stimuli were delivered simultaneously, the resulting motor
neuron output could be described as an evenly weighted linear combination of the responses to the constituent stimuli. However, when stimuli were delivered sequentially,
the second stimulus had greater impact on the motor neuron output, implying that the positive feedback in the system is not strong enough to render it immune to further
input.
The Journal of Neuroscience, February 11, 2015 • 35(6):2398 –2406
Photoreceptor Ablation Initiates the Immediate Loss of Glutamate Receptors in Postsynaptic
Bipolar Cells in Retina
Felice A. Dunn
Department of Ophthalmology, University of California, San Francisco, San Francisco, California 94143
Structural changes underlying neurodegenerative diseases include dismantling of synapses, degradation of circuitry, and even massive rewiring. Our limited understanding of synapse dismantling stems from the inability to control the timing and extent of cell death. In this study, selective ablation of cone photoreceptors in live mouse retina
and tracking of postsynaptic partners at the cone-to-ON cone bipolar cell synapse reveals that early reaction to cone loss involves rapid and local changes in postsynaptic
glutamate receptor distribution. Glutamate receptors disappear with a time constant of 2 h. Furthermore, binding of glutamate receptors by agonists and antagonists is
insufficient to rescue glutamate receptor loss, suggesting that receptor allocation depends on the physical presence of cones. These findings demonstrate that the initial step
in synapse disassembly involves postsynaptic receptor loss rather than dendritic retraction, providing insight into the early stages of neurodegenerative disease.
The Journal of Neuroscience, February 11, 2015 • 35(6):2423–2431
The Nucleus Prepositus Hypoglossi Contributes to Head Direction Cell Stability in Rats
William N. Butler and Jeffrey S. Taube
Dartmouth College, Hanover, New Hampshire 03755
Head direction (HD) cells in the rat limbic system fire according to the animal’s orientation independently of the animal’s environmental location or behavior. These HD
cells receive strong inputs from the vestibular system, among other areas, as evidenced by disruption of their directional firing after lesions or inactivation of vestibular
inputs. Two brainstem nuclei, the supragenual nucleus (SGN) and nucleus prepositus hypoglossi (NPH), are known to project to the HD network and are thought to be
possible relays of vestibular information. Previous work has shown that lesioning the SGN leads to a loss of spatial tuning in downstream HD cells, but the NPH has
historically been defined as an oculomotor nuclei and therefore its role in contributing to the HD signal is less clear. Here, we investigated this role by recording HD cells in
the anterior thalamus after either neurotoxic or electrolytic lesions of the NPH. There was a total loss of direction-specific firing in anterodorsal thalamus cells in animals
with complete NPH lesions. However, many cells were identified that fired in bursts unrelated to the animals’ directional heading and were similar to cells seen in previous
studies that damaged vestibular-associated areas. Some animals with significant but incomplete lesions of the NPH had HD cells that were stable under normal conditions,
but were unstable under conditions designed to minimize the use of external cues. These results support the hypothesis that the NPH, beyond its traditional oculomotor
function, plays a critical role in conveying vestibular-related information to the HD circuit.
The Journal of Neuroscience, February 11, 2015 • 35(6):2547–2558
Behavioral Relevance Helps Untangle Natural Vocal Categories in a Specific Subset of Core
Auditory Cortical Pyramidal Neurons
Kathryn N. Shepard,1,2* Frank G. Lin,4* Charles L. Zhao,4 Kelly K. Chong,4 and Robert C. Liu2,3
Graduate Program in Neuroscience, 2Department of Biology, and 3Center for Translational Social Neuroscience, Emory University, Atlanta, Georgia 30322,
and 4Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30332
1
Sound categorization is essential for auditory behaviors like acoustic communication, but its genesis within the auditory pathway is not well understood— especially for
learned natural categories like vocalizations, which often share overlapping acoustic features that must be distinguished (e.g., speech). We use electrophysiological
mapping and single-unit recordings in mice to investigate how representations of natural vocal categories within core auditory cortex are modulated when one category
acquires enhanced behavioral relevance. Taking advantage of a maternal mouse model of acoustic communication, we found no long-term auditory cortical map expansion
to represent a behaviorally relevant pup vocalization category— contrary to expectations from the cortical plasticity literature on conditioning with pure tones. Instead, we
observed plasticity that improved the separation between acoustically similar pup and adult vocalization categories among a physiologically defined subset of late-onset,
putative pyramidal neurons, but not among putative interneurons. Additionally, a larger proportion of these putative pyramidal neurons in maternal animals compared
with nonmaternal animals responded to the individual pup call exemplars having combinations of acoustic features most typical of that category. Together, these data
suggest that higher-order representations of acoustic categories arise from a subset of core auditory cortical pyramidal neurons that become biased toward the combination
of acoustic features statistically predictive of membership to a behaviorally relevant sound category.
The Journal of Neuroscience, February 11, 2015 • 35(6):2636 –2645
Gain Modulation of Synaptic Inputs by Network State in Auditory Cortex In Vivo
Ramon Reig,1 Yann Zerlaut,2 Ramiro Vergara,1 Alain Destexhe,2 and Maria V. Sanchez-Vives1,3
Institut d’Investigacions Biome`diques August Pi i Sunyer, 08036 Barcelona, Spain, 2Unite´ de Neurosciences, Information et Complexite´, CNRS, 91198 Gif
sur Yvette, France, and 3Institucio´ Catalana de Recerca i Estudis Avanc¸ats, 08010 Barcelona, Spain
1
The cortical network recurrent circuitry generates spontaneous activity organized into Up (active) and Down (quiescent) states during slow-wave sleep or anesthesia. These
different states of cortical activation gain modulate synaptic transmission. However, the reported modulation that Up states impose on synaptic inputs is disparate in the
literature, including both increases and decreases of responsiveness. Here, we tested the hypothesis that such disparate observations may depend on the intensity of the
stimulation. By means of intracellular recordings, we studied synaptic transmission during Up and Down states in rat auditory cortex in vivo. Synaptic potentials were
evoked either by auditory or electrical (thalamocortical, intracortical) stimulation while randomly varying the intensity of the stimulus. Synaptic potentials evoked by the
same stimulus intensity were compared in Up/Down states. Up states had a scaling effect on the stimulus-evoked synaptic responses: the amplitude of weaker responses was
potentiated whereas that of larger responses was maintained or decreased with respect to the amplitude during Down states. We used a computational model to explore the
potential mechanisms explaining this nontrivial stimulus–response relationship. During Up/Down states, there is different excitability in the network and the neuronal
conductance varies. We demonstrate that the competition between presynaptic recruitment and the changing conductance might be the central mechanism explaining the
experimentally observed stimulus–response relationships. We conclude that the effect that cortical network activation has on synaptic transmission is not constant but
contingent on the strength of the stimulation, with a larger modulation for stimuli involving both thalamic and cortical networks.
The Journal of Neuroscience, February 11, 2015 • 35(6):2689 –2702
Prospective Coding of Dorsal Raphe Reward Signals by the Orbitofrontal Cortex
Jingfeng Zhou,1,2 Chunying Jia,2 Qiru Feng,2 Junhong Bao,2 and Minmin Luo2,3
School of Life Sciences, Peking University, Beijing 100081, People’s Republic of China, 2National Institute of Biological Sciences, Beijing 102206, People’s
Republic of China, and 3School of Life Sciences, Tsinghua University, Beijing 100084, People’s Republic of China
1
The orbitofrontal cortex (OFC) is important for the cognitive processes of learning and decision making. Previous recordings have revealed that OFC neurons encode
predictions of reward outcomes. The OFC is interconnected with the dorsal raphe nucleus (DRN), which is a major serotonin (5-HT) center of the brain. Recent studies have
provided increasing evidence that the DRN encodes reward signals. However, it remains unclear how the activity of DRN neurons affects the prospective reward coding of
OFC neurons. By combining single-unit recordings from the OFC and optogenetic activation of the DRN in behaving mice, we found that DRN stimulation is sufficient to
organize and modulate the anticipatory responses of OFC neurons. During pavlovian conditioning tasks for mice, odorant cues were associated with the delayed delivery of
natural rewards of sucrose solution or DRN stimulation. After training, OFC neurons exhibited prospective responses to the sucrose solution. More importantly, the
coupling of an odorant with delayed DRN stimulation resulted in tonic excitation or inhibition of OFC neurons during the delay period. The intensity of the prospective
responses was affected by the frequency and duration of DRN stimulation. Additionally, DRN stimulation bidirectionally modulated the prospective responses to natural
rewards. These experiments indicate that signals from the DRN are incorporated into the brain reward system to shape the cortical prospective coding of rewards.
The Journal of Neuroscience, February 11, 2015 • 35(6):2717–2730
A Functional Link between MT Neurons and Depth Perception Based on Motion Parallax
HyungGoo R. Kim,1 Dora E. Angelaki,2 and Gregory C. DeAngelis1
Department of Brain and Cognitive Sciences, Center for Visual Science, University of Rochester, Rochester, New York 14627, and 2Department of
Neuroscience, Baylor College of Medicine, Houston, Texas 77030
1
As an observer translates, objects lying at different distances from the observer have differential image motion on the retina (motion parallax). It is well established
psychophysically that humans perceive depth rather precisely from motion parallax and that extraretinal signals may be used to correctly perceive the sign of depth (near
vs far) when binocular and pictorial depth cues are absent or weak. However, the neural basis for this capacity remains poorly understood. We have shown previously that
neurons in the macaque middle temporal (MT) area combine retinal image motion with smooth eye movement command signals to signal depth sign from motion parallax.
However, those studies were performed in animals that were required simply to track a visual target, thus precluding direct comparisons between neural activity and
behavior. Here, we examine the activity of MT neurons in rhesus monkeys that were trained to discriminate depth sign based on motion parallax, in the absence of binocular
disparity and pictorial depth cues. We find that the most sensitive MT neurons approach behavioral sensitivity, whereas the average neuron is twofold to threefold less
sensitive than the animal. We also find that MT responses are predictive of perceptual decisions (independent of the visual stimulus), consistent with a role for MT in
providing sensory signals for this behavior. Our findings suggest that, in addition to its established roles in processing stereoscopic depth, area MT is well suited to
contribute to perception of depth based on motion parallax.
The Journal of Neuroscience, February 11, 2015 • 35(6):2766 –2777
Adult Cortical Plasticity Studied with Chronically Implanted Electrode Arrays
Hiroshi Abe,1 Justin N.J. McManus,1 Nirmala Ramalingam,1 Wu Li,2 Sally A. Marik,1
Stephan Meyer zum Alten Borgloh,1 and Charles D. Gilbert1
1The Rockefeller University, 1230 York Avenue, New York, New York 10065, and 2State Key Laboratory of Cognitive Neuroscience and Learning and IDG/
McGovern Institute for Brain Research, Beijing Normal University, Beijing 100875, China
The functional architecture of adult cerebral cortex retains a capacity for experience-dependent change. This is seen after focal binocular lesions as rapid changes in
receptive field (RF) of the lesion projection zone (LPZ) in the primary visual cortex (V1). To study the dynamics of the circuitry underlying these changes longitudinally, we
implanted microelectrode arrays in macaque (Macaca mulatta) V1, eliminating the possibility of sampling bias, which was a concern in previous studies. With this method,
we observed a rapid initial recovery in the LPZ and, during the following weeks, 63– 89% of the sites in the LPZ showed recovery of visual responses with significant position
tuning. The RFs shifted ⬃3° away from the scotoma. In the absence of a lesion, visual stimulation surrounding an artificial scotoma did not elicit visual responses,
suggesting that the postlesion RF shifts resulted from cortical reorganization. Interestingly, although both spikes and LFPs gave consistent prelesion position tuning, only
spikes reflected the postlesion remapping.
The Journal of Neuroscience, February 11, 2015 • 35(6):2778 –2790
BEHAVIORAL/COGNITIVE
Loss of Cyclin-Dependent Kinase 5 from Parvalbumin Interneurons Leads to Hyperinhibition,
Decreased Anxiety, and Memory Impairment
Andrii Rudenko,1,2* Jinsoo Seo,1,2* Ji Hu,1,2 Susan C. Su,1,2 Froylan Calderon de Anda,1,2 Omer Durak,1,2 Maria Ericsson,4
Marie Carle´n,1,2 and Li-Huei Tsai1,2,3
Picower Institute for Learning and Memory, 2Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, 3Broad Institute, Cambridge, Massachusetts 02142, and 4Department of Cell Biology, Harvard Medical School, Boston, Massachusetts
02115
1
Perturbations in fast-spiking parvalbumin (PV) interneurons are hypothesized to be a major component of various neuropsychiatric disorders; however, the mechanisms
regulating PV interneurons remain mostly unknown. Recently, cyclin-dependent kinase 5 (Cdk5) has been shown to function as a major regulator of synaptic plasticity.
Here, we demonstrate that genetic ablation of Cdk5 in PV interneurons in mouse brain leads to an increase in GABAergic neurotransmission and impaired synaptic
plasticity. PVCre;fCdk5 mice display a range of behavioral abnormalities, including decreased anxiety and memory impairment. Our results reveal a central role of Cdk5
expressed in PV interneurons in gating inhibitory neurotransmission and underscore the importance of such regulation during behavioral tasks. Our findings suggest that
Cdk5 can be considered a promising therapeutic target in a variety of conditions attributed to inhibitory interneuronal dysfunction, such as epilepsy, anxiety disorders, and
schizophrenia.
The Journal of Neuroscience, February 11, 2015 • 35(6):2372–2383
Reversal Learning and Dopamine: A Bayesian Perspective
Vincent D. Costa, Valery L. Tran, Janita Turchi, and Bruno B. Averbeck
Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Bethesda Maryland 20892-4415
Reversal learning has been studied as the process of learning to inhibit previously rewarded actions. Deficits in reversal learning have been seen after manipulations of
dopamine and lesions of the orbitofrontal cortex. However, reversal learning is often studied in animals that have limited experience with reversals. As such, the animals are
learning that reversals occur during data collection. We have examined a task regime in which monkeys have extensive experience with reversals and stable behavioral
performance on a probabilistic two-arm bandit reversal learning task. We developed a Bayesian analysis approach to examine the effects of manipulations of dopamine on
reversal performance in this regime. We find that the analysis can clarify the strategy of the animal. Specifically, at reversal, the monkeys switch quickly from choosing one
stimulus to choosing the other, as opposed to gradually transitioning, which might be expected if they were using a naive reinforcement learning (RL) update of value.
Furthermore, we found that administration of haloperidol affects the way the animals integrate prior knowledge into their choice behavior. Animals had a stronger prior
on where reversals would occur on haloperidol than on levodopa (L-DOPA) or placebo. This strong prior was appropriate, because the animals had extensive experience with
reversals occurring in the middle of the block. Overall, we find that Bayesian dissection of the behavior clarifies the strategy of the animals and reveals an effect of
haloperidol on integration of prior information with evidence in favor of a choice reversal.
The Journal of Neuroscience, February 11, 2015 • 35(6):2407–2416
Memory Retrieval Requires Ongoing Protein Synthesis and NMDA Receptor Activity-Mediated
AMPA Receptor Trafficking
Joe¨lle Lopez, Karine Gamache, Rilla Schneider, and Karim Nader
Department of Psychology, McGill University, Montreal, Quebec H3A 1B1, Canada
Whereas consolidation and reconsolidation are considered dynamic processes requiring protein synthesis, memory retrieval has long been considered a passive readout of
previously established plasticity. However, previous findings suggest that memory retrieval may be more dynamic than previously thought. This study therefore aimed at
investigating the molecular mechanisms underlying memory retrieval in the rat. Infusion of protein synthesis inhibitors (rapamycin or anisomycin) in the amygdala 10 min
before memory retrieval transiently impaired auditory fear memory expression, suggesting ongoing protein synthesis is required to enable memory retrieval. We then
investigated the role of protein synthesis in NMDA receptor activity-mediated AMPA receptor trafficking. Coinfusion of an NMDA receptor antagonist (ifenprodil) or
infusion of an AMPA receptor endocytosis inhibitor (GluA23Y ) before rapamycin prevented this memory impairment. Furthermore, rapamycin transiently decreased
GluA1 levels at the postsynaptic density (PSD), but did not affect extrasynaptic sites. This effect at the PSD was prevented by an infusion of GluA23Y before rapamycin.
Together, these data show that ongoing protein synthesis is required before memory retrieval is engaged, and suggest that this protein synthesis may be involved in the
NMDAR activity-mediated trafficking of AMPA receptors that takes place during memory retrieval.
The Journal of Neuroscience, February 11, 2015 • 35(6):2465–2475
Revisiting the Evidence for Collapsing Boundaries and Urgency Signals in Perceptual DecisionMaking
Guy E. Hawkins,1 Birte U. Forstmann,2 Eric-Jan Wagenmakers,3 Roger Ratcliff,4 and Scott D. Brown1
School of Psychology, University of Newcastle, Callaghan, NSW 2308, Australia, 2Amsterdam Brain and Cognition and 3Department of Psychology,
University of Amsterdam, Amsterdam 1018WS, The Netherlands, and 4Department of Psychology, The Ohio State University, Columbus, Ohio 43210
1
For nearly 50 years, the dominant account of decision-making holds that noisy information is accumulated until a fixed threshold is crossed. This account has been tested
extensively against behavioral and neurophysiological data for decisions about consumer goods, perceptual stimuli, eyewitness testimony, memories, and dozens of other
paradigms, with no systematic misfit between model and data. Recently, the standard model has been challenged by alternative accounts that assume that less evidence is
required to trigger a decision as time passes. Such “collapsing boundaries” or “urgency signals” have gained popularity in some theoretical accounts of neurophysiology.
Nevertheless, evidence in favor of these models is mixed, with support coming from only a narrow range of decision paradigms compared with a long history of support
from dozens of paradigms for the standard theory. We conducted the first large-scale analysis of data from humans and nonhuman primates across three distinct
paradigms using powerful model-selection methods to compare evidence for fixed versus collapsing bounds. Overall, we identified evidence in favor of the standard model
with fixed decision boundaries. We further found that evidence for static or dynamic response boundaries may depend on specific paradigms or procedures, such as the
extent of task practice. We conclude that the difficulty of selecting between collapsing and fixed bounds models has received insufficient attention in previous research,
calling into question some previous results.
The Journal of Neuroscience, February 11, 2015 • 35(6):2476 –2484
Circadian Modulation of Dopamine Levels and Dopaminergic Neuron Development Contributes
to Attention Deficiency and Hyperactive Behavior
Jian Huang,1,2* Zhaomin Zhong,1,2* Mingyong Wang,1,2 Xifeng Chen,1,2 Yicheng Tan,1,2 Shuqing Zhang,1,2 Wei He,1,2
Xiong He,1,2 Guodong Huang,1,2 Haiping Lu,3 Ping Wu,2 Yi Che,2 Yi-Lin Yan,1,4 John H. Postlethwait,4 Wenbiao Chen,1,5
and Han Wang1,2
Center for Circadian Clocks, 2School of Biology & Basic Medical Sciences, Medical College, 3Department of Pediatrics and Child Health, Affiliated
Children’s Hospital, Soochow University, Suzhou 215003, Jiangsu, China, 4Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403, and
5Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
1
Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in children and adults. While ADHD patients often display circadian
abnormalities, the underlying mechanisms are unclear. Here we found that the zebrafish mutant for the circadian gene period1b (per1b) displays hyperactive, impulsivelike, and attention deficit-like behaviors and low levels of dopamine, reminiscent of human ADHD patients. We found that the circadian clock directly regulates dopaminerelated genes monoamine oxidase and dopamine ␤ hydroxylase, and acts via genes important for the development or maintenance of dopaminergic neurons to regulate their
number and organization in the ventral diencephalic posterior tuberculum. We then found that Per1 knock-out mice also display ADHD-like symptoms and reduced levels
of dopamine, thereby showing highly conserved roles of the circadian clock in ADHD. Our studies demonstrate that disruption of a circadian clock gene elicits ADHD-like
syndrome. The circadian model for attention deficiency and hyperactive behavior sheds light on ADHD pathogenesis and opens avenues for exploring novel targets for
diagnosis and therapy for this common psychiatric disorder.
The Journal of Neuroscience, February 11, 2015 • 35(6):2572–2587
Differential Magnetic Resonance Neurofeedback Modulations across Extrinsic (Visual) and
Intrinsic (Default-Mode) Nodes of the Human Cortex
Tal Harmelech,1 Doron Friedman,2 and Rafael Malach1
Department of Neurobiology, Weizmann Institute of Science, Rehovot 7610001, Israel and 2School of Communications, The Interdisciplinary Center,
Herzliya 46150, Israel
1
Previous advances in magnetic resonance imaging allow the analysis of blood oxygen level-dependent signals in real time, thus opening the possibility of feeding an index
of these signals back to scanned human participants. However, it is still not known to what extent different cortical networks may differ in their sensitivity to such internally
generated neurofeedback (NF). Here, we compare NF efficacy across six cortical regions including: early and high-order visual areas and the posterior parietal lobe, a
prominent node of the default mode network (DMN). Our results reveal a consistent difference in NF activation across these areas. Sham controls ruled out a role of
attention/arousal in these effects. These differences are suggestive of a relationship to the relative reliance on intrinsic information, moving from early visual cortex (lowest)
to the DMN (highest). Interestingly, the visual parahippocampal place area showed NF activation closer to the DMN node. The results are compatible with the notion of the
DMN as an intrinsically oriented system.
The Journal of Neuroscience, February 11, 2015 • 35(6):2588 –2595
Basal Ganglia Outputs Map Instantaneous Position Coordinates during Behavior
Joseph W. Barter,1,3 Suellen Li,1 Tatyana Sukharnikova,1 Mark A. Rossi,1 Ryan A. Bartholomew,1 and Henry H. Yin1,2,3
1Department of Psychology and Neuroscience, 2Department of Neurobiology, and 3Center for Cognitive Neuroscience, Duke University, Durham, North
Carolina 27708
The basal ganglia (BG) are implicated in many movement disorders, yet how they contribute to movement remains unclear. Using wireless in vivo recording, we measured
BG output from the substantia nigra pars reticulata (SNr) in mice while monitoring their movements with video tracking. The firing rate of most nigral neurons reflected
Cartesian coordinates (either x- or y-coordinates) of the animal’s head position during movement. The firing rates of SNr neurons are either positively or negatively
correlated with the coordinates. Using an egocentric reference frame, four types of neurons can be classified: each type increases firing during movement in a particular
direction (left, right, up, down), and decreases firing during movement in the opposite direction. Given the high correlation between the firing rate and the x and y
components of the position vector, the movement trajectory can be reconstructed from neural activity. Our results therefore demonstrate a quantitative and continuous
relationship between BG output and behavior. Thus, a steady BG output signal from the SNr (i.e., constant firing rate) is associated with the lack of overt movement, when
a stable posture is maintained by structures downstream of the BG. Any change in SNr firing rate is associated with a change in position (i.e., movement). We hypothesize
that the SNr output quantitatively determines the direction, velocity, and amplitude of voluntary movements. By changing the reference signals to downstream position
control systems, the BG can produce transitions in body configurations and initiate actions.
The Journal of Neuroscience, February 11, 2015 • 35(6):2703–2716
Single-Unit Recordings in the Macaque Face Patch System Reveal Limitations of fMRI MVPA
Julien Dubois,1 Archy Otto de Berker,2 and Doris Ying Tsao1
Division of Biology, California Institute of Technology, Pasadena, California 91125, and 2Pembroke College, University of Cambridge, Cambridge CB21RF,
United Kingdom
1
Multivariate pattern analysis (MVPA) of fMRI data has become an important technique for cognitive neuroscientists in recent years; however, the relationship between
fMRI MVPA and the underlying neural population activity remains unexamined. Here, we performed MVPA of fMRI data and single-unit data in the same species, the
macaque monkey. Facial recognition in the macaque is subserved by a well characterized system of cortical patches, which provided the test bed for our comparison. We
showed that neural population information about face viewpoint was readily accessible with fMRI MVPA from all face patches, in agreement with single-unit data.
Information about face identity, although it was very strongly represented in the populations of units of the anterior face patches, could not be retrieved from the same data.
The discrepancy was especially striking in patch AL, where neurons encode both the identity and viewpoint of human faces. From an analysis of the characteristics of the
neural representations for viewpoint and identity, we conclude that fMRI MVPA cannot decode information contained in the weakly clustered neuronal responses
responsible for coding the identity of human faces in the macaque brain. Although further studies are needed to elucidate the relationship between information decodable
from fMRI multivoxel patterns versus single-unit populations for other variables in other brain regions, our result has important implications for the interpretation of
negative findings in fMRI multivoxel pattern analyses.
The Journal of Neuroscience, February 11, 2015 • 35(6):2791–2802
Behavioral Oscillation in Priming: Competing Perceptual Predictions Conveyed in Alternating
Theta-Band Rhythms
Yan Huang,1 Lin Chen,1 and Huan Luo2,3
State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, P.R. China, 2Department of
Psychology, Peking University, and 3PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, P.R. China
1
The brain constantly creates perceptual predictions about forthcoming stimuli to guide perception efficiently. Abundant studies have demonstrated that perceptual
predictions modulate sensory activities depending on whether the actual inputs are consistent with one particular prediction. In real-life contexts, however, multiple and
even conflicting predictions might concurrently exist to be tested, requiring a multiprediction coordination process. It remains largely unknown how multiple hypotheses
are conveyed and harmonized to guide moment-by-moment perception. Based on recent findings revealing that multiple locations are sampled alternatively in various
phase of attentional rhythms, we hypothesize that this oscillation-based temporal organization mechanism may also underlie the multiprediction coordination process. To
address the issue, we used well established priming paradigms in combination with a time-resolved behavioral approach to investigate the fine temporal dynamics of the
multiprediction harmonization course in human subjects. We first replicate classical priming effects in slowly developing trends of priming time courses. Second, after
removing the typical priming patterns, we reveal a new theta-band (⬃4 Hz) oscillatory component in the priming behavioral data regardless of whether the prime was
masked. Third, we show that these theta-band priming oscillations triggered by congruent and incongruent primes are in an out-of-phase relationship. These findings
suggest that perceptual predictions return to low-sensory areas not continuously but recurrently in a theta-band rhythm (every 200 –300 ms) and that multiple predictions
are dynamically coordinated in time by being conveyed in different phases of the theta-band oscillations to achieve dissociated but temporally organized neural
representations.
The Journal of Neuroscience, February 11, 2015 • 35(6):2830 –2837
NEUROBIOLOGY OF DISEASE
Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic
Mice
Dena B. Dubal,1,2 Lei Zhu,1,2 Pascal E. Sanchez,1,2 Kurtresha Worden,1,2 Lauren Broestl,2 Erik Johnson,1,2 Kaitlyn Ho,1
Gui-Qiu Yu,1 Daniel Kim,1 Alexander Betourne,2 Makoto Kuro-o,3 Eliezer Masliah,4 Carmela R. Abraham,5 and
Lennart Mucke1,2
Gladstone Institute of Neurological Disease, San Francisco, California 94158, 2Department of Neurology, University of California, San Francisco, California
94158, 3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, 4Departments of Neurosciences and Pathology,
University of California, San Diego, San Diego, California 92093, and 5Department of Biochemistry, Boston University School of Medicine, Boston,
Massachusetts 02118
1
Aging is the principal demographic risk factor for Alzheimer disease (AD), the most common neurodegenerative disorder. Klotho is a key modulator of the aging process
and, when overexpressed, extends mammalian lifespan, increases synaptic plasticity, and enhances cognition. Whether klotho can counteract deficits related to neurodegenerative diseases, such as AD, is unknown. Here we show that elevating klotho expression decreases premature mortality and network dysfunction in human amyloid
precursor protein (hAPP) transgenic mice, which simulate key aspects of AD. Increasing klotho levels prevented depletion of NMDA receptor (NMDAR) subunits in the
hippocampus and enhanced spatial learning and memory in hAPP mice. Klotho elevation in hAPP mice increased the abundance of the GluN2B subunit of NMDAR in
postsynaptic densities and NMDAR-dependent long-term potentiation, which is critical for learning and memory. Thus, increasing wild-type klotho levels or activities
improves synaptic and cognitive functions, and may be of therapeutic benefit in AD and other cognitive disorders.
The Journal of Neuroscience, February 11, 2015 • 35(6):2358 –2371
Inspiration Is the Major Regulator of Human CSF Flow
Steffi Dreha-Kulaczewski,1 Arun A. Joseph,2,3 Klaus-Dietmar Merboldt,2 Hans-Christoph Ludwig,4 Jutta Ga¨rtner,1 and
Jens Frahm2,3
Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Go¨ttingen, 37075 Go¨ttingen, Germany,
Biomedizinische NMR Forschungs GmbH am Max-Planck-Institut fu¨r biophysikalische Chemie, 37077 Go¨ttingen, Germany, 3DZHK (German Center for
Cardiovascular Research), 37075 Go¨ttingen, Germany, and 4Department of Neurosurgery, Division of Pediatric Neurosurgery, University Medical Center
Go¨ttingen, 37075 Go¨ttingen, Germany
1
2
The mechanisms behind CSF flow in humans are still not fully known. CSF circulates from its primary production sites at the choroid plexus through the brain ventricles to
reach the outer surface of the brain in the subarachnoid spaces from where it drains into venous bloodstream and cervical lymphatics. According to a recent concept of brain
fluid transport, established in rodents, CSF from the brain surface also enters the brain tissue along para-arterial routes and exits through paravenous spaces again into
subarachnoid compartments. This unidirectional flow is mainly driven by arterial pulsation. To investigate how CSF flow is regulated in humans, we applied a novel
real-time magnetic resonance imaging technique at high spatial (0.75 mm) and temporal (50 ms) resolution in healthy human subjects. We observed significant CSF flow
exclusively with inspiration. In particular, during forced breathing, high CSF flow was elicited during every inspiration, whereas breath holding suppressed it. Only a minor
flow component could be ascribed to cardiac pulsation. The present results unambiguously identify inspiration as the most important driving force for CSF flow in humans.
Inspiratory thoracic pressure reduction is expected to directly modulate the hydrostatic pressure conditions for the low-resistance paravenous, venous, and lymphatic
clearance routes of CSF. Furthermore, the experimental approach opens new clinical opportunities to study the pathophysiology of various forms of hydrocephalus and to
design therapeutic strategies in relation to CSF flow alterations.
The Journal of Neuroscience, February 11, 2015 • 35(6):2485–2491
Anatomical Changes at the Level of the Primary Synapse in Neuropathic Pain: Evidence from
the Spinal Trigeminal Nucleus
Sophie L. Wilcox,1 Sylvia M. Gustin,1 Paul M. Macey,2 Chris C. Peck,3 Greg M. Murray,3 and Luke A. Henderson1
1Department of Anatomy and Histology, University of Sydney, Sydney, New South Wales, Australia 2006, 2University of California, Los Angeles, School of
Nursing and Brain Research Institute, Los Angeles, California 90095, and 3Jaw Function and Orofacial Pain Research Unit, Faculty of Dentistry, Westmead
Hospital, University of Sydney, Australia 2145
Accumulated evidence from experimental animal models suggests that neuronal loss within the dorsal horn is involved in the development and/or maintenance of
peripheral neuropathic pain. However, to date, no study has specifically investigated whether such neuroanatomical changes also occur at this level in humans. Using brain
imaging techniques, we sought to determine whether anatomical changes were present in the spinal trigeminal nucleus in subjects with chronic orofacial neuropathic pain.
In 22 subjects with painful trigeminal neuropathy and 44 pain-free controls, voxel-based morphometry of T1-weighted anatomical images and diffusion tensor images were
used to assess regional gray matter volume and microstructural changes within the brainstem. In addition, deterministic tractography was used to assess the integrity of
ascending pain pathways. Orofacial neuropathic pain was associated with significant regional gray matter volume decreases, fractional anisotropy increases, and mean
diffusivity decreases within the spinal trigeminal nucleus, specifically the subnucleus oralis. In addition, tractography revealed no significant differences in diffusivity
properties in the root entry zone of the trigeminal nerve, the spinal trigeminal tract, or the ventral trigeminothalamic tracts in painful trigeminal neuropathy subjects
compared with controls. These data reveal that chronic neuropathic pain in humans is associated with discrete alterations in the anatomy of the primary synapse. These
neuroanatomical changes may be critical for the generation and/or maintenance of pathological pain.
The Journal of Neuroscience, February 11, 2015 • 35(6):2508 –2515
Dysregulation of Glutamine Transporter SNAT1 in Rett Syndrome Microglia: A Mechanism for
Mitochondrial Dysfunction and Neurotoxicity
Lee-Way Jin,1,2 Makoto Horiuchi,1 Heike Wulff,3 Xiao-Bo Liu,1 Gino A. Cortopassi,4 Jeffrey D. Erickson,5 and
Izumi Maezawa1,2
1Department of Pathology and Laboratory Medicine and 2M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute, University of
California Davis Medical Center, Sacramento, California 95817, Departments of 3Pharmacology and 4Molecular Biosciences, University of California Davis,
Davis, California 95618, and 5Neuroscience Center, Louisiana State University Health Science Center, New Orleans, Louisiana 70118
Rett syndrome (RTT) is an autism spectrum disorder caused by loss-of-function mutations in the gene encoding MeCP2, an epigenetic modulator that binds the methyl CpG
dinucleotide in target genes to regulate transcription. Previously, we and others reported a role of microglia in the pathophysiology of RTT. To understand the mechanism
of microglia dysfunction in RTT, we identified a MeCP2 target gene, SLC38A1, which encodes a major glutamine transporter (SNAT1), and characterized its role in
microglia. We found that MeCP2 acts as a microglia-specific transcriptional repressor of SNAT1. Because glutamine is mainly metabolized in the mitochondria, where it is
used as an energy substrate and a precursor for glutamate production, we hypothesize that SNAT1 overexpression in MeCP2-deficient microglia would impair the
glutamine homeostasis, resulting in mitochondrial dysfunction as well as microglial neurotoxicity because of glutamate overproduction. Supporting this hypothesis, we
found that MeCP2 downregulation or SNAT1 overexpression in microglia resulted in (1) glutamine-dependent decrease in microglial viability, which was corroborated by
reduced microglia counts in the brains of MECP2 knock-out mice; (2) proliferation of mitochondria and enhanced mitochondrial production of reactive oxygen species; (3)
increased oxygen consumption but decreased ATP production (an energy-wasting state); and (4) overproduction of glutamate that caused NMDA receptor-dependent
neurotoxicity. The abnormalities could be rectified by mitochondria-targeted expression of catalase and a mitochondria-targeted peptide antioxidant, Szeto-Schiller 31.
Our results reveal a novel mechanism via which MeCP2 regulates bioenergetic pathways in microglia and suggest a therapeutic potential of mitochondria-targeted
antioxidants for RTT.
The Journal of Neuroscience, February 11, 2015 • 35(6):2516 –2529
Posttraumatic Stress Disorder-Like Induction Elevates ␤-Amyloid Levels, Which Directly
Activates Corticotropin-Releasing Factor Neurons to Exacerbate Stress Responses
Nicholas J. Justice,1,2,4,5 Longwen Huang,5,6 Jin-Bin Tian,3 Allysa Cole,4 Melissa Pruski,1 Albert J. Hunt, Jr.,1,2
Rene Flores,1 Michael X. Zhu,3 Benjamin R. Arenkiel,5,6 and Hui Zheng4,5
1Institute of Molecular Medicine, 2Program in Neuroscience, and 3Department of Integrative Biology and Pharmacology, University of Texas Health
Sciences Center, Houston, Texas 77030, 4Huffington Center on Aging and 5Department of Human and Molecular Genetics, Baylor College of Medicine,
Houston, Texas 77030, and 6Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, Texas 77030
Recent studies have found that those who suffer from posttraumatic stress disorder (PTSD) are more likely to experience dementia as they age, most often Alzheimer’s
disease (AD). These findings suggest that the symptoms of PTSD might have an exacerbating effect on AD progression. AD and PTSD might also share common susceptibility factors such that those who experience trauma-induced disease were already more likely to succumb to dementia with age. Here, we explored these two hypotheses
using a mouse model of PTSD in wild-type and AD model animals. We found that expression of human familial AD mutations in amyloid precursor protein and presenilin
1 leads to sensitivity to trauma-induced PTSD-like changes in behavioral and endocrine stress responses. PTSD-like induction, in turn, chronically elevates levels of CSF
␤-amyloid (A␤), exacerbating ongoing AD pathogenesis. We show that PTSD-like induction and A␤ elevation are dependent on corticotropin-releasing factor (CRF)
receptor 1 signaling and an intact hypothalamic–pituitary–adrenal axis. Furthermore, we show that A␤ species can hyperexcite CRF neurons, providing a mechanism by
which A␤ influences stress-related symptoms and PTSD-like phenotypes. Consistent with A␤ causing excitability of the stress circuitry, we attenuate PTSD-like phenotypes
in vivo by lowering A␤ levels during PTSD-like trauma exposure. Together, these data demonstrate that exposure to PTSD-like trauma can drive AD pathogenesis, which
directly perturbs CRF signaling, thereby enhancing chronic PTSD symptoms while increasing risk for AD-related dementia.
The Journal of Neuroscience, February 11, 2015 • 35(6):2612–2623