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not, indicating that T channels were necessary and sufficient for I-LTD induction.
Blocking metabotropic glutamate receptors
blocked I-LTD, suggesting there was a heterosynaptic component (activation of glutamatergic synapses was required to alter
GABAergic synapses), but stimulating a
subset of GABAergic inputs to a cell produced I-LTD selectively at those synapses,
indicating there was also a homosynaptic
component. Finally, I-LTD required activation of GABAA receptors and the Ca 2/
calmodulin-dependent phosphatase calcineurin, which has been previously
shown to mediate LTD through interactions with GABAA receptor subunits.
Journal Club
1
Brief Communications
366
Bridging the Gap between Perceptual and Cognitive Perspectives on Absolute Pitch
Stefan Elmer, Lars Rogenmoser, Jurg Kuhnis, and Lutz Jancke
Articles
CELLULAR/MOLECULAR
21
64
112
221
325
352
372
386
DEVELOPMENT/PLASTICITY/REPAIR
140
234
409
SYSTEMS/CIRCUITS
53
Imaging the Awake Visual Cortex with a Genetically Encoded Voltage Indicator
Matteo Carandini, Daisuke Shimaoka, L. Federico Rossi, Tatsuo K. Sato,
Andrea Benucci, and Thomas Knopfel
84
Temporal Plasticity Involved in Recovery from Manual Dexterity Deficit after Motor
Cortex Lesion in Macaque Monkeys
Yumi Murata, Noriyuki Higo, Takuya Hayashi, Yukio Nishimura,
Yoko Sugiyama, Takao Oishi, Hideo Tsukada, Tadashi Isa, and Hirotaka Onoe
146
Circuit Formation and Function in the Olfactory Bulb of Mice with Reduced
Spontaneous Afferent Activity
Paolo Lorenzon, Nelly Redolfi, Michael J. Podolsky, Ilaria Zamparo,
Sira Angela Franchi, Gianluca Pietra, Anna Boccaccio, Anna Menini,
Venkatesh N. Murthy, and Claudia Lodovichi
170
198
299
BEHAVIORAL/COGNITIVE
74
128
161
179
209
The Neural Substrate for Binaural Masking Level Differences in the Auditory Cortex
Heather J. Gilbert, Trevor M. Shackleton, Katrin Krumbholz, and Alan R. Palmer
245
253
339
NEUROBIOLOGY OF DISEASE
4
36
Caveolin-1 in the Anterior Cingulate Cortex Modulates Chronic Neuropathic Pain via
Regulation of NMDA Receptor 2B Subunit
Jun-Xia Yang, Lu Hua, Yan-Qiang Li, Yan-Yu Jiang, Dong Han, He Liu,
Qian-Qian Tang, Xiao-Na Yang, Cui Yin, Ling-Yun Hao, Le Yu, Peng Wu,
Cui-Jie Shao, Hai-Lei Ding, Yong-Mei Zhang, and Jun-Li Cao
96
267
287
Altered Sensory Experience Exacerbates Stable Dendritic Spine and Synapse Loss in a
Mouse Model of Huntingtons Disease
Reena Prity Murmu, Wen Li, Zsuzsanna Szepesi, and Jia-Yi Li
308
316
396
422
438
BRIEF COMMUNICATIONS
Bridging the Gap between Perceptual and Cognitive Perspectives on Absolute Pitch
Stefan Elmer,1* Lars Rogenmoser,1* Jurg Kuhnis,1 and Lutz Jancke1,2,3,4,5
Division Neuropsychology, Institute of Psychology, 2Center for Integrative Human Physiology (ZIHP), 3International Normal Aging and Plasticity Imaging
Center (INAPIC), and 4University Research Priority Program (URPP) Dynamic of Healthy Aging, University of Zurich, CH-8050 Zurich, Switzerland and
5Department of Special Education, King Abdulaziz University, 21589 Jeddah, Saudi Arabia
1
Absolute pitch (AP) refers to the rare ability to identify the chroma of a tone or to produce a specific pitch without reference to keyality (e.g., G or C). Previously, AP has been
proposed to rely on the distinctive functional-anatomical architecture of the left auditory-related cortex (ARC), this specific trait possibly enabling an optimized early
categorical perception. In contrast, currently prevailing models of AP postulate that cognitive rather than perceptual processes, namely pitch labeling mechanisms,
more likely constitute the bearing skeleton of AP. This associative memory component has previously been proposed to be dependent, among other mechanisms, on the
recruitment of the left dorsolateral prefrontal cortex (DLPFC) as well as on the integrity of the left arcuate fasciculus, a fiber bundle linking the posterior supratemporal
plane with the DLPFC. Here, we attempted to integrate these two apparently conflicting perspectives on AP, namely early categorical perception and pitch labeling. We
used electroencephalography and evaluated resting-state intracranial functional connectivity between the left ARC and DLPFC in a sample of musicians with and without
AP. Results demonstrate significantly increased left-hemispheric theta phase synchronization in AP compared with non-AP musicians. Within the AP group, this specific
electrophysiological marker was predictive of absolute-hearing behavior and explained 30% of variance. Thus, we propose that in AP subjects the tonal inputs and the
corresponding mnemonic representations are tightly coupled in such a manner that the distinctive electrophysiological signature of AP can saliently be detected in only 3
min of resting-state measurements.
The Journal of Neuroscience, January 7, 2015 35(1):366 371
Articles
CELLULAR/MOLECULAR
Myelinating Schwann cells in the vertebrate peripheral nervous system rely on Brg1 (Smarca4) for terminal differentiation. Brg1 serves as central ATP-hydrolyzing subunit
of the chromatin remodelling BAF complexes and is recruited during myelination as part of these complexes by the transcription factor Sox10 in Schwann cells. Here, we
analyzed the role of Brg1 during development of myelinating oligodendrocytes in the CNS of the mouse. Following Brg1 deletion in oligodendrocyte precursors, these cells
showed normal survival, proliferation, and migration. A mild but significant reduction in the number of oligodendrocytes with myelin gene expression in the absence of
Brg1 points to a contribution to oligodendroglial differentiation but also shows that the role of Brg1 is much less prominent than during Schwann cell differentiation.
Additionally, we failed to obtain evidence for a genetic interaction between Brg1 and Sox10 comparable with the one in Schwann cells. This argues that similarities exist
between the regulatory networks and mechanisms in both types of myelinating glia but that the exact mode of action and the relevance of functional interactions differ,
pointing to a surprising degree of variability in the control of myelination.
The Journal of Neuroscience, January 7, 2015 35(1):2135
Slow waves of non-REM sleep are suggested to play a role in shaping synaptic connectivity to consolidate recently acquired memories and/or restore synaptic homeostasis.
During sleep slow waves, both GABAergic neurons of the nucleus reticularis thalami (NRT) and thalamocortical (TC) neurons discharge high-frequency bursts of action
potentials mediated by low-threshold calcium spikes due to T-type Ca 2 channel activation. Although such activity of the intrathalamic network characterized by
high-frequency firing and calcium influx is highly suited to modify synaptic efficacy, very little is still known about its consequences on intrathalamic synapse strength.
Combining in vitro electrophysiological recordings and calcium imaging, here we show that the inhibitory GABAergic synapses between NRT and TC neurons of the rat
somatosensory nucleus develop a long-term depression (I-LTD) when challenged by a stimulation paradigm that mimics the thalamic network activity occurring during
sleep slow waves. The mechanism underlying this plasticity presents unique features as it is both heterosynaptic and homosynaptic in nature and requires Ca 2 entry
selectively through T-type Ca 2 channels and activation of the Ca 2-activated phosphatase, calcineurin. We propose that during slow-wave sleep the tight functional
coupling between GABAA receptors, calcineurin, and T-type Ca 2 channels will elicit LTD of the activated GABAergic synapses when coupled with concomitant activation
of metabotropic glutamate receptors postsynaptic to cortical afferences. This I-LTD may be a key element involved in the reshaping of the somatosensory information
pathway during sleep.
The Journal of Neuroscience, January 7, 2015 35(1):64 73
Itk Signals Promote Neuroinflammation by Regulating CD4 T-Cell Activation and Trafficking
Arun K. Kannan,* Do-Geun Kim,* Avery August, and Margaret S. Bynoe
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853
Here we demonstrate that interleukin-2-inducible T-cell kinase (Itk) signaling in cluster of differentiation 4-positive (CD4 ) T cells promotes experimental autoimmune
encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). We show that Itk/ mice exhibit reduced disease severity, and transfer of Itk/ CD4 T cells into
T cell-deficient recipients results in lower disease severity. We observed a significant reduction of CD4 T cells in the CNS of Itk/ mice or recipients of Itk/ CD4 T cells
during EAE, which is consistent with attenuated disease. Itk/ CD4 T cells exhibit defective response to myelin antigen stimulation attributable to displacement of
filamentous actin from the CD4 coreceptor. This results in inadequate transmigration of Itk/ CD4 T cells into the CNS and across brain endothelial barriers in vitro.
Finally, Itk/ CD4 T cells show significant reduction in production of T-helper 1 (Th1) and Th17 cytokines and exhibit skewed T effector/T regulatory cell ratios. These
results indicate that signaling by Itk promotes autoimmunity and CNS inflammation, suggesting that it may be a viable target for treatment of MS.
The Journal of Neuroscience, January 7, 2015 35(1):221233
Neurodevelopmental disorders arise from single or multiple gene defects. However, the way multiple loci interact to modify phenotypic outcomes remains poorly
understood. Here, we studied phenotypes associated with mutations in the schizophrenia susceptibility gene dysbindin (dysb), in isolation or in combination with null
alleles in the dysb network component Blos1. In humans, the Blos1 ortholog Bloc1s1 encodes a polypeptide that assembles, with dysbindin, into the octameric BLOC-1
complex. We biochemically confirmed BLOC-1 presence in Drosophila neurons, and measured synaptic output and complex adaptive behavior in response to BLOC-1
perturbation. Homozygous loss-of-function alleles of dysb, Blos1, or compound heterozygotes of these alleles impaired neurotransmitter release, synapse morphology, and
homeostatic plasticity at the larval neuromuscular junction, and impaired olfactory habituation. This multiparameter assessment indicated that phenotypes were differentially sensitive to genetic dosages of loss-of-function BLOC-1 alleles. Our findings suggest that modification of a second genetic locus in a defined neurodevelopmental
regulatory network does not follow a strict additive genetic inheritance, but rather, precise stoichiometry within the network determines phenotypic outcomes.
The Journal of Neuroscience, January 7, 2015 35(1):325338
In many cell types, differentiation requires an interplay between extrinsic signals and transcriptional changes mediated by repressive and activating histone modifications.
Oligodendrocyte progenitors (OPCs) are electrically responsive cells receiving synaptic input. The differentiation of these cells into myelinating oligodendrocytes is
characterized by temporal waves of gene repression followed by activation of myelin genes and progressive decline of electrical responsiveness. In this study, we used
chromatin isolated from rat OPCs and immature oligodendrocytes, to characterize the genome-wide distribution of the repressive histone marks, H3K9me3 and
H3K27me3, during differentiation. Although both marks were present at the OPC stage, only H3K9me3 marks (but not H3K27me3) were found to be increased during
differentiation, at genes related to neuronal lineage and regulation of membrane excitability. Consistent with these findings, the levels and activity of H3K9 methyltransferases (H3K9 HMT), but not H3K27 HMT, increased more prominently upon exposure to oligodendrocyte differentiating stimuli and were detected in stage-specific
repressive protein complexes containing the transcription factors SOX10 or YY1. Silencing H3K9 HMT, but not H3K27 HMT, impaired oligodendrocyte differentiation and
functionally altered the response of oligodendrocytes to electrical stimulation. Together, these results identify repressive H3K9 methylation as critical for gene repression
during oligodendrocyte differentiation.
The Journal of Neuroscience, January 7, 2015 35(1):352365
cJun and CREB2 in the Postsynaptic Neuron Contribute to Persistent Long-Term Facilitation at
a Behaviorally Relevant Synapse
Jiang-Yuan Hu,1 Amir Levine,1 Ying-Ju Sung,2 and Samuel Schacher1
Department of Neuroscience, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York, New York 10032
and 2The Commonwealth Medical College, Department of Basic Sciences, Scranton, Pennsylvania 18509
Basic region leucine zipper (bZIP) transcription factors regulate gene expression critical for long-term synaptic plasticity or neuronal excitability contributing to learning
and memory. At sensorimotor synapses of Aplysia, changes in activation or expression of CREB1 and CREB2 in sensory neurons are required for long-term synaptic
plasticity. However, it is unknown whether concomitant stimulus-induced changes in expression and activation of bZIP transcription factors in the postsynaptic motor
neuron also contribute to persistent long-term facilitation (P-LTF). We overexpressed various forms of CREB1, CREB2, or cJun in the postsynaptic motor neuron L7 in cell
culture to examine whether these factors contribute to P-LTF. P-LTF is evoked by 2 consecutive days of 5-HT applications (2 5-HT), while a transient form of LTF is produced
by 1 day of 5-HT applications (1 5-HT). Significant increases in the expression of both cJun and CREB2 mRNA in L7 accompany P-LTF. Overexpressing each bZIP factor in
L7 did not alter basal synapse strength, while coexpressing cJun and CREB2 in L7 evoked persistent increases in basal synapse strength. In contrast, overexpressing cJun and
CREB2 in sensory neurons evoked persistent decreases in basal synapse strength. Overexpressing wild-type cJun or CREB2, but not CREB1, in L7 can replace the second day
of 5-HT applications in producing P-LTF. Reducing cJun activity in L7 blocked P-LTF evoked by 2 5-HT. These results suggest that expression and activation of different
bZIP factors in both presynaptic and postsynaptic neurons contribute to persistent change in synapse strength including stimulus-dependent long-term synaptic plasticity.
The Journal of Neuroscience, January 7, 2015 35(1):386 395
DEVELOPMENT/PLASTICITY/REPAIR
Mapping the Stability of Human Brain Asymmetry across Five Sex-Chromosome Aneuploidies
Amy Lin,1 Liv Clasen,1 Nancy Raitano Lee,1 Gregory L. Wallace,1,2 Francois Lalonde,1 Jonathan Blumenthal,1
Jay N. Giedd,1 and Armin Raznahan1
1
2
Section on Brain Imaging, Child Psychiatry Branch, National Institute of Mental HealthNational Institutes of Health, Bethesda, Maryland 20892 and
Department of Speech and Hearing Sciences, George Washington University, Washington, DC 20052
The human brain displays stereotyped and early emerging patterns of cortical asymmetry in health. It is unclear if these asymmetries are highly sensitive to genetic and
environmental variation or fundamental features of the brain that can survive severe developmental perturbations. To address this question, we mapped cortical thickness
(CT) asymmetry in a group of genetically defined disorders known to impact CT development. Participants included 137 youth with one of five sex-chromosome aneuploidies [SCAs; XXX (n 28), XXY (n 58), XYY (n 26), XXYY (n 20), and XXXXY (n 5)], and 169 age-matched typically developing controls (80 female). In controls,
we replicated previously reported rightward inferior frontal and leftward lateral parietal CT asymmetry. These opposing frontoparietal CT asymmetries were broadly
preserved in all five SCA groups. However, we also detected foci of shifting CT asymmetry with aneuploidy, which fell almost exclusively within regions of significant CT
asymmetry in controls. Specifically, X-chromosome aneuploidy accentuated normative rightward inferior frontal asymmetries, while Y-chromosome aneuploidy reversed
normative rightward medial prefrontal and lateral temporal asymmetries. These findings indicate that (1) the stereotyped normative pattern of opposing frontoparietal CT
asymmetry arises from developmental mechanisms that can withstand gross chromosomal aneuploidy and (2) X and Y chromosomes can exert focal, nonoverlapping and
directionally opposed influences on CT asymmetry within cortical regions of significant asymmetry in health. Our study attests to the resilience of developmental
mechanisms that support the global patterning of CT asymmetry in humans, and motivates future research into the molecular bases and functional consequences of sex
chromosome dosage effects on CT asymmetry.
The Journal of Neuroscience, January 7, 2015 35(1):140 145
Brain-derived neurotrophic factor (BDNF) is expressed in gustatory epithelia and is required for gustatory neurons to locate and innervate their correct target during
development. When BDNF is overexpressed throughout the lingual epithelium, beginning embryonically, chorda tympani fibers are misdirected and innervate inappropriate targets, leading to a loss of taste buds. The remaining taste buds are hyperinnervated, demonstrating a disruption of nerve/target matching in the tongue. We tested
the hypothesis here that overexpression of BDNF peripherally leads to a disrupted terminal field organization of nerves that carry taste information to the brainstem. The
chorda tympani, greater superficial petrosal, and glossopharyngeal nerves were labeled in adult wild-type (WT) mice and in adult mice in which BDNF was overexpressed
(OE) to examine the volume and density of their central projections in the nucleus of the solitary tract. We found that the terminal fields of the chorda tympani and greater
superficial petrosal nerves and overlapping fields that included these nerves in OE mice were at least 80% greater than the respective field volumes in WT mice. The shapes
of terminal fields were similar between the two groups; however, the density and spread of labels were greater in OE mice. Unexpectedly, there were also group-related
differences in chorda tympani nerve function, with OE mice showing a greater relative taste response to a concentration series of sucrose. Overall, our results show that
disruption in peripheral innervation patterns of sensory neurons have significant effects on peripheral nerve function and central organization of their terminal fields.
The Journal of Neuroscience, January 7, 2015 35(1):409 421
SYSTEMS/CIRCUITS
Imaging the Awake Visual Cortex with a Genetically Encoded Voltage Indicator
Matteo Carandini,1 Daisuke Shimaoka,1,2 L. Federico Rossi,1 Tatsuo K. Sato,1 Andrea Benucci,1,2*
and Thomas Knopfel2,3*
UCL Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom, 2RIKEN Brain Science Institute, Wako City 351-0198,
Japan, and 3Division of Brain Sciences, Imperial College London, London SW7 2AZ, United Kingdom
Genetically encoded voltage indicators (GEVIs) promise to reveal the membrane potential of genetically targeted neuronal populations through noninvasive, chronic
imaging of large portions of cortical space. Here we test a promising GEVI in mouse cortex during wakefulness, a challenging condition due to large hemodynamic activity,
and we introduce a straightforward projection method to separate a signal dominated by membrane voltage from a signal dominated by hemodynamic activity. We
expressed VSFP-Butterfly 1.2 plasmid in layer 2/3 pyramidal cells of visual cortex through electroporation in utero. We then used wide-field imaging with two cameras to
measure both fluorophores of the indicator in response to visual stimuli. By taking weighted sums and differences of the two measurements, we obtained clear separation
of hemodynamic and voltage signals. The hemodynamic signal showed strong heartbeat oscillations, superimposed on slow dynamics similar to blood oxygen leveldependent (BOLD) or intrinsic signals. The voltage signal had fast dynamics similar to neural responses measured electrically, and showed an orderly retinotopic
mapping. We compared this voltage signal with calcium signals imaged in transgenic mice that express a calcium indicator (GCaMP3) throughout cortex. The voltage signal
from VSFP had similar signal-to-noise ratios as the calcium signal, it was more immune to vascular artifacts, and it integrated over larger regions of visual space, which was
consistent with its reporting mostly subthreshold activity rather than the spiking activity revealed by calcium signals. These results demonstrate that GEVIs provide a
powerful tool to study the dynamics of neural populations at mesoscopic spatial scales in the awake cortex.
The Journal of Neuroscience, January 7, 2015 35(1):53 63
Temporal Plasticity Involved in Recovery from Manual Dexterity Deficit after Motor Cortex
Lesion in Macaque Monkeys
Yumi Murata,1,2 Noriyuki Higo,1,3,4 Takuya Hayashi,5 Yukio Nishimura,4,6 Yoko Sugiyama,1,7 Takao Oishi,1,3,8
Hideo Tsukada,3,9 Tadashi Isa,3,6 and Hirotaka Onoe3,5
Human Technology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 3058568, Japan,
Research Fellow of the Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo, 1020083, Japan, 3Core Research for Evolutional Science and
Technology, Japan Science and Technology Agency, Kawaguchi, Saitama, 3320012, Japan, 4Precursory Research for Embryonic Science and Technology,
Japan Science and Technology Agency, Kawaguchi, Saitama, 3320012, Japan, 5Division of Bio-Function Dynamics Imaging, Center for Life Science
Technologies, RIKEN, Kobe, Hyogo, 6500047, Japan, 6Department of Developmental Physiology, National Institute for Physiological Sciences, National
Institutes of Natural Sciences, Okazaki, Aichi, 4448585, Japan, 7Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba,
Ibaraki, 3058577, Japan, 8Department of Cellular and Molecular Biology, Primate Research Institute, Kyoto University, Inuyama, Aichi, 4848506, Japan, and
9Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Shizuoka, 4348601, Japan
1
2
The question of how intensive motor training restores motor function after brain damage or stroke remains unresolved. Here we show that the ipsilesional ventral premotor cortex
(PMv) and perilesional primary motor cortex (M1) of rhesus macaque monkeys are involved in the recovery of manual dexterity after a lesion of M1. A focal lesion of the hand digit
area in M1 was made by means of ibotenic acid injection. This lesion initially caused flaccid paralysis in the contralateral hand but was followed by functional recovery of hand
movements, including precision grip, during the course of daily postlesion motor training. Brain imaging of regional cerebral blood flow by means of H2 15O-positron emission
tomography revealed enhanced activity of the PMv during the early postrecovery period and increased functional connectivity within M1 during the late postrecovery period. The
causalroleoftheseareasinmotorrecoverywasconfirmedbymeansofpharmacologicalinactivationbymuscimolduringthedifferentrecoveryperiods.Thesefindingsindicatethat,
in both the remaining primary motor and premotor cortical areas, time-dependent plastic changes in neural activity and connectivity are involved in functional recovery from the
motor deficit caused by the M1 lesion. Therefore, it is likely that the PMv, an area distant from the core of the lesion, plays an important role during the early postrecovery period,
whereas the perilesional M1 contributes to functional recovery especially during the late postrecovery period.
The Journal of Neuroscience, January 7, 2015 35(1):84 95
Circuit Formation and Function in the Olfactory Bulb of Mice with Reduced Spontaneous
Afferent Activity
Paolo Lorenzon,1* Nelly Redolfi,1* Michael J. Podolsky,2 Ilaria Zamparo,1 Sira Angela Franchi,1 Gianluca Pietra,3
Anna Boccaccio,4 Anna Menini,3 Venkatesh N. Murthy,5 and Claudia Lodovichi 1,6
1Venetian Institute of Molecular Medicine (VIMM), 35129 Padua, Italy, 2Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
02114, 3Neurobiology Group, SISSA, International School for Advanced Studies, 34136 Trieste, Italy, 4Biophysics Institute, CNR, 16149 Genova, Italy,
5Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, Massachusetts 02138, and 6Neuroscience
Institute, CNR, 35129 Padua, Italy
The type of neuronal activity required for circuit development is a matter of significant debate. We addressed this issue by analyzing the topographic organization of the
olfactory bulb in transgenic mice engineered to have very little afferent spontaneous activity due to the overexpression of the inwardly rectifying potassium channel Kir2.1
in the olfactory sensory neurons (Kir2.1 mice). In these conditions, the topography of the olfactory bulb was unrefined. Odor-evoked responses were readily recorded in
glomeruli with reduced spontaneous afferent activity, although the functional maps were coarser than in controls and contributed to altered olfactory discrimination
behavior. In addition, overexpression of Kir2.1 in adults induced a regression of the already refined connectivity to an immature (i.e., coarser) status. Our data suggest that
spontaneous activity plays a critical role not only in the development but also in the maintenance of the topography of the olfactory bulb and in sensory information
processing.
The Journal of Neuroscience, January 7, 2015 35(1):146 160
Theresponseofneuronsinsensorycortextorepeatedstimuluspresentationsishighlyvariable.Toinvestigatethenatureofthisvariability,wecomparedthespikeactivityofneurons
in the primary visual cortex (V1) of cats with that of their afferents from lateral geniculate nucleus (LGN), in response to similar stimuli. We found variability to be much higher in
V1 than in LGN. To investigate the sources of the additional variability, we measured the spiking activity of large V1 populations and found that much of the variability was shared
across neurons: the variable portion of the responses of one neuron could be well predicted from the summed activity of the rest of the neurons. Variability thus mostly reflected
global fluctuations affecting all neurons. The size and prevalence of these fluctuations, both in responses to stimuli and in ongoing activity, depended on cortical state, being larger
in synchronized states than in more desynchronized states. Contrary to previous reports, these fluctuations invested the overall population, regardless of preferred orientation. The
global fluctuations substantially increased variability in single neurons and correlations among pairs of neurons. Once this effect was removed, pairwise correlations were reduced
and were similar regardless of cortical state. These results highlight the importance of cortical state in controlling cortical operation and can help reconcile previous studies, which
differed widely in their estimate of neuronal variability and pairwise correlations.
The Journal of Neuroscience, January 7, 2015 35(1):170 178
Distinct Midbrain and Habenula Pathways Are Involved in Processing Aversive Events in
Humans
Kelly Hennigan,1 Kimberlee DArdenne,2 and Samuel M. McClure1
1
Department of Psychology, Stanford University, Stanford, California 94305, and 2Virginia Tech Carilion Research Institute, Roanoke, Virginia 24016
Emerging evidence implicates the midbrain dopamine system and its interactions with the lateral habenula in processing aversive information and learning to avoid
negative outcomes. We examined neural responses to unexpected, aversive events using methods specialized for imaging the midbrain and habenula in humans. Robust
activation to aversive relative to neutral events was observed in the habenula and two regions within the ventral midbrain: one located within the ventral tegmental area
(VTA) and the other in the substantia nigra (SN). Aversive processing increased functional connectivity between the VTA and the habenula, putamen, and medial prefrontal
cortex, whereas the SN exhibited a different pattern of functional connectivity. Our findings provide evidence for a network comprising the VTA and SN, the habenula, and
mesocorticolimbic structures that supports processing aversive events in humans.
The Journal of Neuroscience, January 7, 2015 35(1):198 208
Motor Origin of Precise Synaptic Inputs onto Forebrain Neurons Driving a Skilled Behavior
Daniela Vallentin1,2 and Michael A. Long1,2
NYU Neuroscience Institute and Department of Otolaryngology, New York University Langone Medical Center, New York, New York 10016 and 2Center for
Neural Science, New York University, New York, New York 10003
1
Sensory feedback is crucial for learning and performing many behaviors, but its role in the execution of complex motor sequences is poorly understood. To address this, we
consider the forebrain nucleus HVC in the songbird, which contains the premotor circuitry for song production and receives multiple convergent sensory inputs. During
singing, projection neurons within HVC exhibit precisely timed synaptic events that may represent the ongoing motor program or song-related sensory feedback. To
distinguish between these possibilities, we recorded the membrane potential from identified HVC projection neurons in singing zebra finches. External auditory perturbations during song production did not affect synaptic inputs in these neurons. Furthermore, the systematic removal of three sensory feedback streams (auditory,
proprioceptive, and vagal) did not alter the frequency or temporal precision of synaptic activity observed. These findings support a motor origin for song-related synaptic
events and suggest an updated circuit model for generating behavioral sequences.
The Journal of Neuroscience, January 7, 2015 35(1):299 307
BEHAVIORAL/COGNITIVE
Methylphenidate and Atomoxetine Inhibit Social Play Behavior through Prefrontal and
Subcortical Limbic Mechanisms in Rats
E.J. Marijke Achterberg,1* Linda W.M. van Kerkhof,2* Ruth Damsteegt,2 Viviana Trezza,3
and Louk J.M.J. Vanderschuren1,2
Department of Animals in Science and Society, Division of Behavioural Neuroscience, Faculty of Veterinary Medicine, Utrecht University, 3584 CM
Utrecht, The Netherlands, 2Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG Utrecht,
The Netherlands, and 3Department of Science, Section of Biomedical Sciences and Technologies, University Roma Tre, 00146 Rome, Italy
1
Positive social interactions during the juvenile and adolescent phases of life, in the form of social play behavior, are important for social and cognitive development.
However, the neural mechanisms of social play behavior remain incompletely understood. We have previously shown that methylphenidate and atomoxetine, drugs widely
used for the treatment of attention-deficit hyperactivity disorder (ADHD), suppress social play in rats through a noradrenergic mechanism of action. Here, we aimed to
identify the neural substrates of the play-suppressant effects of these drugs. Methylphenidate is thought to exert its effects on cognition and emotion through limbic
corticostriatal systems. Therefore, methylphenidate was infused into prefrontal and orbitofrontal cortical regions as well as into several subcortical limbic areas implicated
in social play. Infusion of methylphenidate into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala, and habenula inhibited social play, but not social
exploratory behavior or locomotor activity. Consistent with a noradrenergic mechanism of action of methylphenidate, infusion of the noradrenaline reuptake inhibitor
atomoxetine into these same regions also reduced social play. Methylphenidate administration into the prelimbic, medial/ventral orbitofrontal, and ventrolateral orbitofrontal cortex, mediodorsal thalamus, or nucleus accumbens shell was ineffective. Our data show that the inhibitory effects of methylphenidate and atomoxetine on social
play are mediated through a distributed network of prefrontal and limbic subcortical regions implicated in cognitive control and emotional processes. These findings
increase our understanding of the neural underpinnings of this developmentally important social behavior, as well as the mechanism of action of two widely used
treatments for ADHD.
The Journal of Neuroscience, January 7, 2015 35(1):161169
Honey bees have a rich repertoire of olfactory learning behaviors, and they therefore are an excellent model to study plasticity in olfactory circuits. Recent behavioral,
physiological, and molecular evidence suggested that the antennal lobe, the first relay of the olfactory system in insects and analog to the olfactory bulb in vertebrates, is
involved in associative and nonassociative olfactory learning. Here we use calcium imaging to reveal how responses across antennal lobe projection neurons change after
association of an input odor with appetitive reinforcement. After appetitive conditioning to 1-hexanol, the representation of an odor mixture containing 1-hexanol becomes
more similar to this odor and less similar to the background odor acetophenone. We then apply computational modeling to investigate how changes in synaptic connectivity
can account for the observed plasticity. Our study suggests that experience-dependent modulation of inhibitory interactions in the antennal lobe aids perception of salient
odor components mixed with behaviorally irrelevant background odors.
The Journal of Neuroscience, January 7, 2015 35(1):179 197
The Neural Substrate for Binaural Masking Level Differences in the Auditory Cortex
Heather J. Gilbert, Trevor M. Shackleton, Katrin Krumbholz, and Alan R. Palmer
MRC Institute of Hearing Research, University Park, Nottingham, NG7 2RD, United Kingdom
The binaural masking level difference (BMLD) is a phenomenon whereby a signal that is identical at each ear (S0), masked by a noise that is identical at each ear (N0), can
be made 1215 dB more detectable by inverting the waveform of either the tone or noise at one ear (S, N). Single-cell responses to BMLD stimuli were measured in the
primary auditory cortex of urethane-anesthetized guinea pigs. Firing rate was measured as a function of signal level of a 500 Hz pure tone masked by low-passed white noise.
Responses were similar to those reported in the inferior colliculus. At low signal levels, the response was dominated by the masker. At higher signal levels, firing rate either
increased or decreased. Detection thresholds for each neuron were determined using signal detection theory. Few neurons yielded measurable detection thresholds for all
stimulus conditions, with a wide range in thresholds. However, across the entire population, the lowest thresholds were consistent with human psychophysical BMLDs. As
in the inferior colliculus, the shape of the firing-rate versus signal-level functions depended on the neurons selectivity for interaural time difference. Our results suggest
that, in cortex, BMLD signals are detected from increases or decreases in the firing rate, consistent with predictions of cross-correlation models of binaural processing and
that the psychophysical detection threshold is based on the lowest neural thresholds across the population.
The Journal of Neuroscience, January 7, 2015 35(1):209 220
Saccade Planning Evokes Topographically Specific Activity in the Dorsal and Ventral Streams
Golbarg T. Saber,1* Franco Pestilli,3* and Clayton E. Curtis1,2
Center for Neural Science, and 2Department of Psychology, New York University, New York, New York 10003, and 3Department of Psychological and Brain
Sciences, Indiana University, Bloomington, Indiana 47405
Saccade planning may invoke spatially-specific feedback signals that bias early visual activity in favor of top-down goals. We tested this hypothesis by measuring cortical
activity at the early stages of the dorsal and ventral visual processing streams. Human subjects maintained saccade plans to (prosaccade) or away (antisaccade) from a
spatial location over long memory-delays. Results show that cortical activity persists in early visual cortex at the retinotopic location of upcoming saccade goals. Topographically specific activity persists as early as V1, and activity increases along both dorsal (V3A/B, IPS0) and ventral (hV4, VO1) visual areas. Importantly, activity persists
when saccade goals are available only via working memory and when visual targets and saccade goals are spatially disassociated. We conclude that top-down signals elicit
retinotopically specific activity in visual cortex both in the dorsal and ventral streams. Such activity may underlie mechanisms that prioritize locations of task-relevant
objects.
The Journal of Neuroscience, January 7, 2015 35(1):245252
A number of studies have focused on the role of specific brain regions, such as the dorsal anterior cingulate cortex during trials on which participants make errors, whereas
others have implicated a host of more widely distributed regions in the human brain. Previous work has proposed that there are multiple cognitive control networks, raising
the question of whether error-related activity can be found in each of these networks. Thus, to examine error-related activity broadly, we conducted a meta-analysis
consisting of 12 tasks that included both error and correct trials. These tasks varied by stimulus input (visual, auditory), response output (button press, speech), stimulus
category (words, pictures), and task type (e.g., recognition memory, mental rotation). We identified 41 brain regions that showed a differential fMRI BOLD response to error
and correct trials across a majority of tasks. These regions displayed three unique response profiles: (1) fast, (2) prolonged, and (3) a delayed response to errors, as well as
a more canonical response to correct trials. These regions were found mostly in several control networks, each network predominantly displaying one response profile. The
one exception to this one network, one response profile observation is the frontoparietal network, which showed prolonged response profiles (all in the right hemisphere),
and fast profiles (all but one in the left hemisphere). We suggest that, in the place of a single localized error mechanism, these findings point to a large-scale set of
error-related regions across multiple systems that likely subserve different functions.
The Journal of Neuroscience, January 7, 2015 35(1):253266
Overexpression of the Type 1 Adenylyl Cyclase in the Forebrain Leads to Deficits of Behavioral
Inhibition
Xuanmao Chen,1 Hong Cao,1,2 Amit Saraf,1 Larry S. Zweifel,1 and Daniel R. Storm1
Department of Pharmacology, School of Medicine, University of Washington, Seattle, Washington 98195, 2Institute of Neurobiology, Institute of Brain
Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai 200032, China
The type 1 adenylyl cyclase (AC1) is an activity-dependent, calcium-stimulated adenylyl cyclase expressed in the nervous system that is implicated in memory formation.
We examined the locomotor activity, and impulsive and social behaviors of AC1 mice, a transgenic mouse strain overexpressing AC1 in the forebrain. Here we report that
AC1 mice exhibit hyperactive behaviors and demonstrate increased impulsivity and reduced sociability. In contrast, AC1 and AC8 double knock-out mice are hypoactive,
and exhibit increased sociability and reduced impulsivity. Interestingly, the hyperactivity of AC1 mice can be corrected by valproate, a mood-stabilizing drug. These data
indicate that increased expression of AC1 in the forebrain leads to deficits in behavioral inhibition.
The Journal of Neuroscience, January 7, 2015 35(1):339 351
NEUROBIOLOGY OF DISEASE
Demyelination Causes Adult CNS Progenitors to Revert to an Immature State and Express
Immune Cues That Support Their Migration
Sarah Moyon,1,2,3 Anne Laure Dubessy,1,2,3 Marie Stephane Aigrot,1,2,3 Matthew Trotter,7 Jeffrey K. Huang,6
Luce Dauphinot,1,2,3 Marie Claude Potier,1,2,3 Christophe Kerninon,4 Stephane Melik Parsadaniantz,8
Robin J. M. Franklin,6 and Catherine Lubetzki1,2,3,5
Universite Pierre et Marie Curie-Paris 6, Centre de Recherche de lInstitut du Cerveau et de la Moelle Epinie`re, 75013 Paris, France, 2Institut National de la
Sante et de la Recherche Medicale, U 1127, 75013 Paris, France, 3CNRS, Unite Mixte de Recherche 7225, 75013 Paris, France, 4Institut Hospitalo
Universitaire-A-Institut du Cerveau et de la Moelle Epinie`re, 75013 Paris, France, 5Groupe Hospitalier Pitie-Salpetrie`re, 75013 Paris, France, 6Department of
Clinical Neuroscience, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB3 0ES, United
Kingdom, 7Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Forvie Site, Cambridge CB2 0SZ, United Kingdom, and 8Institut
de la Vision, UMRS 968, UMR 7210 CNRS, Universite Pierre et Marie Curie-Paris 6, 75012 Paris, France
1
The declining efficiency of myelin regeneration in individuals with multiple sclerosis has stimulated a search for ways by which it might be therapeutically enhanced. Here
we have used gene expression profiling on purified murine oligodendrocyte progenitor cells (OPCs), the remyelinating cells of the adult CNS, to obtain a comprehensive
picture of how they become activated after demyelination and how this enables them to contribute to remyelination. We find that adult OPCs have a transcriptome more
similar to that of oligodendrocytes than to neonatal OPCs, but revert to a neonatal-like transcriptome when activated. Part of the activation response involves increased
expression of two genes of the innate immune system, IL1 and CCL2, which enhance the mobilization of OPCs. Our results add a new dimension to the role of the innate
immune system in CNS regeneration, revealing how OPCs themselves contribute to the postinjury inflammatory milieu by producing cytokines that directly enhance their
repopulation of areas of demyelination and hence their ability to contribute to remyelination.
The Journal of Neuroscience, January 7, 2015 35(1):4 20
Caveolin-1 in the Anterior Cingulate Cortex Modulates Chronic Neuropathic Pain via Regulation
of NMDA Receptor 2B Subunit
Jun-Xia Yang,1,2* Lu Hua,1,2* Yan-Qiang Li,1,2* Yan-Yu Jiang,1,2 Dong Han,1,2 He Liu,1,2 Qian-Qian Tang,1,2
Xiao-Na Yang,1,2 Cui Yin,1,2 Ling-Yun Hao,1,2 Le Yu,1,2 Peng Wu,1,2 Cui-Jie Shao,1,2 Hai-Lei Ding,1,2 Yong-Mei Zhang,1,2
and Jun-Li Cao1,2,3
Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221004, China, 2Jiangsu Province Key Laboratory of Anesthesia and
Analgesia Application Technology, Xuzhou Medical College, Xuzhou 221004, China, and 3Department of Anesthesiology, The Affiliated Hospital of Xuzhou
Medical College, Xuzhou 221002, China
1
Chronic pain is still a basic science and clinical challenge. Unraveling of the neurobiological mechanisms involved in chronic pain will offer novel targets for the development of therapeutic strategies. It is well known that central sensitization in the anterior cingulate cortex (ACC) plays a critical role in initiation, development, and
maintenance of chronic pain. However, the underlying mechanisms still remain elusive. Here, we reported that caveolin-1 (Cav-1), a scaffolding protein in membrane rafts,
was persistently upregulated and activated in the ACC neurons after chronic constriction injury (CCI) in mice. Knockdown or blocking of Cav-1 in the contralateral ACC to
the injury side reversed CCI-induced pain behavioral and neuronal sensitization and overexpression of Cav-1 in the ipsilateral ACC-induced pain behavior in the unaffected
hindpaw. Furthermore, we found that Cav-1 directly binding with NMDA receptor 2B subunit (NR2B) and promotion of NR2B surface levels in the ACC contributed to
modulation of chronic neuropathic pain. Disrupting the interaction of Cav-1 and NR2B through microinjection of a short peptide derived from the C-terminal of NR2B into
the ACC exhibited a significant anti-nociception effect associated with decrease of surface NR2B expression. Moreover, Cav-1 increased intracellular Ca 2 concentration
and activated the ERK/CREB signaling pathway in an NR2B-dependent manner in the ACC. Our findings implicate that Cav-1 in the ACC neurons modulates chronic
neuropathic pain via regulation of NR2B and subsequent activation of ERK/CREB signaling, suggesting a possible caveolin-mediated process would participate in neuronal
transmission pathways implicated in pain modulation.
The Journal of Neuroscience, January 7, 2015 35(1):36 52
In Parkinsons disease, long-term dopamine replacement therapy is complicated by the appearance of L-DOPA-induced dyskinesia (LID). One major hypothesis is that LID results
from an aberrant transcriptional program in striatal neurons induced by L-DOPA and triggered by the activation of ERK. To identify these genes, we performed transcriptome
analyses in the striatum in 6-hydroxydopamine-lesioned mice. A time course analysis (0 6 h after treatment with L-DOPA) identified an acute signature of 709 genes, among which
genes involved in protein phosphatase activity were overrepresented, suggesting a negative feedback on ERK activation by L-DOPA. L-DOPA-dependent deregulation of 28
genes was blocked by pretreatment with SL327, an inhibitor of ERK activation, and 26 genes were found differentially expressed between highly and weakly dyskinetic
animals after treatment with L-DOPA. The intersection list identified five genes: FosB, Th, Nptx2, Nedd4l, and Ccrn4l. Nptx2 encodes neuronal pentraxin II (or neuronal
activity-regulated pentraxin, Narp), which is involved in the clustering of glutamate receptors. We confirmed increased Nptx2 expression after L-DOPA and its blockade by
SL327 using quantitative RT-PCR in independent experiments. Using an escalating L-DOPA dose protocol, LID severity was decreased in Narp knock-out mice compared
with their wild-type littermates or after overexpression of a dominant-negative form of Narp in the striatum. In conclusion, we have identified a molecular signature
induced by L-DOPA in the dopamine-denervated striatum that is dependent on ERK and associated with LID. Here, we demonstrate the implication of one of these genes,
Nptx2, in the development of LID.
The Journal of Neuroscience, January 7, 2015 35(1):96 111
Strong evidence implicates prefrontal cortex (PFC) as a major source of functional impairment in severe mental illness such as schizophrenia. Numerous schizophrenia
studies report deficits in PFC structure, activation, and functional connectivity in patients with chronic illness, suggesting that deficient PFC functional connectivity occurs
in this disorder. However, the PFC functional connectivity patterns during illness onset and its longitudinal progression remain uncharacterized. Emerging evidence
suggests that early-course schizophrenia involves increased PFC glutamate, which might elevate PFC functional connectivity. To test this hypothesis, we examined 129
non-medicated, human subjects diagnosed with early-course schizophrenia and 106 matched healthy human subjects using both whole-brain data-driven and hypothesisdriven PFC analyses of resting-state fMRI. We identified increased PFC connectivity in early-course patients, predictive of symptoms and diagnostic classification, but less
evidence for hypoconnectivity. At the whole-brain level, we observed hyperconnectivity around areas centered on the default system, with modest overlap with
PFC-specific effects. The PFC hyperconnectivity normalized for a subset of the sample followed longitudinally (n 25), which also predicted immediate symptom
improvement. Biologically informed computational modeling implicates altered overall connection strength in schizophrenia. The initial hyperconnectivity, which may
decrease longitudinally, could have prognostic and therapeutic implications.
The Journal of Neuroscience, January 7, 2015 35(1):267286
Altered Sensory Experience Exacerbates Stable Dendritic Spine and Synapse Loss in a Mouse
Model of Huntingtons Disease
Reena Prity Murmu,1 Wen Li,1 Zsuzsanna Szepesi,1 and Jia-Yi Li1,2
Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, BMC A10, 22184
Lund, Sweden, and 2Neuroscience Institute, College of Life and Health Sciences, Northeastern University, Shenyang 110015, Peoples Republic of China
A key question in Huntingtons disease (HD) is what underlies the early cognitive deficits that precede the motor symptoms and the characteristic neuronal death observed
in HD. The mechanisms underlying cognitive symptoms in HD remain unknown. Postmortem HD brain and animal model studies demonstrate pathologies in dendritic
spines and abnormal synaptic plasticity before motor symptoms and neurodegeneration. Experience-dependent synaptic plasticity caused by mechanisms such as LTP or
novel sensory experience potentiates synaptic strength, enhances new dendritic spine formation and stabilization, and may contribute to normal cognitive processes, such
as learning and memory. We have previously reported that under baseline conditions (without any sensory manipulation) neuronal circuitry in HD (R6/2 mouse model)
was highly unstable, which led to a progressive loss of persistent spines in these mice, and that mutant huntingtin was directly involved in the process. Here, we investigated
whether pathological processes of HD interfere with the normal experience-dependent plasticity of dendritic spines in the R6/2 model. Six weeks of two-photon in vivo
imaging before and after whisker trimming revealed that sensory deprivation exacerbates loss of persistent-type, stable spines in R6/2 mice compared with wild-type
littermates. In addition, sensory deprivation leads to impaired transformation of newly generated spines into persistent spines in R6/2 mice. As a consequence, reduced
synaptic density and decreased PSD-95 protein levels are evident in their barrel cortical neurons. These data suggest that mutant huntingtin is implicated in maladaptive
synaptic plasticity, which could be one of the plausible mechanisms underlying early cognitive deficits in HD.
The Journal of Neuroscience, January 7, 2015 35(1):287298
induction was prevented by protein synthesis inhibitor (anisomycin). The results suggest that stimulation of group I mGluRs during glutamate exposure caused proteolysis
of FMRP. Reduction of FMRP led to enhanced synaptic group I mGluR-mediated translation. Elevated translation facilitated the recruitment of group I mGluR-mediated
prolonged epileptiform discharges.
The Journal of Neuroscience, January 7, 2015 35(1):308 315
Stress Induces the Danger-Associated Molecular Pattern HMGB-1 in the Hippocampus of Male
Sprague Dawley Rats: A Priming Stimulus of Microglia and the NLRP3 Inflammasome
Michael D. Weber,1* Matthew G. Frank,1* Kevin J. Tracey,2 Linda R. Watkins,1 and Steven F. Maier1
Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, Colorado 80309, and 2Laboratory of Biomedical
Science, Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York 11030
1
Exposure to acute and chronic stressors sensitizes the proinflammatory response of microglia to a subsequent immune challenge. However, the proximal signal by which
stressors prime microglia remains unclear. Here, high mobility group box-1 (HMGB-1) protein was explored as a potential mediator of stress-induced microglial priming
and whether HMGB-1 does so via the nucleotide-binding domain, leucine-rich repeat, pyrin domain containing protein 3 (NLRP3) inflammasome. Exposure to 100
inescapable tail shocks (ISs) increased HMGB-1 and NLRP3 protein in the hippocampus and led isolated microglia to release HMGB-1 ex vivo. To determine whether
HMGB-1 signaling is necessary for stress-induced sensitization of microglia, the HMGB-1 antagonist BoxA was injected into the cisterna magna before IS. Hippocampal
microglia were isolated 24 h later and stimulated with LPS ex vivo to probe for stress-induced sensitization of proinflammatory responses. Previous IS potentiated gene
expression of NLRP3 and proinflammatory cytokines to LPS, that is, microglia were sensitized. Treatment with BoxA abolished this effect. To determine whether HMGB-1
is sufficient to prime microglia, IS was replaced with intracerebral administration of disulfide or fully reduced HMGB-1. Intracerebral disulfide HMGB-1 mimicked the
effect of the stressor, because microglia isolated from HMGB-1-treated rats expressed exaggerated NLRP3 and proinflammatory cytokine expression after LPS treatment, whereas
fully reduced HMGB-1 had no effect. The present results suggest that the CNS innate immune system can respond to an acute stressor as if it were cellular damage, thereby releasing
the danger signal HMGB-1 in the brain to prime microglia by acting on the NLRP3 inflammasome, in preparation for a later immune challenge.
The Journal of Neuroscience, January 7, 2015 35(1):316 324
PDE-4 Inhibition Rescues Aberrant Synaptic Plasticity in Drosophila and Mouse Models of
Fragile X Syndrome
Catherine H. Choi,1,2,3 Brian P. Schoenfeld,1,4* Eliana D. Weisz,4* Aaron J. Bell,1,4 Daniel B. Chambers,5 Joseph Hinchey,1
Richard J. Choi,1 Paul Hinchey,1 Maria Kollaros,1 Michael J. Gertner,6 Neal J. Ferrick,1,4 Allison M. Terlizzi,1
Nicole Yohn,4 Eric Koenigsberg,1 David A. Liebelt,1 R. Suzanne Zukin,6 Newton H. Woo,7 Michael R. Tranfaglia,8
Natalia Louneva,9 Steven E. Arnold,9 Steven J. Siegel,9 Francois V. Bolduc,5 Thomas V. McDonald,1 Thomas A. Jongens,4
and Sean M. J. McBride1,4,9
Section of Molecular Cardiology, Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461,
Department of Medicine, Lehigh Valley Health System, Allentown, Pennsylvania 18103, 3Department of Dermatology, Drexel University College of
Medicine, Philadelphia, Pennsylvania 19107, 4Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,
5Department of Pediatrics, Center for Neuroscience, University of Alberta, Edmonton, Alberta T6G 2N8, Canada, 6Dominick P. Purpura Department of
Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, 7Division of Anesthesia, Analgesia and Addiction Products, Office of Drug
Evaluation II, OND/CDER/FDA, Silver Spring, Maryland 20993, 8FRAXA Research Foundation, Newburyport, Massachusetts 01950, and 9Department of
Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
1
2
Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive
impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate
receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels
can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects
in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate
that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating
the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates
PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.
The Journal of Neuroscience, January 7, 2015 35(1):396 408
Recent studies on the pathogenic mechanisms of recessive hyperekplexia indicate disturbances in glycine receptor (GlyR) 1 biogenesis. Here, we examine the properties
of a range of novel glycine receptor mutants identified in human hyperekplexia patients using expression in transfected cell lines and primary neurons. All of the novel
mutants localized in the large extracellular domain of the GlyR 1 have reduced cell surface expression with a high proportion of receptors being retained in the ER,
although there is forward trafficking of glycosylated subpopulations into the ER-Golgi intermediate compartment and cis-Golgi compartment. CD spectroscopy revealed
that the mutant receptors have proportions of secondary structural elements similar to wild-type receptors. Two mutants in loop B (G160R, T162M) were functional, but
none of those in loop D/23 were. One nonfunctional truncated mutant (R316X) could be rescued by coexpression with the lacking C-terminal domain. We conclude that
a proportion of GlyR 1 mutants can be transported to the plasma membrane but do not necessarily form functional ion channels. We suggest that loop D/23 is an
important determinant for GlyR trafficking and functionality, whereas alterations to loop B alter agonist potencies, indicating that residues here are critical elements in
ligand binding.
The Journal of Neuroscience, January 7, 2015 35(1):422 437