Publications by authors named "Eric F Schmidt"

19 Publications

  • Page 1 of 1

Serotonin receptor 4 in the hippocampus modulates mood and anxiety.

Mol Psychiatry 2021 Jan 13. Epub 2021 Jan 13.

Laboratory of Molecular Biology, The Rockefeller University, New York, NY, 10065, USA.

Serotonin receptor 4 (5-HTR) plays an important role in regulating mood, anxiety, and cognition, and drugs that activate this receptor have fast-acting antidepressant (AD)-like effects in preclinical models. However, 5-HTR is widely expressed throughout the central nervous system (CNS) and periphery, making it difficult to pinpoint the cell types and circuits underlying its effects. Therefore, we generated a Cre-dependent 5-HTR knockout mouse line to dissect the function of 5-HTR in specific brain regions and cell types. We show that the loss of functional 5-HTR specifically from excitatory neurons of hippocampus led to robust AD-like behavioral responses and an elevation in baseline anxiety. 5-HTR was necessary to maintain the proper excitability of dentate gyrus (DG) granule cells and cell type-specific molecular profiling revealed a dysregulation of genes necessary for normal neural function and plasticity in cells lacking 5-HTR. These adaptations were accompanied by an increase in the number of immature neurons in ventral, but not dorsal, dentate gyrus, indicating a broad impact of 5-HTR loss on the local cellular environment. This study is the first to use conditional genetic targeting to demonstrate a direct role for hippocampal 5-HTR signaling in modulating mood and anxiety. Our findings also underscore the need for cell type-based approaches to elucidate the complex action of neuromodulatory systems on distinct neural circuits.
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http://dx.doi.org/10.1038/s41380-020-00994-yDOI Listing
January 2021

Selective Neuronal Vulnerability in Alzheimer's Disease: A Network-Based Analysis.

Neuron 2020 09 29;107(5):821-835.e12. Epub 2020 Jun 29.

Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.

A major obstacle to treating Alzheimer's disease (AD) is our lack of understanding of the molecular mechanisms underlying selective neuronal vulnerability, a key characteristic of the disease. Here, we present a framework integrating high-quality neuron-type-specific molecular profiles across the lifetime of the healthy mouse, which we generated using bacTRAP, with postmortem human functional genomics and quantitative genetics data. We demonstrate human-mouse conservation of cellular taxonomy at the molecular level for neurons vulnerable and resistant in AD, identify specific genes and pathways associated with AD neuropathology, and pinpoint a specific functional gene module underlying selective vulnerability, enriched in processes associated with axonal remodeling, and affected by amyloid accumulation and aging. We have made all cell-type-specific profiles and functional networks available at http://alz.princeton.edu. Overall, our study provides a molecular framework for understanding the complex interplay between Aβ, aging, and neurodegeneration within the most vulnerable neurons in AD.
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http://dx.doi.org/10.1016/j.neuron.2020.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580783PMC
September 2020

Clostridium perfringens epsilon toxin induces blood brain barrier permeability via caveolae-dependent transcytosis and requires expression of MAL.

PLoS Pathog 2019 11 8;15(11):e1008014. Epub 2019 Nov 8.

The Brain and Mind Research Institute and the Department of Neurology, Weill Cornell Medical College, New York, New York, United States of America.

Clostridium perfringens epsilon toxin (ETX) is responsible for causing the economically devastating disease, enterotoxaemia, in livestock. It is well accepted that ETX causes blood brain barrier (BBB) permeability, however the mechanisms involved in this process are not well understood. Using in vivo and in vitro methods, we determined that ETX causes BBB permeability in mice by increasing caveolae-dependent transcytosis in brain endothelial cells. When mice are intravenously injected with ETX, robust ETX binding is observed in the microvasculature of the central nervous system (CNS) with limited to no binding observed in the vasculature of peripheral organs, indicating that ETX specifically targets CNS endothelial cells. ETX binding to CNS microvasculature is dependent on MAL expression, as ETX binding to CNS microvasculature of MAL-deficient mice was not detected. ETX treatment also induces extravasation of molecular tracers including 376Da fluorescein salt, 60kDA serum albumin, 70kDa dextran, and 155kDA IgG. Importantly, ETX-induced BBB permeability requires expression of both MAL and caveolin-1, as mice deficient in MAL or caveolin-1 did not exhibit ETX-induced BBB permeability. Examination of primary murine brain endothelial cells revealed an increase in caveolae in ETX-treated cells, resulting in dynamin and lipid raft-dependent vacuolation without cell death. ETX-treatment also results in a rapid loss of EEA1 positive early endosomes and accumulation of large, RAB7-positive late endosomes and multivesicular bodies. Based on these results, we hypothesize that ETX binds to MAL on the apical surface of brain endothelial cells, causing recruitment of caveolin-1, triggering caveolae formation and internalization. Internalized caveolae fuse with early endosomes which traffic to late endosomes and multivesicular bodies. We believe that these multivesicular bodies fuse basally, releasing their contents into the brain parenchyma.
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http://dx.doi.org/10.1371/journal.ppat.1008014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867657PMC
November 2019

Mapping the physiological and molecular markers of stress and SSRI antidepressant treatment in S100a10 corticostriatal neurons.

Mol Psychiatry 2020 05 20;25(5):1112-1129. Epub 2019 Aug 20.

Department of Physiology, University of Toronto, Toronto, ON, Canada.

In mood disorders, psychomotor and sensory abnormalities are prevalent, disabling, and intertwined with emotional and cognitive symptoms. Corticostriatal neurons in motor and somatosensory cortex are implicated in these symptoms, yet mechanisms of their vulnerability are unknown. Here, we demonstrate that S100a10 corticostriatal neurons exhibit distinct serotonin responses and have increased excitability, compared with S100a10-negative neurons. We reveal that prolonged social isolation disrupts the specific serotonin response which gets restored by chronic antidepressant treatment. We identify cell-type-specific transcriptional signatures in S100a10 neurons that contribute to serotonin responses and strongly associate with psychomotor and somatosensory function. Our studies provide a strong framework to understand the pathogenesis and create new avenues for the treatment of mood disorders.
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http://dx.doi.org/10.1038/s41380-019-0473-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031043PMC
May 2020

Early Life Stress Restricts Translational Reactivity in CA3 Neurons Associated With Altered Stress Responses in Adulthood.

Front Behav Neurosci 2019 11;13:157. Epub 2019 Jul 11.

Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, United States.

Early life experiences program brain structure and function and contribute to behavioral endophenotypes in adulthood. Epigenetic control of gene expression by those experiences affect discrete brain regions involved in mood, cognitive function and regulation of hypothalamic-pituitary-adrenal (HPA) axis. In rodents, acute restraint stress increases the expression of the repressive histone H3 lysine 9 tri-methylation (H3K9me3) in hippocampal fields, including the CA3 pyramidal neurons. These CA3 neurons are crucially involved in cognitive function and mood regulation as well as activation of glucocorticoid (CORT) secretion. CA3 neurons also exhibit structural and functional changes after early-life stress (ELS) as well as after chronic stress in adulthood. Using a protocol of chronic ELS induced by limited bedding and nesting material followed by acute-swim stress (AS) in adulthood, we show that mice with a history of ELS display a blunted CORT response to AS, despite exhibiting activation of immediate early genes after stress similar to that found in control mice. We find that ELS induced persistently increased expression of the repressive H3K9me3 histone mark in the CA3 subfield at baseline that was subsequently decreased following AS. In contrast, AS induced a transient increase of this mark in control mice. Using translating ribosome affinity purification (TRAP) method to isolate CA3 translating mRNAs, we found that expression of genes of the epigenetic gene family, GABA/glutamate family, and glucocorticoid receptors binding genes were decreased transiently in control mice by AS and showed a persistent reduction in ELS mice. In most cases, AS in ELS mice did not induce gene expression changes. A stringent filtering of genes affected by AS in control and ELS mice revealed a noteworthy decrease in gene expression change in ELS mice compared to control. Only 18 genes were selectively regulated by AS in ELS mice and encompassed pathways such as circadian rhythm, inflammatory response, opioid receptors, and more genes included in the glucocorticoid receptor binding family. Thus, ELS programs a restricted translational response to stress in stress-sensitive CA3 neurons leading to persistent changes in gene expression, some of which mimic the transient effects of AS in control mice, while leaving in operation the immediate early gene response to AS.
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http://dx.doi.org/10.3389/fnbeh.2019.00157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637287PMC
July 2019

A sexually dimorphic pre-stressed translational signature in CA3 pyramidal neurons of BDNF Val66Met mice.

Nat Commun 2017 10 9;8(1):808. Epub 2017 Oct 9.

Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.

Males and females use distinct brain circuits to cope with similar challenges. Using RNA sequencing of ribosome-bound mRNA from hippocampal CA3 neurons, we found remarkable sex differences and discovered that female mice displayed greater gene expression activation after acute stress than males. Stress-sensitive BDNF Val66Met mice of both sexes show a pre-stressed translational phenotype in which the same genes that are activated without applied stress are also induced in wild-type mice by an acute stressor. Behaviourally, only heterozygous BDNF Val66Met females exhibit spatial memory impairment, regardless of acute stress. Interestingly, this effect is not observed in ovariectomized heterozygous BDNF Val66Met females, suggesting that circulating ovarian hormones induce cognitive impairment in Met carriers. Cognitive deficits are not observed in males of either genotype. Thus, in a brain region not normally associated with sex differences, this work sheds light on ways that genes, environment and sex interact to affect the transcriptome's response to a stressor.Animals' response to acute stress is known to be influenced by sex and genetics. Here the authors performed RNA-seq on actively translated mRNAs in hippocampal CA3 neurons in mice, and document the effects of sex and genotype (i.e., BDNF Val66Met) on acute stress-induced gene expression.
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http://dx.doi.org/10.1038/s41467-017-01014-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634406PMC
October 2017

Rapid Molecular Profiling of Defined Cell Types Using Viral TRAP.

Cell Rep 2017 04;19(3):655-667

Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Electronic address:

Translational profiling methodologies enable the systematic characterization of cell types in complex tissues, such as the mammalian brain, where neuronal isolation is exceptionally difficult. Here, we report a versatile strategy for profiling CNS cell types in a spatiotemporally restricted fashion by engineering a Cre-dependent adeno-associated virus expressing an EGFP-tagged ribosomal protein (AAV-FLEX-EGFPL10a) to access translating mRNAs by translating ribosome affinity purification (TRAP). We demonstrate the utility of this AAV to target a variety of genetically and anatomically defined neural populations expressing Cre recombinase and illustrate the ability of this viral TRAP (vTRAP) approach to recapitulate the molecular profiles obtained by bacTRAP in corticothalamic neurons across multiple serotypes. Furthermore, spatially restricting adeno-associated virus (AAV) injections enabled the elucidation of regional differences in gene expression within this cell type. Altogether, these results establish the broad applicability of the vTRAP strategy for the molecular dissection of any CNS or peripheral cell type that can be engineered to express Cre.
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http://dx.doi.org/10.1016/j.celrep.2017.03.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476221PMC
April 2017

Serotonergic Suppression of Mouse Prefrontal Circuits Implicated in Task Attention.

eNeuro 2016 Sep-Oct;3(5). Epub 2016 Nov 8.

Department of Physiology, University of Toronto, Toronto, ON, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

Serotonin (5-HT) regulates attention by neurobiological mechanisms that are not well understood. Layer 6 (L6) pyramidal neurons of prefrontal cortex play an important role in attention and express 5-HT receptors, but the serotonergic modulation of this layer and its excitatory output is not known. Here, we performed whole-cell recordings and pharmacological manipulations in acute brain slices from wild-type and transgenic mice expressing either eGFP or eGFP-channelrhodopsin in prefrontal L6 pyramidal neurons. Excitatory circuits between L6 pyramidal neurons and L5 GABAergic interneurons, including a population of interneurons essential for task attention, were investigated using optogenetic techniques. Our experiments show that prefrontal L6 pyramidal neurons are subject to strong serotonergic inhibition and demonstrate direct 5-HT-sensitive connections between prefrontal L6 pyramidal neurons and two classes of L5 interneurons. This work helps to build a neurobiological framework to appreciate serotonergic disruption of task attention and yields insight into the disruptions of attention observed in psychiatric disorders with altered 5-HT receptors and signaling.
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http://dx.doi.org/10.1523/ENEURO.0269-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099606PMC
October 2017

BAC transgenic mice and the GENSAT database of engineered mouse strains.

Cold Spring Harb Protoc 2013 Mar 1;2013(3). Epub 2013 Mar 1.

The brain is a complex tissue comprising hundreds of distinct cell types, each of which has unique circuitry and plays a discrete role in nervous system function. Large-scale studies mapping gene-expression patterns throughout the nervous system have revealed that many genes are exclusively expressed in specific cell populations. The GENSAT (Gene Expression Nervous System Atlas) Project created a library of engineered mice utilizing bacterial artificial chromosomes (BACs) to drive the expression of enhanced green fluorescent protein (eGFP) in genetically defined cell populations. BACs contain large segments of genomic DNA and retain most of the transcriptional regulatory elements directing the expression of a given gene, resulting in more faithful reproduction of endogenous expression patterns. BAC transgenic mice offer a robust solution to the challenging task of stably and reproducibly accessing specific cell types from a heterogeneous tissue such as the brain. A significant advantage of utilizing eGFP as a reporter is the fact that it can fill entire cells, including neuronal dendrites and axons as well as glial processes, making GENSAT reporter mice a powerful tool for neuroimaging studies. This article provides a primer on the generation of BAC transgenic mice and advantages for their use in labeling genetically defined cell types. It also provides an overview of searching the GENSAT database and ordering engineered mouse lines.
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http://dx.doi.org/10.1101/pdb.top073692DOI Listing
March 2013

Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior.

Proc Natl Acad Sci U S A 2012 Jul 25;109(28):11360-5. Epub 2012 Jun 25.

Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.

A large number of studies have demonstrated that the nucleus accumbens (NAC) is a critical site in the neuronal circuits controlling reward responses, motivation, and mood, but the neuronal cell type(s) underlying these processes are not yet known. Identification of the neuronal cell types that regulate depression-like states will guide us in understanding the biological basis of mood and its regulation by diseases like major depressive disorder. Taking advantage of recent findings demonstrating that the serotonin receptor chaperone, p11, is an important molecular regulator of depression-like states, here we identify cholinergic interneurons (CINs) as a primary site of action for p11 in the NAC. Depression-like behavior is observed in mice after decrease of p11 levels in NAC CINs. This phenotype is recapitulated by silencing neuronal transmission in these cells, demonstrating that accumbal cholinergic neuronal activity regulates depression-like behaviors and suggesting that accumbal CIN activity is crucial for the regulation of mood and motivation.
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http://dx.doi.org/10.1073/pnas.1209293109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396525PMC
July 2012

Identification of the cortical neurons that mediate antidepressant responses.

Cell 2012 May;149(5):1152-63

Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Ave., New York, NY 10065, USA.

Our understanding of current treatments for depression, and the development of more specific therapies, is limited by the complexity of the circuits controlling mood and the distributed actions of antidepressants. Although the therapeutic efficacy of serotonin-specific reuptake inhibitors (SSRIs) is correlated with increases in cortical activity, the cell types crucial for their action remain unknown. Here we employ bacTRAP translational profiling to show that layer 5 corticostriatal pyramidal cells expressing p11 (S100a10) are strongly and specifically responsive to chronic antidepressant treatment. This response requires p11 and includes the specific induction of Htr4 expression. Cortex-specific deletion of p11 abolishes behavioral responses to SSRIs, but does not lead to increased depression-like behaviors. Our data identify corticostriatal projection neurons as critical for the response to antidepressants, and suggest that the regulation of serotonergic tone in this single cell type plays a pivotal role in antidepressant therapy.
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http://dx.doi.org/10.1016/j.cell.2012.03.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3397430PMC
May 2012

Analytical approaches to RNA profiling data for the identification of genes enriched in specific cells.

Nucleic Acids Res 2010 Jul 22;38(13):4218-30. Epub 2010 Mar 22.

Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.

We have recently developed a novel method for the affinity purification of the complete suite of translating mRNA from genetically labeled cell populations. This method permits comprehensive quantitative comparisons of the genes employed by each specific cell type. We provide a detailed description of tools for analysis of data generated with this and related methodologies. An essential question that arises from these data is how to identify those genes that are enriched in each cell type relative to all others. Genes relatively specifically employed by a cell type may contribute to the unique functions of that cell, and thus may become useful targets for development of pharmacological tools for cell-specific manipulations. We describe here a novel statistic, the specificity index, which can be used for comparative quantitative analysis to identify genes enriched in specific cell populations across a large number of profiles. This measure correctly predicts in situ hybridization patterns for many cell types. We apply this measure to a large survey of CNS cell-specific microarray data to identify those genes that are significantly enriched in each population Data and algorithms are available online (www.bactrap.org).
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http://dx.doi.org/10.1093/nar/gkq130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2910036PMC
July 2010

Cell-type specific properties of pyramidal neurons in neocortex underlying a layout that is modifiable depending on the cortical area.

Cereb Cortex 2010 Apr 30;20(4):826-36. Epub 2009 Jul 30.

Institute for Neuroscience of Technical University Munich, Biedersteiner Strasse 29, 80802 Munich, Germany.

To understand sensory representation in cortex, it is crucial to identify its constituent cellular components based on cell-type-specific criteria. With the identification of cell types, an important question can be addressed: to what degree does the cellular properties of neurons depend on cortical location? We tested this question using pyramidal neurons in layer 5 (L5) because of their role in providing major cortical output to subcortical targets. Recently developed transgenic mice with cell-type-specific enhanced green fluorescent protein labeling of neuronal subtypes allow reliable identification of 2 cortical cell types in L5 throughout the entire neocortex. A comprehensive investigation of anatomical and functional properties of these 2 cell types in visual and somatosensory cortex demonstrates that, with important exceptions, most properties appear to be cell-type-specific rather than dependent on cortical area. This result suggests that although cortical output neurons share a basic layout throughout the sensory cortex, fine differences in properties are tuned to the cortical area in which neurons reside.
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http://dx.doi.org/10.1093/cercor/bhp152DOI Listing
April 2010

Application of a translational profiling approach for the comparative analysis of CNS cell types.

Cell 2008 Nov;135(4):749-62

Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.

Comparative analysis can provide important insights into complex biological systems. As demonstrated in the accompanying paper, translating ribosome affinity purification (TRAP) permits comprehensive studies of translated mRNAs in genetically defined cell populations after physiological perturbations. To establish the generality of this approach, we present translational profiles for 24 CNS cell populations and identify known cell-specific and enriched transcripts for each population. We report thousands of cell-specific mRNAs that were not detected in whole-tissue microarray studies and provide examples that demonstrate the benefits deriving from comparative analysis. To provide a foundation for further biological and in silico studies, we provide a resource of 16 transgenic mouse lines, their corresponding anatomic characterization, and translational profiles for cell types from a variety of central nervous system structures. This resource will enable a wide spectrum of molecular and mechanistic studies of both well-known and previously uncharacterized neural cell populations.
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http://dx.doi.org/10.1016/j.cell.2008.10.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763427PMC
November 2008

Release of MICAL autoinhibition by semaphorin-plexin signaling promotes interaction with collapsin response mediator protein.

J Neurosci 2008 Feb;28(9):2287-97

Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, Connecticut 06536, USA.

Semaphorin activation of Plexin (Plex) receptors provides axonal guidance during neuronal development. Two families of cytoplasmic proteins, collapsin response mediator proteins (CRMPs) and molecules interacting with CasL (MICALs), have been implicated in Plexin function. The relationship between CRMP and MICAL signaling has not been defined nor is the mechanism by which Plexin activates MICAL clear. Here, we show that CRMP and MICAL physically associate and that Sema signaling promotes this association. MICAL enzymatic activity is inhibited by the C-terminal domain of MICAL. CRMP and Plexin associate with nonenzymatic and enzymatic domains of MICAL and together release MICAL enzymatic autoinhibition. In addition to acting as an upstream MICAL activator, CRMP functions downstream of MICAL, inhibiting the catalytic domain. A constitutively active CRMP mutant inhibits MICAL activity more potently than does wild-type CRMP, suggesting that CRMP or a CRMP-associated factor is a MICAL substrate. Thus, complex Plex/CRMP/MICAL interactions transduce Semaphorin signaling into axon guidance.
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http://dx.doi.org/10.1523/JNEUROSCI.5646-07.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846290PMC
February 2008

The CRMP family of proteins and their role in Sema3A signaling.

Adv Exp Med Biol 2007 ;600:1-11

Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA.

The CRMP proteins were originally identified as mediators of Sema3A signaling and neuronal differentiation. Much has been learned about the mechanism by which CRMPs regulate cellular responses to Sema3A. In this review, the evidence for CRMP as a component of the Sema3A signaling cascade and the modulation of CRMP by plexin and phosphorylation are considered. In addition, current knowledge of the function of CRMP in a variety of cellular processes, including regulation of the cytoskeleton and endocytosis, is discussed in relationship to the mechanisms of axonal growth cone Sema3A response. The secreted protein Sema3A (collapsin-1) was the first identified vertebrate semaphorin. Sema3A acts primarily as a repulsive axon guidance cue, and can cause a dramatic collapse of the growth cone lamellipodium. This process results from the redistribution of the F-actin cytoskeleton and endocytosis of the growth cone cell membrane. Neuropilin-1 (NP1) and members of the class A plexins (PlexA) form a Sema3A receptor complex, with NP1 serving as a high-affinity ligand binding partner, and PlexA transducing the signal into the cell via its large intracellular domain. Although the effect of Sema3A on growth cones was first described nearly 15 years ago, the intracellular signaling pathways that lead to the cellular effects have only recently begun to be understood. Monomeric G-proteins, various kinases, the redox protein, MICAL, and protein turnover have all been implicated in PlexA transduction. In addition, the collapsin-response-mediator protein (CRMP) family of cytosolic phosphoproteins plays a crucial role in Sema3A/NP1/PlexA signal transduction. Current knowledge regarding CRMP functions are reviewed here.
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http://dx.doi.org/10.1007/978-0-387-70956-7_1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853248PMC
August 2007

RanBPM contributes to Semaphorin3A signaling through plexin-A receptors.

J Neurosci 2006 May;26(18):4961-9

Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.

Secreted Semaphorin3A (Sema3A) proteins are known to act as diffusible and repellant axonal guidance cues during nervous system development. A receptor complex consisting of a Neuropilin and a Plexin-A mediates their effects. Plexin-A signal transduction has remained poorly defined despite the documented involvement of collapsin response mediator protein and molecule interacting with CasL proteins (MICALs) as mediators of Plexin-A activation. Here, we defined a domain of Plexin-A1 required for Sema3A signaling in a reconstituted environment and then searched for proteins interacting with this domain. RanBPM is shown to physically interact with Plexin-A1, and the RanBPM/Plexin complex is regulated by MICAL expression. Overexpression of RanBPM cooperates with PlexinA1 to reduce non-neuronal cell spreading and strongly inhibit axonal outgrowth in vitro and in vivo. A truncated RanBPM protein blocks Sema3A responsiveness in non-neuronal and neuronal cells. Suppression of RanBPM expression reduces Sema3A responsiveness. Thus, RanBPM is a mediator of Sema3A signaling through Plexin-A. RanBPM has the potential to link Plexin-A receptors to retrograde transport and microtubule function in axonal guidance.
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http://dx.doi.org/10.1523/JNEUROSCI.0704-06.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2846289PMC
May 2006

Structural bases for CRMP function in plexin-dependent semaphorin3A signaling.

EMBO J 2004 Jan 18;23(1):9-22. Epub 2003 Dec 18.

Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY, USA.

Collapsin response mediator proteins (CRMPs) are cytosolic phosphoproteins involved in neuronal differentiation and axonal guidance. CRMP2 was previously shown to mediate the repulsive effect of Sema3A on axons and to participate in axonal specification. The X-ray crystal structure of murine CRMP1 was determined at 2.1 A resolution and demonstrates that CRMP1 is a bilobed 'lung-shaped' protein forming a tetrameric assembly. Structure-based mutagenesis of surface-exposed residues was employed to map functional domains. As a rapid assay for CRMP, we exploited a reconstituted Sema3A signaling system in COS-7 cells expressing the receptor components Neuropilin1 and PlexinA1 (NP1/PlexA1). In these cells, CRMP and PlexA1 form a physical complex that is reduced in amount by NP1 but enhanced by Sema3A/NP1. Furthermore, CRMP accelerates Sema3A-induced cell contraction. Alanine substitutions in one domain of CRMP1 produce a constitutively active protein that causes Sema3A-independent COS-7 contraction. This mutant CRMP mimics the DRG neurite outgrowth-inhibiting effects of Sema3A and reduces Sema3A-induced axonal repulsion. These data provide a structural view of CRMP function in Plex-dependent Sema3A signaling.
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http://dx.doi.org/10.1038/sj.emboj.7600021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1271659PMC
January 2004

Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour.

Nature 2003 Jan;421(6918):70-5

Division of Molecular Psychiatry and the Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

Cocaine addiction is thought to involve persistent neurobiological changes that facilitate relapse to drug use despite efforts to abstain. But the propensity for relapse may be reduced by extinction training--a form of inhibitory learning that progressively reduces cocaine-seeking behaviour in the absence of cocaine reward. Here we show that extinction training during withdrawal from chronic cocaine self-administration induces experience-dependent increases in the GluR1 and GluR2/3 subunits of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) glutamate receptors in the nucleus accumbens shell, a brain region that is critically involved in cocaine reward. Increases in the GluR1 subunit are positively associated with the level of extinction achieved during training, suggesting that GluR1 may promote extinction of cocaine seeking. Indeed, viral-mediated overexpression of both GluR1 and GluR2 in nucleus accumbens shell neurons facilitates extinction of cocaine- but not sucrose-seeking responses. A single extinction training session, when conducted during GluR subunit overexpression, attenuates stress-induced relapse to cocaine seeking even after GluR overexpression declines. Our findings indicate that extinction-induced plasticity in AMPA receptors may facilitate control over cocaine seeking by restoring glutamatergic tone in the nucleus accumbens, and may reduce the propensity for relapse under stressful situations in prolonged abstinence.
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http://dx.doi.org/10.1038/nature01249DOI Listing
January 2003