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1.
Mol Psychiatry ; 26(3): 927-940, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-31988435

RESUMO

Social memory processing requires functional CA2 neurons, however the specific mechanisms that regulate their activity are poorly understood. Here, we document that SorCS2, a member of the family of the Vps10 family of sorting receptors, is highly expressed in pyramidal neurons of CA2, as well as ventral CA1, a circuit implicated in social memory. SorCS2 specifically localizes to the postsynaptic density and endosomes within dendritic spines of CA2 neurons. We have discovered that SorCS2 is a selective regulator of NMDA receptor surface trafficking in hippocampal neurons, without altering AMPA receptor trafficking. In addition, SorCS2 regulates dendritic spine density in CA2 neurons where SorCS2 expression is enriched, but not in dorsal CA1 neurons, which normally express very low levels of this protein. To specifically test the role of SorCS2 in behavior, we generated a novel SorCS2-deficient mouse, and identify a significant social memory deficit, with no change in sociability, olfaction, anxiety, or several hippocampal-dependent behaviors. Mutations in sorCS2 have been associated with bipolar disease, schizophrenia, and attention deficient-hyperactivity disorder, and abnormalities in social memory are core components of these neuropsychiatric conditions. Thus, our findings provide a new mechanism for social memory formation, through regulating synaptic receptor trafficking in pyramidal neurons by SorCS2.


Assuntos
Memória , Proteínas do Tecido Nervoso , Células Piramidais , Receptores de Superfície Celular , Receptores de N-Metil-D-Aspartato , Animais , Espinhas Dendríticas/metabolismo , Hipocampo/metabolismo , Camundongos , Neurônios/metabolismo , Células Piramidais/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo
2.
Depress Anxiety ; 33(10): 907-916, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27699937

RESUMO

Brain-derived neurotrophic factor (BDNF) is a growth factor that is dynamically expressed in the brain across postnatal development, regulating neuronal differentiation and synaptic plasticity. The neurotrophic hypothesis of psychiatric mood disorders postulates that in the adult brain, decreased BDNF levels leads to altered neural plasticity, contributing to disease. Although BDNF has been established as a key factor regulating the critical period plasticity in the developing visual system, it has recently been shown to also play a role in fear circuitry maturation, which has implications for the emergence of fear-related mood disorders. This review provides a detailed overview of developmental changes in expression of BDNF isoforms, as well as their receptors across postnatal life. In addition, recent developmental studies utilizing a genetic BDNF single nucleotide polymorphism (Val66Met) knock-in mouse highlight the impact of BDNF on fear learning during a sensitive period spanning the transition into adolescent time frame. We hypothesize that BDNF in the developing brain regulates fear circuit plasticity during a sensitive period in early adolescence, and alterations in BDNF expression (genetic or environmental) have a persistent impact on fear behavior and fear-related disorders.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Encéfalo/fisiopatologia , Condicionamento Clássico/fisiologia , Adolescente , Adulto , Animais , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/fisiopatologia , Encéfalo/metabolismo , Criança , Transtorno Depressivo/genética , Transtorno Depressivo/fisiopatologia , Medo/fisiologia , Humanos , Aprendizagem , Camundongos , Rede Nervosa/fisiopatologia , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Polimorfismo de Nucleotídeo Único/genética
3.
Dev Neurosci ; 36(3-4): 269-76, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24992985

RESUMO

Brain-derived neurotrophic factor (BDNF) is a growth factor that plays key roles in regulating higher-order emotional and cognitive processes including fear learning and memory. A common single-nucleotide polymorphism (SNP) has been identified in the human BDNF gene (BDNF Val66Met) that leads to decreased BDNF secretion and impairments in specific forms of fear learning in adult humans and genetically modified mice containing this SNP. As the emergence of anxiety and other fear-related disorders peaks during adolescence, we sought to better understand the impact of this BDNF SNP on fear learning during the transition through adolescence in BDNF Val66Met knock-in mice. Previously, we have shown that contextual fear expression is temporarily suppressed in wild-type mice during a distinct period in adolescence, but re-emerges at later, postadolescent ages. Until recently, it was unclear whether BDNF-TrkB signaling is involved in the modulation of hippocampal-dependent contextual fear learning and memory during this adolescent period. Here we show that in BDNF Val66Met mice, the presence of the Met allele does not alter contextual fear expression during adolescence, but when previously conditioned BDNF(Met/Met) mice are tested in adulthood, they fail to display the delayed expression of contextual fear compared to wild-type BDNF(Val/Val) controls, indicating that the Met allele may permanently alter hippocampal function, leading to persistent functioning that is indistinguishable from the adolescent state. Conversely, truncated TrkB receptor (TrkB.T1)-deficient (TrkB.T1(-/-)) mice, a genetic mouse model with increased BDNF-TrkB signaling through full-length TrkB receptors, exhibit an accelerated expression of contextual fear during adolescence compared to wild-type controls. Our results point to a critical function for BDNF-TrkB signaling in fear regulation in vivo, particularly during a potentially sensitive period in adolescence.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Medo/psicologia , Aprendizagem/fisiologia , Envelhecimento/psicologia , Animais , Gliceraldeído-3-Fosfato Desidrogenases/fisiologia , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Knockout , Polimorfismo de Nucleotídeo Único , Receptor trkB/genética
4.
ACS Chem Neurosci ; 9(5): 925-934, 2018 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-29281252

RESUMO

Ongoing efforts in our laboratories focus on design of optical reporters known as fluorescent false neurotransmitters (FFNs) that enable the visualization of uptake into, packaging within, and release from individual monoaminergic neurons and presynaptic sites in the brain. Here, we introduce the molecular probe FFN246 as an expansion of the FFN platform to the serotonergic system. Combining the acridone fluorophore with the ethylamine recognition element of serotonin, we identified FFN54 and FFN246 as substrates for both the serotonin transporter and the vesicular monoamine transporter 2 (VMAT2). A systematic structure-activity study revealed the basic structural chemotype of aminoalkyl acridones required for serotonin transporter (SERT) activity and enabled lowering the background labeling of these probes while maintaining SERT activity, which proved essential for obtaining sufficient signal in the brain tissue (FFN246). We demonstrate the utility of FFN246 for direct examination of SERT activity and SERT inhibitors in 96-well cell culture assays, as well as specific labeling of serotonergic neurons of the dorsal raphe nucleus in the living tissue of acute mouse brain slices. While we found only minor FFN246 accumulation in serotonergic axons in murine brain tissue, FFN246 effectively traces serotonin uptake and packaging in the soma of serotonergic neurons with improved photophysical properties and loading parameters compared to known serotonin-based fluorescent tracers.


Assuntos
Encéfalo/metabolismo , Neurotransmissores/metabolismo , Neurônios Serotoninérgicos/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Animais , Axônios/metabolismo , Camundongos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
5.
Neuron ; 99(1): 163-178.e6, 2018 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-29909994

RESUMO

A human variant in the BDNF gene (Val66Met; rs6265) is associated with impaired fear extinction. Using super-resolution imaging, we demonstrate that the BDNF Met prodomain disassembles dendritic spines and eliminates synapses in hippocampal neurons. In vivo, ventral CA1 (vCA1) hippocampal neurons undergo similar morphological changes dependent on their transient co-expression of a SorCS2/p75NTR receptor complex during peri-adolescence. BDNF Met prodomain infusion into the vCA1 during this developmental time frame reduces dendritic spine density and prelimbic (PL) projections, impairing cued fear extinction. Adolescent BdnfMet/Met mice display similar spine and PL innervation deficits. Using fiber photometry, we found that, in wild-type mice, vCA1 neurons projecting to the PL encode extinction by enhancing neural activity in threat anticipation and rapidly subsiding their response. This adaptation is absent in BDNFMet/Met mice. We conclude that the BDNF Met prodomain renders vCA1-PL projection neurons underdeveloped, preventing their capacity for subsequent circuit modulation necessary for fear extinction. VIDEO ABSTRACT.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Região CA1 Hipocampal/patologia , Espinhas Dendríticas/patologia , Extinção Psicológica , Medo , Neurônios/patologia , Sinapses/patologia , Animais , Região CA1 Hipocampal/fisiopatologia , Camundongos , Polimorfismo de Nucleotídeo Único
6.
Neuron ; 98(5): 992-1004.e4, 2018 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-29754752

RESUMO

The efficacy and duration of memory storage is regulated by neuromodulatory transmitter actions. While the modulatory transmitter serotonin (5-HT) plays an important role in implicit forms of memory in the invertebrate Aplysia, its function in explicit memory mediated by the mammalian hippocampus is less clear. Specifically, the consequences elicited by the spatio-temporal gradient of endogenous 5-HT release are not known. Here we applied optogenetic techniques in mice to gain insight into this fundamental biological process. We find that activation of serotonergic terminals in the hippocampal CA1 region both potentiates excitatory transmission at CA3-to-CA1 synapses and enhances spatial memory. Conversely, optogenetic silencing of CA1 5-HT terminals inhibits spatial memory. We furthermore find that synaptic potentiation is mediated by 5-HT4 receptors and that systemic modulation of 5-HT4 receptor function can bidirectionally impact memory formation. Collectively, these data reveal powerful modulatory influence of serotonergic synaptic input on hippocampal function and memory formation.


Assuntos
Região CA1 Hipocampal/metabolismo , Região CA3 Hipocampal/metabolismo , Receptores 5-HT4 de Serotonina/metabolismo , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo , Memória Espacial/fisiologia , Animais , Axônios/metabolismo , Região CA1 Hipocampal/fisiologia , Região CA3 Hipocampal/fisiologia , Hipocampo , Potenciação de Longa Duração , Memória , Camundongos , Inibição Neural/fisiologia , Optogenética , Serotonina/fisiologia , Transmissão Sináptica
7.
Am J Psychiatry ; 174(12): 1203-1213, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29084453

RESUMO

OBJECTIVE: Adolescence is a developmental stage in which the incidence of psychiatric disorders, such as anxiety disorders, peaks. Selective serotonin reuptake inhibitors (SSRIs) are the main class of agents used to treat anxiety disorders. However, the impact of SSRIs on the developing brain during adolescence remains unknown. The authors assessed the impact of developmentally timed SSRI administration in a genetic mouse model displaying elevated anxiety-like behaviors. METHOD: Knock-in mice containing a common human single-nucleotide polymorphism (Val66Met; rs6265) in brain-derived neurotrophic factor (BDNF), a growth factor implicated in the mechanism of action of SSRIs, were studied based on their established phenotype of increased anxiety-like behavior. Timed administration of fluoxetine was delivered during one of three developmental periods (postnatal days 21-42, 40-61, or 60-81), spanning the transition from childhood to adulthood. Neurochemical and anxiety-like behavioral analyses were performed. RESULTS: We identified a "sensitive period" during periadolescence (postnatal days 21-42) in which developmentally timed fluoxetine administration rescued anxiety-like phenotypes in BDNF Val66Met mice in adulthood. Compared with littermate controls, BDNFMet/Met mice exhibited diminished maturation of serotonergic fibers projecting particularly to the prefrontal cortex, as well as decreased expression of the serotonergic trophic factor S100B in the dorsal raphe. Interestingly, deficient serotonergic innervation, as well as S100B levels, were rescued with fluoxetine administration during periadolescence. CONCLUSIONS: These findings suggest that SSRI administration during a "sensitive period" during periadolescence leads to long-lasting anxiolytic effects in a genetic mouse model of elevated anxiety-like behaviors. These persistent effects highlight the role of BDNF in the maturation of the serotonin system and the capacity to enhance its development through a pharmacological intervention.


Assuntos
Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Fatores Etários , Animais , Núcleo Dorsal da Rafe/efeitos dos fármacos , Núcleo Dorsal da Rafe/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Medo/efeitos dos fármacos , Técnicas de Introdução de Genes , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Polimorfismo de Nucleotídeo Único/genética , Córtex Pré-Frontal/efeitos dos fármacos , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Neurônios Serotoninérgicos/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico
8.
Nat Commun ; 7: 11475, 2016 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-27215672

RESUMO

Fear can be highly adaptive in promoting survival, yet it can also be detrimental when it persists long after a threat has passed. Flexibility of the fear response may be most advantageous during adolescence when animals are prone to explore novel, potentially threatening environments. Two opposing adolescent fear-related behaviours-diminished extinction of cued fear and suppressed expression of contextual fear-may serve this purpose, but the neural basis underlying these changes is unknown. Using microprisms to image prefrontal cortical spine maturation across development, we identify dynamic BLA-hippocampal-mPFC circuit reorganization associated with these behavioural shifts. Exploiting this sensitive period of neural development, we modified existing behavioural interventions in an age-specific manner to attenuate adolescent fear memories persistently into adulthood. These findings identify novel strategies that leverage dynamic neurodevelopmental changes during adolescence with the potential to extinguish pathological fears implicated in anxiety and stress-related disorders.


Assuntos
Comportamento Animal/fisiologia , Medo/psicologia , Memória/fisiologia , Vias Neurais/fisiologia , Córtex Pré-Frontal/fisiologia , Fatores Etários , Animais , Condicionamento Psicológico/fisiologia , Sinais (Psicologia) , Extinção Psicológica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Medula Espinal/fisiologia
9.
Nat Commun ; 6: 6395, 2015 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-25731744

RESUMO

Cross-species studies enable rapid translational discovery and produce the broadest impact when both mechanism and phenotype are consistent across organisms. We developed a knock-in mouse that biologically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (FAAH) (C385A; rs324420), the primary catabolic enzyme for the endocannabinoid anandamide. This common polymorphism impacts the expression and activity of FAAH, thereby increasing anandamide levels. Here, we show that the genetic knock-in mouse and human variant allele carriers exhibit parallel alterations in biochemisty, neurocircuitry and behaviour. Specifically, there is reduced FAAH expression associated with the variant allele that selectively enhances fronto-amygdala connectivity and fear extinction learning, and decreases anxiety-like behaviours. These results suggest a gain of function in fear regulation and may indicate for whom and for what anxiety symptoms FAAH inhibitors or exposure-based therapies will be most efficacious, bridging an important translational gap between the mouse and human.


Assuntos
Amidoidrolases/genética , Tonsila do Cerebelo/fisiologia , Lobo Frontal/fisiologia , Regulação Enzimológica da Expressão Gênica/genética , Polimorfismo de Nucleotídeo Único/genética , Amidoidrolases/metabolismo , Animais , Western Blotting , Extinção Psicológica/fisiologia , Medo/fisiologia , Técnicas de Introdução de Genes/métodos , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Espectrometria de Massas , Camundongos , Especificidade da Espécie
10.
Dev Cell ; 33(6): 690-702, 2015 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-26004511

RESUMO

Recent studies in humans and in genetic mouse models have identified Slit- and NTRK-like family (Slitrks) as candidate genes for neuropsychiatric disorders. All Slitrk isotypes are highly expressed in the CNS, where they mediate neurite outgrowth, synaptogenesis, and neuronal survival. However, the molecular mechanisms underlying these functions are not known. Here, we report that Slitrk5 modulates brain-derived neurotrophic factor (BDNF)-dependent biological responses through direct interaction with TrkB receptors. Under basal conditions, Slitrk5 interacts primarily with a transsynaptic binding partner, protein tyrosine phosphatase δ (PTPδ); however, upon BDNF stimulation, Slitrk5 shifts to cis-interactions with TrkB. In the absence of Slitrk5, TrkB has a reduced rate of ligand-dependent recycling and altered responsiveness to BDNF treatment. Structured illumination microscopy revealed that Slitrk5 mediates optimal targeting of TrkB receptors to Rab11-positive recycling endosomes through recruitment of a Rab11 effector protein, Rab11-FIP3. Thus, Slitrk5 acts as a TrkB co-receptor that mediates its BDNF-dependent trafficking and signaling.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptor trkB/metabolismo , Animais , Corpo Estriado/metabolismo , Endossomos/metabolismo , Células HEK293 , Humanos , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Ligação Proteica , Transporte Proteico , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Transdução de Sinais , Proteínas rab de Ligação ao GTP/metabolismo
12.
Neuroscientist ; 18(5): 439-51, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22367929

RESUMO

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin growth factor family and is implicated as a modulator of neuronal survival and differentiation, synaptic plasticity, and higher order cognitive functions such as learning and memory. A common single-nucleotide polymorphism (SNP) has been identified in the human BDNF gene (BDNF Val66Met) that leads to decreased BDNF secretion and impairments in specific forms of learning in humans. To better understand the impact of this SNP on biological function, the authors generated a mouse model containing the BDNF Met allele, which they found to replicate the key phenotypes observed in humans and provided further insight into the functional impact of this SNP in vivo. They used a "bottom-up" approach to study the BDNF SNP, which provided external validation in biologically less complex, genetically uniform systems, which minimized the variability inherent in human studies. In this review, the authors discuss the impact of the BDNF SNP on learning and memory while providing arguments for the relevance of a vertically integrated approach to studying human genetic variants.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Transtornos Cognitivos/genética , Genética Comportamental/métodos , Animais , Modelos Animais de Doenças , Técnicas de Introdução de Genes/métodos , Humanos , Transtornos Mentais/genética , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Polimorfismo de Nucleotídeo Único/genética
13.
Neuropsychopharmacology ; 37(5): 1297-304, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22218094

RESUMO

Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRI-induced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild-type (BDNF(Val/Val)) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF(Met/Met)). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF(Met/Met) mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF(Met/Met) mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Giro Denteado/metabolismo , Potenciação de Longa Duração/genética , Metionina/genética , Polimorfismo de Nucleotídeo Único/genética , Valina/genética , Análise de Variância , Animais , Biofísica , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Bromodesoxiuridina/metabolismo , Giro Denteado/efeitos dos fármacos , Estimulação Elétrica , Ensaio de Imunoadsorção Enzimática , Fluoxetina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Técnicas In Vitro , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Patch-Clamp , Receptor trkB/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia
14.
Nat Med ; 16(5): 598-602, 1p following 602, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20418887

RESUMO

Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of obsessive thoughts and repetitive compulsive actions, and it often encompasses anxiety and depressive symptoms. Recently, the corticostriatal circuitry has been implicated in the pathogenesis of OCD. However, the etiology, pathophysiology and molecular basis of OCD remain unknown. Several studies indicate that the pathogenesis of OCD has a genetic component. Here we demonstrate that loss of a neuron-specific transmembrane protein, SLIT and NTRK-like protein-5 (Slitrk5), leads to OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors, and is alleviated by the selective serotonin reuptake inhibitor fluoxetine. Slitrk5(-/-) mice show selective overactivation of the orbitofrontal cortex, abnormalities in striatal anatomy and cell morphology and alterations in glutamate receptor composition, which contribute to deficient corticostriatal neurotransmission. Thus, our studies identify Slitrk5 as an essential molecule at corticostriatal synapses and provide a new mouse model of OCD-like behaviors.


Assuntos
Comportamento Animal , Proteínas de Membrana/deficiência , Neostriado/fisiopatologia , Proteínas do Tecido Nervoso/deficiência , Transtorno Obsessivo-Compulsivo/diagnóstico , Animais , Comportamento Compulsivo/genética , Asseio Animal , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Sinapses , Transmissão Sináptica
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