RESUMO
Synaptogenic adhesion molecules play critical roles in synapse formation. SALM5/Lrfn5, a SALM/Lrfn family adhesion molecule implicated in autism spectrum disorders (ASDs) and schizophrenia, induces presynaptic differentiation in contacting axons, but its presynaptic ligand remains unknown. We found that SALM5 interacts with the Ig domains of LAR family receptor protein tyrosine phosphatases (LAR-RPTPs; LAR, PTPδ, and PTPσ). These interactions are strongly inhibited by the splice insert B in the Ig domain region of LAR-RPTPs, and mediate SALM5-dependent presynaptic differentiation in contacting axons. In addition, SALM5 regulates AMPA receptor-mediated synaptic transmission through mechanisms involving the interaction of postsynaptic SALM5 with presynaptic LAR-RPTPs. These results suggest that postsynaptic SALM5 promotes synapse development by trans-synaptically interacting with presynaptic LAR-RPTPs and is important for the regulation of excitatory synaptic strength.
Assuntos
Processamento Alternativo/fisiologia , Axônios/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Sinapses/metabolismo , Transmissão Sináptica/fisiologia , Animais , Moléculas de Adesão Celular Neuronais/genética , Camundongos , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Sinapses/genéticaRESUMO
Synaptic adhesion molecules regulate synapse development and plasticity through mechanisms that include trans-synaptic adhesion and recruitment of diverse synaptic proteins. We found that the immunoglobulin superfamily member 11 (IgSF11), a homophilic adhesion molecule that preferentially expressed in the brain, is a dual-binding partner of the postsynaptic scaffolding protein PSD-95 and AMPA glutamate receptors (AMPARs). IgSF11 required PSD-95 binding for its excitatory synaptic localization. In addition, IgSF11 stabilized synaptic AMPARs, as determined by IgSF11 knockdown-induced suppression of AMPAR-mediated synaptic transmission and increased surface mobility of AMPARs, measured by high-throughput, single-molecule tracking. IgSF11 deletion in mice led to the suppression of AMPAR-mediated synaptic transmission in the dentate gyrus and long-term potentiation in the CA1 region of the hippocampus. IgSF11 did not regulate the functional characteristics of AMPARs, including desensitization, deactivation or recovery. These results suggest that IgSF11 regulates excitatory synaptic transmission and plasticity through its tripartite interactions with PSD-95 and AMPARs.
Assuntos
Moléculas de Adesão Celular Neuronais/fisiologia , Moléculas de Adesão Celular/fisiologia , Regulação da Expressão Gênica/fisiologia , Hipocampo/metabolismo , Imunoglobulinas/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Receptores de AMPA/metabolismo , Transmissão Sináptica/fisiologia , Animais , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Proteína 4 Homóloga a Disks-Large , Técnicas de Silenciamento de Genes , Cobaias , Humanos , Imunoglobulinas/metabolismo , Camundongos , Técnicas de Patch-Clamp , Coelhos , Ratos , Ratos Sprague-DawleyRESUMO
We report on the neuromorphic sound localization circuit which can enhance the perceptual sensation in a hearing aid system. All elements are simple leaky integrate-and-fire neuron circuits with different parameters optimized to suppress the impacts of synaptic circuit noises. The detection range and resolution of the proposed neuromorphic circuit are 500 us and 5 us, respectively. Our results show that, the proposed technique can localize a sound pulse with extremely narrow duration (â¼ 1 ms) resulting in real-time response.
Assuntos
Auxiliares de Audição , Neurônios/fisiologia , Localização de Som/fisiologia , Potenciais de Ação/fisiologia , Cóclea/fisiologia , Simulação por Computador , Humanos , Modelos Neurológicos , Silício , Som , Sinapses/fisiologia , Fatores de TempoRESUMO
Synaptic adhesion molecules regulate diverse aspects of synapse formation and maintenance. Many known synaptic adhesion molecules localize at excitatory synapses, whereas relatively little is known about inhibitory synaptic adhesion molecules. Here we report that IgSF9b is a novel, brain-specific, homophilic adhesion molecule that is strongly expressed in GABAergic interneurons. IgSF9b was preferentially localized at inhibitory synapses in cultured rat hippocampal and cortical interneurons and was required for the development of inhibitory synapses onto interneurons. IgSF9b formed a subsynaptic domain distinct from the GABAA receptor- and gephyrin-containing domain, as indicated by super-resolution imaging. IgSF9b was linked to neuroligin 2, an inhibitory synaptic adhesion molecule coupled to gephyrin, via the multi-PDZ protein S-SCAM. IgSF9b and neuroligin 2 could reciprocally cluster each other. These results suggest a novel mode of inhibitory synaptic organization in which two subsynaptic domains, one containing IgSF9b for synaptic adhesion and the other containing gephyrin and GABAA receptors for synaptic transmission, are interconnected through S-SCAM and neuroligin 2.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Guanilato Quinases/metabolismo , Imunoglobulinas/metabolismo , Interneurônios/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Inibição Neural/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Adesão Celular/fisiologia , Moléculas de Adesão Celular Neuronais/genética , Técnicas de Cocultura , Guanilato Quinases/genética , Células HEK293 , Hipocampo/citologia , Humanos , Imunoglobulinas/química , Imunoglobulinas/genética , Interneurônios/citologia , Camundongos , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Cultura Primária de Células , Estrutura Terciária de Proteína/fisiologia , Ratos , Receptores de GABA-A/metabolismo , Sinapses/metabolismoRESUMO
Rho family small GTPases are important regulators of neuronal development. Defective Rho regulation causes nervous system dysfunctions including mental retardation and Alzheimer's disease. Rac1, a member of the Rho family, regulates dendritic spines and excitatory synapses, but relatively little is known about how synaptic Rac1 is negatively regulated. Breakpoint cluster region (BCR) is a Rac GTPase-activating protein known to form a fusion protein with the c-Abl tyrosine kinase in Philadelphia chromosome-positive chronic myelogenous leukemia. Despite the fact that BCR mRNAs are abundantly expressed in the brain, the neural functions of BCR protein have remained obscure. We report here that BCR and its close relative active BCR-related (ABR) localize at excitatory synapses and directly interact with PSD-95, an abundant postsynaptic scaffolding protein. Mice deficient for BCR or ABR show enhanced basal Rac1 activity but only a small increase in spine density. Importantly, mice lacking BCR or ABR exhibit a marked decrease in the maintenance, but not induction, of long-term potentiation, and show impaired spatial and object recognition memory. These results suggest that BCR and ABR have novel roles in the regulation of synaptic Rac1 signaling, synaptic plasticity, and learning and memory, and that excessive Rac1 activity negatively affects synaptic and cognitive functions.
Assuntos
Proteínas Ativadoras de GTPase/biossíntese , Aprendizagem/fisiologia , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas rac1 de Ligação ao GTP/biossíntese , Animais , Biolística , Células Cultivadas , Espinhas Dendríticas/metabolismo , Eletrofisiologia , Proteínas Ativadoras de GTPase/genética , Hipocampo/citologia , Hipocampo/metabolismo , Imuno-Histoquímica , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Knockout , Microscopia Eletrônica , Proteínas Serina-Treonina Quinases/genética , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/fisiologia , Transmissão Sináptica/fisiologia , Transfecção , Proteínas rac1 de Ligação ao GTP/genéticaRESUMO
Synaptic cell adhesion molecules regulate various steps of synapse formation. The trans-synaptic adhesion between postsynaptic NGL-3 (for netrin-G ligand-3) and presynaptic LAR (for leukocyte antigen-related) regulates excitatory synapse formation in a bidirectional manner. However, little is known about the molecular details of the NGL-3-LAR adhesion and whether two additional LAR family proteins, protein-tyrosine phosphatase delta (PTPdelta), and PTPsigma, also interact with NGL-3 and are involved in synapse formation. We report here that the leucine-rich repeat (LRR) domain of NGL-3, containing nine LRRs, interacts with the first two fibronectin III (FNIII) domains of LAR to induce bidirectional synapse formation. Moreover, Gln-96 in the first LRR motif of NGL-3 is critical for LAR binding and induction of presynaptic differentiation. PTPdelta and PTPsigma also interact with NGL-3 via their first two FNIII domains. These two interactions promote synapse formation in a different manner; the PTPsigma-NGL-3 interaction promotes synapse formation in a bidirectional manner, whereas the PTPdelta-NGL-3 interaction instructs only presynaptic differentiation in a unidirectional manner. mRNAs encoding LAR family proteins display overlapping and differential expression patterns in various brain regions. These results suggest that trans-synaptic adhesion between NGL-3 and the three LAR family proteins regulates excitatory synapse formation in shared and distinct neural circuits.
Assuntos
Encéfalo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Moléculas de Adesão de Célula Nervosa/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Sinapses/metabolismo , Animais , Cobaias , Humanos , Células L , Camundongos , Proteínas do Tecido Nervoso/genética , Moléculas de Adesão de Célula Nervosa/genética , Ligação Proteica , Estrutura Terciária de Proteína , Ratos , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Sinapses/genéticaRESUMO
Cell adhesion molecules at neuronal synapses regulate diverse aspects of synaptic development, including axo-dendritic contact establishment, early synapse formation, and synaptic maturation. Recent studies have identified several synaptogenic adhesion molecules. The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively. NGLs interact with the abundant postsynaptic density (PSD) protein, PSD-95, and other postsynaptic proteins, including NMDA receptors. These interactions are thought to couple synaptic adhesion events to the assembly of synaptic proteins. In addition, NGL proteins regulate axonal outgrowth and lamina-specific dendritic segmentation, suggesting that the NGL-dependent adhesion system is important for the development of axons, dendrites, and synapses. Consistent with these functions, defects in NGLs and their ligands are associated with impaired learning and memory, hyperactivity, and an abnormal acoustic startle response in transgenic mice, and schizophrenia, bipolar disorder, and Rett syndrome in human patients.
Assuntos
Moléculas de Adesão de Célula Nervosa/fisiologia , Neurônios/citologia , Neurônios/fisiologia , Proteínas/fisiologia , Sinapses/metabolismo , Animais , Proteínas de Repetições Ricas em Leucina , Modelos Biológicos , Modelos Moleculares , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/metabolismo , Moléculas de Adesão de Célula Nervosa/química , Proteínas/químicaRESUMO
Synaptic adhesion molecules regulate multiple steps of synapse formation and maturation. The great diversity of neuronal synapses predicts the presence of a large number of adhesion molecules that control synapse formation through trans-synaptic and heterophilic adhesion. We identified a previously unknown trans-synaptic interaction between netrin-G ligand-3 (NGL-3), a postsynaptic density (PSD) 95-interacting postsynaptic adhesion molecule, and leukocyte common antigen-related (LAR), a receptor protein tyrosine phosphatase. NGL-3 and LAR expressed in heterologous cells induced pre- and postsynaptic differentiation in contacting axons and dendrites of cocultured rat hippocampal neurons, respectively. Neuronal overexpression of NGL-3 increased presynaptic contacts on dendrites of transfected neurons. Direct aggregation of NGL-3 on dendrites induced coclustering of excitatory postsynaptic proteins. Knockdown of NGL-3 reduced the number and function of excitatory synapses. Competitive inhibition by soluble LAR reduced NGL-3-induced presynaptic differentiation. These results suggest that the trans-synaptic adhesion between NGL-3 and LAR regulates excitatory synapse formation in a bidirectional manner.
Assuntos
Moléculas de Adesão Celular/fisiologia , Neurônios/citologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Análise de Variância , Animais , Moléculas de Adesão Celular/genética , Diferenciação Celular/fisiologia , Células Cultivadas , Técnicas de Cocultura/métodos , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas de Fluorescência Verde/genética , Hipocampo/citologia , Humanos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Terminações Pré-Sinápticas/metabolismo , Ratos , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Receptores de Superfície Celular/genética , Sinapses/classificação , Transmissão Sináptica/genética , Transfecção/métodos , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismoRESUMO
Synaptic cell adhesion molecules (CAMs) regulate synapse formation through their trans-synaptic and heterophilic adhesion. Here we show that postsynaptic netrin-G ligand (NGL) CAMs associate with netrin-G CAMs in an isoform-specific manner and, through their cytosolic tail, with the abundant postsynaptic scaffold postsynaptic density-95 (PSD-95). Overexpression of NGL-2 in cultured rat neurons increased the number of PSD-95-positive dendritic protrusions. NGL-2 located on heterologous cells or beads induced functional presynaptic differentiation in contacting neurites. Direct aggregation of NGL-2 on the surface membrane of dendrites induced the clustering of excitatory postsynaptic proteins. Competitive inhibition by soluble NGL-2 reduced the number of excitatory synapses. NGL-2 knockdown reduced excitatory, but not inhibitory, synapse numbers and currents. These results suggest that NGL regulates the formation of excitatory synapses.