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2.
Commun Biol ; 5(1): 838, 2022 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-35982261

RESUMO

IRSp53 (or BAIAP2) is an abundant excitatory postsynaptic scaffolding/adaptor protein that is involved in actin regulation and has been implicated in autism spectrum disorders, schizophrenia, and attention-deficit/hyperactivity disorder. IRSp53 deletion in mice leads to enhanced NMDA receptor (NMDAR) function and social deficits that are responsive to NMDAR inhibition. However, it remains unclear whether IRSp53 re-expression in the adult IRSp53-mutant mouse brain after the completion of brain development could reverse these synaptic and behavioral dysfunctions. Here we employed a brain-blood barrier (BBB)-penetrant adeno-associated virus (AAV) known as PHP.eB to drive adult IRSp53 re-expression in IRSp53-mutant mice. The adult IRSp53 re-expression normalized social deficits without affecting hyperactivity or anxiety-like behavior. In addition, adult IRSp53 re-expression normalized NMDAR-mediated excitatory synaptic transmission in the medial prefrontal cortex. Our results suggest that adult IRSp53 re-expression can normalize synaptic and behavioral deficits in IRSp53-mutant mice and that BBB-penetrant adult gene re-expression has therapeutic potential.


Assuntos
N-Metilaspartato , Proteínas do Tecido Nervoso/metabolismo , Receptores de N-Metil-D-Aspartato , Animais , Camundongos , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais , Comportamento Social , Transmissão Sináptica
3.
Nat Commun ; 12(1): 2695, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976205

RESUMO

mTOR signaling, involving mTORC1 and mTORC2 complexes, critically regulates neural development and is implicated in various brain disorders. However, we do not fully understand all of the upstream signaling components that can regulate mTOR signaling, especially in neurons. Here, we show a direct, regulated inhibition of mTOR by Tanc2, an adaptor/scaffolding protein with strong neurodevelopmental and psychiatric implications. While Tanc2-null mice show embryonic lethality, Tanc2-haploinsufficient mice survive but display mTORC1/2 hyperactivity accompanying synaptic and behavioral deficits reversed by mTOR-inhibiting rapamycin. Tanc2 interacts with and inhibits mTOR, which is suppressed by mTOR-activating serum or ketamine, a fast-acting antidepressant. Tanc2 and Deptor, also known to inhibit mTORC1/2 minimally affecting neurodevelopment, distinctly inhibit mTOR in early- and late-stage neurons. Lastly, Tanc2 inhibits mTORC1/2 in human neural progenitor cells and neurons. In summary, our findings show that Tanc2 is a mTORC1/2 inhibitor affecting neurodevelopment.


Assuntos
Encéfalo/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Neurônios/metabolismo , Proteínas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Células Cultivadas , Células HEK293 , Humanos , Imunossupressores/farmacologia , Deficiências da Aprendizagem/genética , Deficiências da Aprendizagem/fisiopatologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/genética , Transtornos da Memória/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Proteínas/genética , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia
4.
Front Mol Neurosci ; 12: 241, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31680851

RESUMO

Mutations in Tbr1, a high-confidence ASD (autism spectrum disorder)-risk gene encoding the transcriptional regulator TBR1, have been shown to induce diverse ASD-related molecular, synaptic, neuronal, and behavioral dysfunctions in mice. However, whether Tbr1 mutations derived from autistic individuals cause similar dysfunctions in mice remains unclear. Here we generated and characterized mice carrying the TBR1-K228E de novo mutation identified in human ASD and identified various ASD-related phenotypes. In heterozygous mice carrying this mutation (Tbr1 +/K228E mice), levels of the TBR1-K228E protein, which is unable to bind target DNA, were strongly increased. RNA-Seq analysis of the Tbr1 +/K228E embryonic brain indicated significant changes in the expression of genes associated with neurons, astrocytes, ribosomes, neuronal synapses, and ASD risk. The Tbr1 +/K228E neocortex also displayed an abnormal distribution of parvalbumin-positive interneurons, with a lower density in superficial layers but a higher density in deep layers. These changes were associated with an increase in inhibitory synaptic transmission in layer 6 pyramidal neurons that was resistant to compensation by network activity. Behaviorally, Tbr1 +/K228E mice showed decreased social interaction, increased self-grooming, and modestly increased anxiety-like behaviors. These results suggest that the human heterozygous TBR1-K228E mutation induces ASD-related transcriptomic, protein, neuronal, synaptic, and behavioral dysfunctions in mice.

5.
Neuron ; 81(3): 629-40, 2014 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-24412418

RESUMO

The organization of synaptic connectivity within a neuronal circuit is a prime determinant of circuit function. We performed a comprehensive fine-scale circuit mapping of hippocampal regions (CA3-CA1) using the newly developed synapse labeling method, mGRASP. This mapping revealed spatially nonuniform and clustered synaptic connectivity patterns. Furthermore, synaptic clustering was enhanced between groups of neurons that shared a similar developmental/migration time window, suggesting a mechanism for establishing the spatial structure of synaptic connectivity. Such connectivity patterns are thought to effectively engage active dendritic processing and storage mechanisms, thereby potentially enhancing neuronal feature selectivity.


Assuntos
Dendritos/fisiologia , Hipocampo/citologia , Neurônios/fisiologia , Sinapses/fisiologia , Animais , Mapeamento Encefálico , Análise por Conglomerados , Dendritos/ultraestrutura , Eletroporação , Hipocampo/anatomia & histologia , Imageamento Tridimensional , Técnicas In Vitro , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Modelos Neurológicos , Neurônios/ultraestrutura , Lectinas de Plantas/metabolismo , Estatística como Assunto , Estatísticas não Paramétricas
6.
Cell Mol Life Sci ; 70(24): 4747-57, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23864031

RESUMO

Mapping mammalian synaptic connectivity has long been an important goal of neuroscientists since it is considered crucial for explaining human perception and behavior. Yet, despite enormous efforts, the overwhelming complexity of the neural circuitry and the lack of appropriate techniques to unravel it have limited the success of efforts to map connectivity. However, recent technological advances designed to overcome the limitations of conventional methods for connectivity mapping may bring about a turning point. Here, we address the promises and pitfalls of these new mapping technologies.


Assuntos
Conectoma/métodos , Sinapses/fisiologia , Animais , Encéfalo/anatomia & histologia , Encéfalo/fisiologia , Biologia Computacional , Humanos , Mamíferos , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/fisiopatologia
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