Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Más filtros

Banco de datos
Tipo del documento
País de afiliación
Intervalo de año de publicación
1.
Cell ; 148(5): 1051-64, 2012 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-22385968

RESUMEN

How extrinsic stimuli and intrinsic factors interact to regulate continuous neurogenesis in the postnatal mammalian brain is unknown. Here we show that regulation of dendritic development of newborn neurons by Disrupted-in-Schizophrenia 1 (DISC1) during adult hippocampal neurogenesis requires neurotransmitter GABA-induced, NKCC1-dependent depolarization through a convergence onto the AKT-mTOR pathway. In contrast, DISC1 fails to modulate early-postnatal hippocampal neurogenesis when conversion of GABA-induced depolarization to hyperpolarization is accelerated. Extending the period of GABA-induced depolarization or maternal deprivation stress restores DISC1-dependent dendritic regulation through mTOR pathway during early-postnatal hippocampal neurogenesis. Furthermore, DISC1 and NKCC1 interact epistatically to affect risk for schizophrenia in two independent case control studies. Our study uncovers an interplay between intrinsic DISC1 and extrinsic GABA signaling, two schizophrenia susceptibility pathways, in controlling neurogenesis and suggests critical roles of developmental tempo and experience in manifesting the impact of susceptibility genes on neuronal development and risk for mental disorders.


Asunto(s)
Proteínas del Tejido Nervioso/metabolismo , Neurogénesis , Esquizofrenia/metabolismo , Transducción de Señal , Ácido gamma-Aminobutírico/metabolismo , Animales , Dendritas/metabolismo , Susceptibilidad a Enfermedades , Femenino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/genética , Esquizofrenia/genética , Análisis de la Célula Individual , Simportadores de Cloruro de Sodio-Potasio/genética , Simportadores de Cloruro de Sodio-Potasio/metabolismo , Miembro 2 de la Familia de Transportadores de Soluto 12
2.
J Clin Invest ; 123(7): 2961-4, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23921125

RESUMEN

Hippocampal development is coordinated by both extracellular factors like GABA neurotransmission and intracellular components like DISC1. We previously reported that SLC12A2-dependent GABA depolarization and DISC1 coregulate hippocampal neuronal development, and 2 SNPs in these genes linked to mRNA expression interactively increase schizophrenia risk. Using functional MRI, we now confirm this biological interaction in vivo by showing in 2 independent samples of healthy individuals (total N = 349) that subjects homozygous for both risk alleles evince dramatically decreased hippocampal area activation (Cohen's d = 0.78)and connectivity (d = 0.57) during a recognition memory task. These data highlight the importance of epistatic models in understanding genetic association with complex brain phenotypes.


Asunto(s)
Hipocampo/fisiopatología , Proteínas del Tejido Nervioso/genética , Simportadores de Cloruro de Sodio-Potasio/genética , Adolescente , Adulto , Conectoma , Epistasis Genética , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Persona de Mediana Edad , Proteínas del Tejido Nervioso/metabolismo , Giro Parahipocampal/fisiopatología , Polimorfismo de Nucleótido Simple , Esquizofrenia/genética , Esquizofrenia/fisiopatología , Simportadores de Cloruro de Sodio-Potasio/metabolismo , Miembro 2 de la Familia de Transportadores de Soluto 12 , Adulto Joven
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA