Psychiatric Risk Gene Transcription Factor 4 Regulates Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1.
Neuron
; 90(1): 43-55, 2016 Apr 06.
Article
en En
| MEDLINE
| ID: mdl-26971948
ABSTRACT
Transcription Factor 4 (TCF4) is a clinically pleiotropic gene associated with schizophrenia and Pitt-Hopkins syndrome (PTHS). To gain insight about the neurobiology of TCF4, we created an in vivo model of PTHS by suppressing Tcf4 expression in rat prefrontal neurons immediately prior to neurogenesis. This cell-autonomous genetic insult attenuated neuronal spiking by increasing the afterhyperpolarization. At the molecular level, using a novel technique called iTRAP that combined in utero electroporation and translating ribosome affinity purification, we identified increased translation of two ion channel genes, Kcnq1 and Scn10a. These ion channel candidates were validated by pharmacological rescue and molecular phenocopy. Remarkably, similar excitability deficits were observed in prefrontal neurons from a Tcf4(+/tr) mouse model of PTHS. Thus, we identify TCF4 as a regulator of neuronal intrinsic excitability in part by repression of Kcnq1 and Scn10a and suggest that this molecular function may underlie pathophysiology associated with neuropsychiatric disorders.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
ARN Mensajero
/
Corteza Prefrontal
/
Proteínas de Unión al ADN
/
Canal de Potasio KCNQ1
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice
/
Canal de Sodio Activado por Voltaje NAV1.8
/
Hiperventilación
/
Discapacidad Intelectual
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
/
Pregnancy
Idioma:
En
Revista:
Neuron
Asunto de la revista:
NEUROLOGIA
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos