Psychiatric Risk Gene Transcription Factor 4 Regulates Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1

被引：74

作者：

Rannals, Matthew D. ^{[1
]}

Hamersky, Gregory R. ^{[1
]}

Page, Stephanie Cerceo ^{[1
]}

Campbell, Morganne N. ^{[1
]}

Briley, Aaron ^{[1
]}

Gallo, Ryan A. ^{[1
]}

Phan, Badoi N. ^{[1
]}

Hyde, Thomas M. ^{[1
,2
,6
,7
]}

Kleinman, Joel E. ^{[1
,2
,6
,7
]}

Shin, Joo Heon ^{[1
]}

Jaffe, Andrew E. ^{[1
,4
,5
]}

Weinberger, Daniel R. ^{[1
,2
,3
,6
,7
]}

Maher, Brady J. ^{[1
,2
,3
]}

机构：

[1] Lieber Inst Brain Dev, Johns Hopkins Med Campus, Baltimore, MD 21205 USA

[2] Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA

[3] Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD 21205 USA

[4] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA

[5] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21205 USA

[6] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD 21205 USA

[7] Johns Hopkins Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA

来源：

NEURON | 2016年 / 90卷 / 01期

关键词：

PITT-HOPKINS-SYNDROME; HIPPOCAMPAL PYRAMIDAL CELLS; ROOT GANGLION NEURONS; ADULT HUMAN BRAIN; SLOW AFTERHYPERPOLARIZATION; INTRACELLULAR CALCIUM; POTASSIUM CHANNELS; WORKING-MEMORY; TCF4; GENE; SCHIZOPHRENIA;

D O I：

10.1016/j.neuron.2016.02.021

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 after-hyperpolarization. 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.

引用

页码：43 / 55

页数：13

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