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

Matthew D Rannals; Gregory R Hamersky; Stephanie Cerceo Page; Morganne N Campbell; Aaron Briley; Ryan A Gallo; BaDoi N Phan; Thomas M Hyde; Joel E Kleinman; Joo Heon Shin; Andrew E Jaffe; Daniel R Weinberger; Brady J Maher

doi:10.1016/j.neuron.2016.02.021

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

Neuron. 2016 Apr 6;90(1):43-55. doi: 10.1016/j.neuron.2016.02.021. Epub 2016 Mar 10.

Affiliations

¹ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA.
² Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Department of Neurology and the McKusick Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
³ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA; Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
⁴ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; Department of Neurology and the McKusick Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
⁵ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. Electronic address: brady.maher@libd.org.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics*
CRISPR-Cas Systems
DNA-Binding Proteins / genetics*
Disease Models, Animal
Electroporation
Facies
Female
Gene Expression Regulation, Developmental
Genetic Predisposition to Disease
Haploinsufficiency
Hyperventilation / genetics*
Intellectual Disability / genetics*
KCNQ1 Potassium Channel / genetics*
Mice
NAV1.8 Voltage-Gated Sodium Channel / genetics*
Patch-Clamp Techniques
Prefrontal Cortex / embryology
Prefrontal Cortex / metabolism*
Pregnancy
RNA, Messenger / metabolism*
RNA, Small Interfering
Rats
Rats, Wistar
Schizophrenia / genetics
Transcription Factor 4
Transcription Factors / genetics*

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
DNA-Binding Proteins
KCNQ1 Potassium Channel
NAV1.8 Voltage-Gated Sodium Channel
RNA, Messenger
RNA, Small Interfering
Tcf4 protein, mouse
Tcf4 protein, rat
Transcription Factor 4
Transcription Factors

Supplementary concepts

Pitt-Hopkins syndrome

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

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding