TY - JOUR
T1 - Psychiatric Risk Gene Transcription Factor 4 Regulates Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1
AU - Rannals, Matthew D D.
AU - Hamersky, Gregory R R.
AU - Page, Stephanie Cerceo C.
AU - Campbell, Morganne N N.
AU - Briley, Aaron
AU - Gallo, Ryan A A.
AU - Phan, Ba Doi N
AU - Hyde, Thomas M M.
AU - Kleinman, Joel E E.
AU - Shin, Joo Heon H.
AU - Jaffe, Andrew E E.
AU - Weinberger, Daniel R R.
AU - Maher, Brady J J.
N1 - Funding Information:
We are grateful for the vision and generosity of the Lieber and Maltz families, who made this work possible. We thank the families who donated to this research. Human brain material was acquired from the Offices of the Chief Medical Examiner of the District of Columbia, and of the Commonwealth of Virginia, Northern District, the National Institute of Child and Health Development Brain and Tissue Bank, and processed and stored at the NIH Clinical Center in Bethesda, Maryland. We thank M. Sepp and T. Timmusk for TCF4B expression construct; N. Heintz for L10a-EGFP construct; T.-P. Su for B104 cells; and J. LoTurco for mu6 pro construct. This work was supported by the Lieber Institute, NIH (K01MH086050 and R56MH104593), NARSAD Young Investigator Award, and Pitt-Hopkins Research Foundation Award to B.J.M.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/4/6
Y1 - 2016/4/6
N2 - 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.
AB - 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.
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U2 - 10.1016/j.neuron.2016.02.021
DO - 10.1016/j.neuron.2016.02.021
M3 - Article
C2 - 26971948
AN - SCOPUS:84959887346
SN - 0896-6273
VL - 90
SP - 43
EP - 55
JO - Neuron
JF - Neuron
IS - 1
ER -