| 1 | Proc. Natl. Acad. Sci. U.S.A. 2011 Nov 108: 19413-8 |
|---|---|
| PMID | 22087007 |
| Title | Hypermorphic mutation of the voltage-gated sodium channel encoding gene Scn10a causes a dramatic stimulus-dependent neurobehavioral phenotype. |
| Abstract | 的voltage-gated sodium channel Na(v)1.8 is known to function in the transmission of pain signals induced by cold, heat, and mechanical stimuli. Sequence variants of human Na(v)1.8 have been linked to altered cardiac conduction. We identified an allele ofSCN10Aencoding the ?-subunit of Na(v)1.8 among mice homozygous for N-ethyl-N-nitrosourea-induced mutations. The allele creates a dominant neurobehavioral phenotype termed Possum, characterized by transient whole-body tonic immobility induced by pinching the skin at the back of the neck ("scruffing"). The Possum mutation enhanced Na(v)1.8 sodium currents and neuronal excitability and heightened sensitivity of mutants to cold stimuli. Striking electroencephalographic changes were observed concomitant with the scruffing-induced behavioral change. In addition, electrocardiography demonstrated that Possum mice exhibited marked sinus bradycardia and R-R variability upon scruffing, abrogated by infusion of atropine. However, atropine failed to prevent or mitigate the tonic immobility response. Hyperactive sodium conduction via Na(v)1.8 thus leads to a complex neurobehavioral phenotype, which resembles catatonia in精神分裂症humans and tonic immobility in other mammals upon application of a discrete stimulus; no other form of mechanosensory stimulus could induce the immobility phenotype. Our data confirm the involvement of Na(v)1.8 in transducing pain initiated by cold and additionally implicate Na(v)1.8 in previously unknown functions in the central nervous system and heart. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Neuron 2016 Apr 90: 43-55 |
| PMID | 26971948 |
| Title | Psychiatric Risk Gene Transcription Factor 4 Regulates Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1. |
| Abstract | Transcription Factor 4 (TCF4) is a clinically pleiotropic gene associated withschizophreniaand 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 andSCN10A. 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 andSCN10Aand suggest that this molecular function may underlie pathophysiology associated with neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |