Hypermorphic mutation of the voltage-gated sodium channel encoding gene Scn10a causes a dramatic stimulus-dependent neurobehavioral phenotype

Abstract

The 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 of Scn10a encoding the α-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 schizophrenic 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.

Heterochronicity of white matter development and aging explains regional patient control differences in schizophrenia

“…The findings were interpreted as potentially reduced myelin level or abnormalities in trans-membrane ion channels. This is consistent with reports of reduced axonal myelin levels and glial cells density by postmortem brain studies (Tkachev, et al 2003; Uranova, et al 2001; Uranova, et al 2011; Uranova, et al 2004) and findings from cellular neurobiology and genetic discovery studies (Blasius, et al 2011; Freedman, et al 2000; Huffaker, et al 2009; Meyer, et al 2001; Smolin, et al 2011; Smoller, et al 2013). Further analyses are needed to clarify the biological factors that underwrite the findings of reduced FA values in this disorder.…”

Multimodal white matter imaging to investigate reduced fractional anisotropy and its age-related decline in schizophrenia

“…Gray matter PDI measurements were unrelated to the HWM volume burden in either group ( p >0.3), suggsting that the finding of a PDI correlation with FA in patients may reflect the sensitivity of both indices to a malleable component of schizophrenia instead of being due to a direct biophysical linkage. Schizophrenia is associated with structural abnormalities in ion channel proteins and reduced densities of trans-membrane ion channels (Freedman et al, 2000; Meyer et al, 2001; Huffaker et al, 2009; Blasius et al, 2011; Smolin et al, 2011; Smoller et al, 2013). FA measurements in white matter and PDI measurements in both white and gray matter are perhaps both sensitive to these abnormalities.…”

Functional Na V 1.8 Channels in Intracardiac Neurons

“…Interesting in this respect is the finding that mice carrying the Possum mutation in SCN10A, which enhances Na V 1.8 sodium currents and neuronal excitability, respond to "scruffing" not only with a characteristic transient whole-body tonic immobility but also with marked sinus bradycardia and R-R variability, which was probably due to increased vagal tone and could be abrogated by infusion of the anticholinergic agent atropine. 31 This potential mechanism of Na V 1.8-mediated control of cardiac electrophysiological properties will require future additional detailed investigations.…”