Mice Lacking Sodium Channel β1 Subunits Display Defects in Neuronal Excitability, Sodium Channel Expression, and Nodal Architecture

Abstract

Sodium channel ␤1 subunits modulate ␣ subunit gating and cell surface expression and participate in cell adhesive interactions in vitro. ␤1 (Ϫ/Ϫ) mice appear ataxic and display spontaneous generalized seizures. In the optic nerve, the fastest components of the compound action potential are slowed and the number of mature nodes of Ranvier is reduced, but Na v 1.6, contactin, caspr 1, and K v 1 channels are all localized normally at nodes. At the ultrastructural level, the paranodal septate-like junctions immediately adjacent to the node are missing in a subset of axons, suggesting that ␤1 may participate in axo-glial communication at the periphery of the nodal gap. Sodium currents in dissociated hippocampal neurons are normal, but Na v 1.1 expression is reduced and Na v 1.3 expression is increased in a subset of pyramidal neurons in the CA2/CA3 region, suggesting a basis for the epileptic phenotype. Our results show that ␤1 subunits play important roles in the regulation of sodium channel density and localization, are involved in axo-glial communication at nodes of Ranvier, and are required for normal action potential conduction and control of excitability in vivo.

Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

“…Consistent with previous studies of Scn1b null hippocampal and cerebellar Purkinje neurons [12,26], no significant differences were detected in the voltage-dependence of sodium channel activation or inactivation (Fig. 2B), time-course of inactivation (Fig.…”

“…We showed previously, using Scn1b null mice, that β1 plays important roles in the regulation of neuronal excitability in vivo [12]. In the present study, we used Scn1b null mice to investigate the role of β1 in cardiac excitability.…”

“…Scn1b null and wildtype mice were generated from Scn1b heterozygotes as described [12]. All procedures were performed in accordance with University of Michigan guidelines for animal use and care.…”

“…Total RNA was prepared from each sample using Trizol reagent (Invitrogen, Carlsbad, CA), according to the manufacturer's instructions. Northern blots were prepared and probed with a digoxigenin-labeled antisense Scn1b probe as previously described [12].…”

“…In view of the neurological effects resulting from the loss of β1 expression [12], it was possible that the altered ECG waveform of Scn1b null mice resulted from impaired cardiac innervation. To examine this, ECGs were recorded following administration of propranolol and atropine to block β-adrenergic and muscarinic receptors, respectively [28].…”