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 ␤-subunits modulate channel gating, assembly, and cell surface expression in heterologous cell systems. We generated ␤2 ؊/؊ mice to investigate the role of ␤2 in control of sodium channel density, localization, and function in neurons in vivo. Measurements of [ 3 H]saxitoxin (STX) binding showed a significant reduction in the level of plasma membrane sodium channels in ␤2 ؊/؊ neurons. The loss of ␤2 resulted in negative shifts in the voltage dependence of inactivation as well as significant decreases in sodium current density in acutely dissociated hippocampal neurons. The integral of the compound action potential in optic nerve was significantly reduced, and the threshold for action potential generation was increased, indicating a reduction in the level of functional plasma membrane sodium channels. In contrast, the conduction velocity, the number and size of axons in the optic nerve, and the specific localization of Na v1.6 channels in the nodes of Ranvier were unchanged. ␤2 ؊/؊ mice displayed increased susceptibility to seizures, as indicated by reduced latency and threshold for pilocarpine-induced seizures, but seemed normal in other neurological tests. Our observations show that ␤2-subunits play an important role in the regulation of sodium channel density and function in neurons in vivo and are required for normal action potential generation and control of excitability.auxiliary subunits ͉ gene targeting ͉ epilepsy ͉ action potential conduction

To elucidate the role of axonal plasma membrane factors in the differentiation of Schwann cells, we investigated the effect of an axolemma-enriched fraction (AEF) isolated from myelinated CNS tissue on the expression of P0 glycoprotein, the major glycoprotein in peripheral myelin, in primary rat Schwann cells (PSC) isolated from sciatic nerve, as well as in a transfected rat Schwann cell line (TSC). AEF increased PO-mRNA levels in PSC and TSC in a concentration-dependent manner, producing a maximal induction of nearly twofold after 48 hr of treatment. A similar induction of P0 mRNA was elicited in TSC by the cAMP-activating agents 8-bromo-cAMP and forskolin, which have been shown to induce myelin proteins in PSC. In addition to inducing P0 mRNA, AEF and forskolin also increased the amount of P0 protein in TSC, as indicated by increased P0-immunoreactive staining. However, in TSC, axolemma caused no increase in expression of CAT linked to a P0 promoter while forskolin caused a marked increase in the expression from the P0 promoter. These results suggest that AEF, in contrast to forskolin, does not regulate P0-mRNA expression at the level of transcriptional activity. These in vitro systems may be useful for the study of axolemmal factors that induce Schwann cell differentiation.