Abstracts

Rationale: The voltage-gated sodium channel α-subunit Na_V1.6 (Scn8a) is one of the most abundantly expressed sodium channels in the adult central nervous system. Mice with one allele of the motor endplate disease (Med) mutation in Scn8a are phenotypically normal, but have elevated seizure thresholds and reduced seizure susceptibility. Methods: To investigate the contribution of Na_V1.6 in reducing excitability of the neuronal circuits that underlie seizure generation, we analyzed extracellular recordings in Mg²⁺-free ACSF from the hippocampal CA1 layer of Scn8a^Med/+ mice. To elucidate the synaptic function in these animals, we recorded spontaneous inhibitory post-synaptic current (sIPSC) and spontaneous excitatory post-synaptic current (sEPSC) from visually identified CA1 pyramidal neurons in hippocampal slices prepared from Scn8a^Med/+ mice. Results: We observed a reduction in spontaneous activity in Scn8a^Med/+ mice compared to age-matched controls in Mg2+-free ACSF. Activity-dependent sIPSC frequency was decreased in Scn8a^Med/+ mice, suggesting decreased sodium channel activity in inhibitory neurons. Because Na_V1.6 is also expressed in CA1 pyramidal cells, we predict that there will be decreased frequency of sEPSC, which we are now testing. Conclusions: These data indicate that a global decrease in synaptic activity in the hippocampus may contribute to reduced seizure susceptibility in Scn8a^Med/+ mice, and suggest that specific inhibition of Na_V1.6 could be a promising therapeutic strategy as a treatment for epilepsy.