Pyramidal Neuron Axon Initial Segment Dysregulation in Nav β1 Subunit Epilepsy: A Tip of the Iceberg.

Commentary Voltage-gated sodium channels (Nav) are composed of multi-subunit protein complexes, and their density becomes greatest at the axon initial segment where action potentials initiate. Mutations of the Nav β1 subunit (encoded by the SCN1B gene) are associated with genetic (generalized) epilepsy with febrile seizures (FS) plus (GEFS+) in a subset of patients with GEFS+. Wimmer et al. have now reported a new mouse model of human familial epilepsy resulting from a GEFS+ epilepsy-associated mutation (C121W, adjacent to an Ig-like extracellular loop) and reconstitute febrile seizure susceptibility (1). Of interest, an adjacent β1-subunit mutation, R125C, was recently found to be homozygous in a patient with Dravet syndrome (severe myoclonic epilepsy of infancy, SMEI). As the vast majority of SMEI patients display haploid insufficiency of α subunit Nav1.1, and many GEFS+ patients display α-subunit Nav1.1 mutations, Occam's razor or the law of parsimony would suggest that all Nav mutations, whether of the Nav1.1 α or even the β1 subunit, should generate epilepsy through a common mechanism (2). This common mechanism was discovered during studies of mice with an α-subunit Nav1.1 haploid insufficiency; GABAergic inhibitory, but not glutamatergic pyramidal, neurons in the hippocam-pus are uniquely dependent on Nav1.1 and therefore display impaired Nav current and a failure to sustain high action potential firing rates even when missing half of the normal number of channels (3, 4). Occam's razor might in this case be a Gillette twin blade, since β1-subunit knockout mice failed to identify defects in Nav currents of hippocampal GABAergic neurons, suggesting that α-(Nav1.1) and β1-subunit mutations might cause GEFS+ and SMEI through distinct mechanisms (5). Patino et al. (5) focused on GABAergic neurons from the hippocampal CA3 region, where β1-subunit defects did lead to a loss of Nav1.1 protein staining and a compensatory increase of Nav1.3 (6). They found that the sodium currents of GABAergic neurons from CA3 were unaltered while pyramidal neurons displayed an increased peak voltage and amplitude of sodium action potentials, suggesting a possible increased excitability of pyramidal neurons rather than a decreased excitability of GABAergic neurons. Wimmer et al. extended this finding, reporting that mice engineered with the Nav β1-subunit mutation C121W displayed increases in subiculum pyramidal neuron excitability (1). Intriguingly, they also provided evidence for a temperature sensitive increase of AIS excitability. While this new finding should be factored into the potential circuit changes that might contribute to seizure susceptibility in these patients, one must …