SCN2A, encoding the NaV1.2 voltage-gated sodium channel α subunit, is one of the more frequently mutated genes in individuals with autism. Its restricted expression to the axon initial segment in glutamatergic neurons relatively early in development has suggested that its key role must be in the early initiation and propagation of action potentials.
Now, SFARI Investigators Kevin Bender and Stephan Sanders have shown that Scn2a has broader and more persistent neuronal functions, including roles in regulating dendritic excitability and synaptic plasticity in mature pyramidal neurons.
In the new work — partly funded by a SFARI Pilot Award — the team showed that layer 5b neurons in slice preparations of medial prefrontal cortex from Scn2a heterozygous mice had slower action potentials in somatodendritic compartments of the cells. Synaptic function was also impaired in postnatal mice, with miniature excitatory postsynaptic currents reduced by 48 percent in Scn2a heterozygotes. By using a mouse line with conditional deletion of one copy of Scn2a only after postnatal day 10, Bender and colleagues showed that impaired dendritic excitability is sufficient to alter synaptic strength in the absence of early deficits in axonal excitability.
By establishing these roles for NaV1.2 in the dendrites of mature neurons, the investigators show that it has similar roles to many other ‘synaptic’ players in autism and also suggest that restoring function of this sodium channel relatively late in development may be a plausible therapeutic option.