Unexpected synaptic role for the autism risk gene Scn2a

Late-developing impairment in Scn2a-dependent dendritic excitability. This graph shows the rate of membrane potential depolarization as a function of developmental age. The top curve is derived from measurements of wild-type mice and the lower curve is derived from measurements of mice with a constitutive deletion of one copy of Scn2a (Scn2a+/-). The purple dots represent measurements of mice with a conditional deletion of one copy of Scn2a after postnatal day 10 (Scn2a+/fl::CaMKIIa-Cre). The black dots represent measurements of littermate mice that do not carry the cre recombinase (Cre-). Note the overlap between the conditional Scn2a mice and the wild-type developmental curve at P18 and the eventual overlap with the Scn2a+/- curve after P50; thus, these mice developed without early deficits in axonal excitability and exhibited impaired dendritic excitability only later in development. Image adapted from Spratt P.W.E. et al. (2019).

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.


The autism-associated gene Scn2a contributes to dendritic excitability and synaptic function in the prefrontal cortex.

Spratt P.W.E., Ben-Shalom R., Keeshen C.M., Burke Jr. K.J., Clarkson R.L., Sanders S., Bender K.

Neuron 103, 673-685 (August 20, 2019) PubMed

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