Autistic behavior in Scn1a(+/−) mice and rescue by enhanced GABAergic transmission

Haploinsufficiency of the SCN1A gene encoding voltage-gated sodium channel Na(V)1.1 causes Dravet Syndrome (DS), a childhood neuropsychiatric disorder including recurrent intractable seizures, cognitive deficit, and autism-spectrum behaviors. The neural mechanisms responsible for cognitive deficit and autism-spectrum behaviors in DS are poorly understood. Here we show that mice with Scn1a haploinsufficiency display hyperactivity, stereotyped behaviors, social interaction deficits, and impaired context-dependent spatial memory. Olfactory sensitivity is retained, but novel food odors and social odors are aversive to Scn1a(+/−) mice. GABAergic neurotransmission is specifically impaired by this mutation, and selective deletion of Na(V)1.1 channels in forebrain interneurons is sufficient to cause these behavioral and cognitive impairments. Remarkably, treatment with low-dose clonazepam, a positive allosteric modulator of GABA(A) receptors, completely rescued the abnormal social behaviors and deficits in fear memory in DS mice, demonstrating that they are caused by impaired GABAergic neurotransmission and not by neuronal damage from recurrent seizures. These results demonstrate a critical role for Na(V)1.1 channels in neuropsychiatric functions and provide a potential therapeutic strategy for cognitive deficit and autism-spectrum behaviors in DS.