Autistic-like behaviour in Scn1a+/− mice and rescue by enhanced GABA-mediated neurotransmission

Haploinsufficiency of the SCN1A gene encoding voltage-gated sodium channel Na V 1.1 causes Dravet’s syndrome, a childhood neuropsychiatric disorder including recurrent intractable seizures, cognitive deficit and autism-spectrum behaviours. The neural mechanisms responsible for cognitive deficit and autism-spectrum behaviours in Dravet’s syndrome are poorly understood. Here we report that mice with Scn1a haploinsufficiency exhibit hyperactivity, stereotyped behaviours, social interaction deficits and impaired context-dependent spatial memory. Olfactory sensitivity is retained, but novel food odours and social odours 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 behavioural and cognitive impairments. Remarkably, treatment with low-dose clonazepam, a positive allosteric modulator of GABA A receptors, completely rescued the abnormal social behaviours and deficits in fear memory in the mouse model of Dravet’s syndrome, 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 behaviours in Dravet’s syndrome. Haploinsufficiency of the gene SCN1A ( SCN1A +/− ) causes Dravet’s syndrome in humans, a form of epilepsy with autistic features; this paper shows that Scn1a +/− mice have the same symptoms, and that social behaviours can be improved by pharmacological treatment with clonazepam. Sodium-channel mutant linked to autism Haploinsufficiency of the gene SCN1A, which encodes a voltage-gated sodium channel, causes Dravet’s syndrome, a form of childhood epilepsy that sometimes includes autistic features. This paper shows that mice with Scn1a haploinsufficiency also display autism-related behaviours, including hyperactivity and impaired social interaction. GABAergic neurotransmission is reduced in these mice, and social behaviours can be improved by pharmacological treatment with clonazepam.