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

Sung Han, Chao Tai, Ruth E. Westenbroek, Frank H. Yu, Christine S. Cheah, Gregory B. Potter, John L. Rubenstein, Todd Scheuer, Horacio O. De La Iglesia, William A. Catterall

    Research output: Contribution to journalArticlepeer-review

    363 Scopus citations


    Haploinsufficiency of the SCN1A gene encoding voltage-gated sodium channel Na V 1.1 causes Dravets 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 Dravets 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 Dravets 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 Dravets syndrome.

    Original languageEnglish (US)
    Pages (from-to)385-390
    Number of pages6
    Issue number7416
    StatePublished - Sep 20 2012

    ASJC Scopus subject areas

    • General


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