Cognitive and social impairment in mouse models mirrors dravet syndrome.

Commentary Dravet syndrome is an infant-onset epileptic encephalopathy characterized by generalized clonic, tonic–clonic, or hemi-clonic seizures. Patients subsequently develop other types of seizures, including myoclonic, absence, or partial seizures. Seizures are often refractory to conventional antiepileptic drugs and lack ofadequate seizure control is correlated with poor outcomes. Development is normal prior to seizure onset, but once seizures begin, there is disease progression accompanied by a decline of cognitive development and often by autistic-like behaviors (1, 2). The most commonly reported behavioral co-morbidities are poor language ability, hyperactivity, and impaired social behavior (3). Two mouse models of Dravet syndrome were recently evaluated for comorbid cognitive and behavioral deficits.Like Behavior in Scn1a +/-Mice and Rescue by Enhanced GABA-Mediated Neurotransmission [published online ahead of print]. Haploinsufficiency of the SCN1A gene encoding voltage-gated sodium channel NaV1.1 causes Dravet syndrome, a childhood neuropsychiatric disorder that includes recurrent intractable seizures, cognitive deficit, and autism-spectrum behaviors. The neural mechanisms responsible for cognitive deficit and autism-spectrum behaviors in Dravet syndrome are poorly understood. Here, the authors report that mice with SCN1A haploinsufficiency exhibit 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 NaV1.1 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 abnormal social behaviors and deficits in fear memory in the mouse model of Dravet syndrome, demonstrating that they are caused by impaired GABAergic neurotransmis-sion and not by neuronal damage from recurrent seizures. These results demonstrate a critical role for NaV1.1 channels in neuropsychiatric functions and provide a potential therapeutic strategy for cognitive deficit and autism-spectrum behaviors in Dravet syndrome. Dravet syndrome is an intractable epileptic encephalopathy characterized by early onset epileptic seizures and followed by cognitive decline, hyperactivity, autistic behaviors, and ataxia. Most Dravet syndrome patients possess het-erozygous mutations in SCN1A gene encoding voltage-gated sodium channel α I subunit (NaV1.1). We have previously reported that mice heterozygous for a nonsense mutation in SCN1A develop early onset epileptic seizures. However, the learning ability and sociability of the mice remained to be investigated. In the present study, we subjected hetero-zygous SCN1A mice to a comprehensive behavioral test battery. We found that while heterozygous SCN1A mice had lowered spontaneous motor …