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. 2018 Apr:112:24-34.
doi: 10.1016/j.nbd.2018.01.009. Epub 2018 Jan 11.

Impairments in social novelty recognition and spatial memory in mice with conditional deletion of Scn1a in parvalbumin-expressing cells

Tetsuya Tatsukawa  1 , Ikuo Ogiwara  2 , Emi Mazaki  1 , Atsushi Shimohata  1 , Kazuhiro Yamakawa  3
Affiliations

Impairments in social novelty recognition and spatial memory in mice with conditional deletion of Scn1a in parvalbumin-expressing cells

Tetsuya Tatsukawa et al. Neurobiol Dis. 2018 Apr.

Abstract

Loss of function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel Nav1.1, have been described in the majority of Dravet syndrome patients presenting with epileptic seizures, hyperactivity, autistic traits, and cognitive decline. We previously reported predominant Nav1.1 expression in parvalbumin-expressing (PV+) inhibitory neurons in juvenile mouse brain and observed epileptic seizures in mice with selective deletion of Scn1a in PV+ cells mediated by PV-Cre transgene expression (Scn1afl/+/PV-Cre-TG). Here we investigate the behavior of Scn1afl/+/PV-Cre-TG mice using a comprehensive battery of behavioral tests. We observed that Scn1afl/+/PV-Cre-TG mice display hyperactive behavior, impaired social novelty recognition, and altered spatial memory. We also generated Scn1afl/+/SST-Cre-KI mice with a selective Scn1a deletion in somatostatin-expressing (SST+) inhibitory neurons using an SST-IRES-Cre knock-in driver line. We observed that Scn1afl/+/SST-Cre-KI mice display no spontaneous convulsive seizures and that Scn1afl/+/SST-Cre-KI mice have a lowered threshold temperature for hyperthermia-induced seizures, although their threshold values are much higher than those of Scn1afl/+/PV-Cre-TG mice. We finally show that Scn1afl/+/SST-Cre-KI mice exhibited no noticeable behavioral abnormalities. These observations suggest that impaired Nav1.1 function in PV+ interneurons is critically involved in the pathogenesis of hyperactivity, autistic traits, and cognitive decline, as well as epileptic seizures, in Dravet syndrome.

Keywords: Autism spectrum disorder; Conditional knockout mouse model; Dravet syndrome; Epilepsy; Hyperactivity; Interneuron; Parvalbumin; Scn1a; Somatostatin.

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