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 Potter, John L. Rubenstein, Todd Scheuer, Horacio O. De La Iglesia, William A. Catterall

Research output: Contribution to journalArticle

274 Citations (Scopus)

Abstract

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
JournalNature
Volume489
Issue number7416
DOIs
StatePublished - Sep 20 2012
Externally publishedYes

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Myoclonic Epilepsy
Synaptic Transmission
gamma-Aminobutyric Acid
Autistic Disorder
Haploinsufficiency
Seizures
Voltage-Gated Sodium Channels
Stereotyped Behavior
Clonazepam
Social Behavior
Sequence Deletion
Interneurons
GABA-A Receptors
Interpersonal Relations
Prosencephalon
Fear
Food
Genes
Odorants

ASJC Scopus subject areas

  • General

Cite this

Han, S., Tai, C., Westenbroek, R. E., Yu, F. H., Cheah, C. S., Potter, G., ... Catterall, W. A. (2012). Autistic-like behaviour in Scn1a +- mice and rescue by enhanced GABA-mediated neurotransmission. Nature, 489(7416), 385-390. https://doi.org/10.1038/nature11356

Autistic-like behaviour in Scn1a +- mice and rescue by enhanced GABA-mediated neurotransmission. / Han, Sung; Tai, Chao; Westenbroek, Ruth E.; Yu, Frank H.; Cheah, Christine S.; Potter, Gregory; Rubenstein, John L.; Scheuer, Todd; De La Iglesia, Horacio O.; Catterall, William A.

In: Nature, Vol. 489, No. 7416, 20.09.2012, p. 385-390.

Research output: Contribution to journalArticle

Han, S, Tai, C, Westenbroek, RE, Yu, FH, Cheah, CS, Potter, G, Rubenstein, JL, Scheuer, T, De La Iglesia, HO & Catterall, WA 2012, 'Autistic-like behaviour in Scn1a +- mice and rescue by enhanced GABA-mediated neurotransmission', Nature, vol. 489, no. 7416, pp. 385-390. https://doi.org/10.1038/nature11356
Han S, Tai C, Westenbroek RE, Yu FH, Cheah CS, Potter G et al. Autistic-like behaviour in Scn1a +- mice and rescue by enhanced GABA-mediated neurotransmission. Nature. 2012 Sep 20;489(7416):385-390. https://doi.org/10.1038/nature11356
Han, Sung ; Tai, Chao ; Westenbroek, Ruth E. ; Yu, Frank H. ; Cheah, Christine S. ; Potter, Gregory ; Rubenstein, John L. ; Scheuer, Todd ; De La Iglesia, Horacio O. ; Catterall, William A. / Autistic-like behaviour in Scn1a +- mice and rescue by enhanced GABA-mediated neurotransmission. In: Nature. 2012 ; Vol. 489, No. 7416. pp. 385-390.
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