Article | Published:

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

Nature volume 489, pages 385390 (20 September 2012) | Download Citation

Abstract

Haploinsufficiency of the SCN1A gene encoding voltage-gated sodium channel NaV1.1 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 NaV1.1 channels in forebrain interneurons is sufficient to cause these behavioural and cognitive impairments. Remarkably, treatment with low-dose clonazepam, a positive allosteric modulator of GABAA 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 NaV1.1 channels in neuropsychiatric functions and provide a potential therapeutic strategy for cognitive deficit and autism-spectrum behaviours in Dravet’s syndrome.

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Acknowledgements

This work was supported by Research Grants R01 NS25704 (W.A.C.), R01 MH075016 (H.O.d.) and R37 MH049428 (J.L.R.) from the National Institutes of Health and by a grant from the McKnight Foundation (W.A.C.). The authors thank E. Strakbein in the Machine Division at the University of Washington for making all the mazes for the behavioural experiments in this study.

Author information

Author notes

    • Frank H. Yu

    Present address: Program in Neurobiology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 110-749, Korea.

Affiliations

  1. Graduate Program in Neurobiology & Behavior, University of Washington, Seattle, Washington 98195, USA

    • Sung Han
    • , Horacio O. de la Iglesia
    •  & William A. Catterall
  2. Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA

    • Sung Han
    • , Chao Tai
    • , Ruth E. Westenbroek
    • , Frank H. Yu
    • , Christine S. Cheah
    • , Todd Scheuer
    •  & William A. Catterall
  3. Department of Biology, University of Washington, Seattle, Washington 98195, USA

    • Sung Han
    •  & Horacio O. de la Iglesia
  4. Department of Psychiatry, University of California at San Francisco, San Francisco, California 94158, USA

    • Gregory B. Potter
    •  & John L. Rubenstein

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Contributions

W.A.C. and H.O.d. are co-senior authors. S.H., C.T., R.E.W., C.S.C., T.S., H.O.d. and W.A.C. designed the experiments. S.H., C.T., R.E.W., C.S.C. and T.S. performed the experiments. F.H.Y., C.S.C., G.B.P., J.L.R. and W.A.C. designed, prepared and characterized the genetically modified mouse lines. S.H., C.T., J.L.R., H.O.d. and W.A.C. wrote and revised the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Horacio O. de la Iglesia or William A. Catterall.

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    Supplementary Information

    This file contains Supplementary Methods, additional references, Supplementary Table 1 and Supplementary Figures 1-24.

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DOI

https://doi.org/10.1038/nature11356

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