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

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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Figure 1: Scn1a +/− mice show hyperactivity, anxiety-like behaviour, increased stereotypies, and impaired social behaviour.
Figure 2: Profound deficits in context-dependent spatial learning and memory in Scn1a +/− mice.
Figure 3: Dlx1/2-Scn1a +/− mice have the impaired spatial learning and autism-related phenotypes observed in Scn1a +/− mice.
Figure 4: Deficit of Na V 1.1 channels and GABAergic neurotransmission in Scn1a +/− hippocampal GABAergic interneurons.
Figure 5: Complete rescue of impaired social behaviour and fear-associated memory deficits by low-dose clonazepam treatment.

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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.

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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.

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

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The authors declare no competing financial interests.

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Han, S., Tai, C., Westenbroek, R. et al. Autistic-like behaviour in Scn1a+/− mice and rescue by enhanced GABA-mediated neurotransmission. Nature 489, 385–390 (2012). https://doi.org/10.1038/nature11356

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