Publication Date:
2012-08-24
Description:
Haploinsufficiency of the SCN1A gene encoding voltage-gated sodium channel Na(V)1.1 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 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 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 Na(V)1.1 channels in neuropsychiatric functions and provide a potential therapeutic strategy for cognitive deficit and autism-spectrum behaviours in Dravet's syndrome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448848/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448848/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Han, Sung -- Tai, Chao -- Westenbroek, Ruth E -- Yu, Frank H -- Cheah, Christine S -- Potter, Gregory B -- Rubenstein, John L -- Scheuer, Todd -- de la Iglesia, Horacio O -- Catterall, William A -- R01 MH075016/MH/NIMH NIH HHS/ -- R01 NS025704/NS/NINDS NIH HHS/ -- R01 NS25704/NS/NINDS NIH HHS/ -- R37 MH049428/MH/NIMH NIH HHS/ -- England -- Nature. 2012 Sep 20;489(7416):385-90. doi: 10.1038/nature11356. Epub 2012 Aug 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Graduate Program in Neurobiology & Behavior, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22914087" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Anxiety/physiopathology
;
Autistic Disorder/complications/*drug therapy/genetics/*physiopathology
;
Clonazepam/pharmacology/therapeutic use
;
Epilepsies, Myoclonic/complications/genetics/physiopathology
;
GABA Modulators/pharmacology/*therapeutic use
;
GABAergic Neurons/metabolism
;
Haploinsufficiency/genetics
;
Heterozygote
;
Hippocampus/cytology
;
Homeodomain Proteins/genetics
;
Hyperkinesis/physiopathology
;
Interneurons/metabolism
;
Male
;
Memory
;
Mice
;
NAV1.1 Voltage-Gated Sodium Channel
;
Nerve Tissue Proteins/*genetics/*metabolism
;
Social Behavior
;
Sodium Channels/*genetics/*metabolism
;
Space Perception
;
Stereotypic Movement Disorder/physiopathology
;
Synaptic Transmission/*drug effects
;
Syndrome
;
Transcription Factors/genetics
;
gamma-Aminobutyric Acid/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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