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Autistic-like behaviour in Scn1a+/− mice and rescue by enhanced GABA-mediated neurotransmission
Open accessAbstract
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.
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“Loss of function variants of NaV1.1 cause Dravet syndrome [48], generalized epilepsy with febrile seizures plus [49], and have also been associated with ASD [50,51].”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [51]
In the citing paper
“Low doses of clonazepam completely rescued the abnormal social behaviors and deficits in fear memory typically presented by Scn1a+/- mice (Han et al., 2012), demonstrating the impact of restoring the proper coordination of inhibitory transmissions.”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Han et al., 2012
In the citing paper
“Low doses of clonazepam completely rescued the abnormal social behaviors and deficits in fear memory typically presented by Scn1a+/- mice (Han et al., 2012), demonstrating the impact of restoring the proper coordination of inhibitory transmissions.”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Han et al., 2012
In the citing paper
“In mice haploinsufficient for Scn1a , treatment with low-dose clonazepam, a positive allosteric modulator of GABAA receptors, completely reversed the abnormal social behaviors and deficits in fear memory 77 .”
From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [77]
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Metadata
- Authors
- Han, S., Tai, C., Westenbroek, R. E., Yu, F. H., Cheah, C. S., Potter, G. B., Rubenstein, J. L., Scheuer, T., de la Iglesia, H. O., & Catterall, W. A.
- Affiliations
- University of Washington (US)
- University of California, San Francisco (US)
- Corresponding author
- Catterall, William A.
- ORCID
- Venue
- Nature
- Published
- 2012-08-22
- Volume
- 489
- Issue
- 7416
- Pages
- 385-390
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3448848
- OpenAlex
- W2050659319
- Cited by
- 643
- References
- 47
- Citations by year
- 2026: 23 · 2025: 35 · 2024: 43 · 2023: 57 · 2022: 39 · 2021: 62 · 2020: 54 · 2019: 48 · 2018: 37 · 2017: 55 · 2016: 49 · 2015: 47 · 2014: 44 · 2013: 48 · 2012: 2
- FWCI
- 31.70
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Mental Health (R01MH075016, R37MH049428)
- National Institute of Neurological Disorders and Stroke (R01NS025704)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- SCN1A, haploinsufficiency, GABAergic neurotransmission, GABAA receptor, clonazepam, social interaction deficits, hyperactivity, stereotypy, fear memory, spatial memory, interneurons, epilepsy, cognitive impairment
- MeSH terms
- Animals, Anxiety, Autistic Disorder, Clonazepam, Epilepsies, Myoclonic, gamma-Aminobutyric Acid, Heterozygote, Hippocampus, Hyperkinesis, Interneurons, Male, Memory, Nerve Tissue Proteins, Synaptic Transmission, Social Behavior, Space Perception, Syndrome, Transcription Factors, Sodium Channels, Homeodomain Proteins, GABA Modulators, Stereotypic Movement Disorder, Mice, Haploinsufficiency, GABAergic Neurons, NAV1.1 Voltage-Gated Sodium Channel
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