Autistic-like behaviour in Scn1a+/− mice and rescue by enhanced GABA-mediated neurotransmission
Autor: | Gregory B. Potter, Todd Scheuer, Frank H. Yu, Horacio O. de la Iglesia, Chao Tai, Sung Han, John L.R. Rubenstein, Christine S. Cheah, Ruth E. Westenbroek, William A. Catterall |
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Rok vydání: | 2012 |
Předmět: |
Male
Heterozygote Stereotypic Movement Disorder Hippocampus Epilepsies Myoclonic Nerve Tissue Proteins Haploinsufficiency Anxiety Hyperkinesis Neurotransmission Biology Synaptic Transmission Clonazepam Sodium Channels Article gamma-Aminobutyric acid Mice 03 medical and health sciences 0302 clinical medicine Interneurons Memory medicine Animals Autistic Disorder GABAergic Neurons GABA Modulators Social Behavior gamma-Aminobutyric Acid Cognitive deficit 030304 developmental biology Homeodomain Proteins 0303 health sciences Multidisciplinary Syndrome medicine.disease NAV1.1 Voltage-Gated Sodium Channel Stereotypic movement disorder Space Perception Forebrain medicine.symptom Neuroscience 030217 neurology & neurosurgery Transcription Factors medicine.drug |
Zdroj: | Nature Rubenstein, John; Han, S; Tai, C; Westenbroek, RE; Yu, FH; Cheah, CS; et al.(2012). Autistic-like behaviour in Scn1a +-mice and rescue by enhanced GABA-mediated neurotransmission. UC San Francisco: Retrieved from: http://www.escholarship.org/uc/item/9740063z |
ISSN: | 1476-4687 0028-0836 |
Popis: | 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. |
Databáze: | OpenAIRE |
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