Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission.
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.
Graduate Program in Neurobiology & Behavior, University of Washington, Seattle, Washington 98195, USA.
Sung
S
Han
Chao
C
Tai
Ruth E
RE
Westenbroek
Frank H
FH
Yu
Christine S
CS
Cheah
Gregory B
GB
Potter
John L
JL
Rubenstein
Todd
T
Scheuer
Horacio O
HO
de la Iglesia
William A
WA
Catterall
D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D001321:Autistic Disorder / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D002998:Clonazepam / Q000494:pharmacology / Q000627:therapeutic use; D004831:Epilepsies, Myoclonic / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D018757:GABA Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D059330:GABAergic Neurons / Q000378:metabolism; D057895:Haploinsufficiency / Q000235:genetics; D006579:Heterozygote; D006624:Hippocampus / Q000166:cytology; D018398:Homeodomain Proteins / Q000235:genetics; D006948:Hyperkinesis / Q000503:physiopathology; D007395:Interneurons / Q000378:metabolism; D008297:Male; D008568:Memory; D051379:Mice; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D012919:Social Behavior; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*; D013028:Space Perception; D019956:Stereotypic Movement Disorder / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects*; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C088334:Distal-less homeobox proteins; D018757:GABA Modulators; D018398:Homeodomain Proteins; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568249:Scn1a protein, mouse; D015222:Sodium Channels; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid; D002998:Clonazepam