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Scn1a+/- 小鼠的自闭症样行为及增强 GABA 能神经传递的挽救作用。

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

机构信息

Graduate Program in Neurobiology & Behavior, University of Washington, Seattle, Washington 98195, USA.

出版信息

Nature. 2012 Sep 20;489(7416):385-90. doi: 10.1038/nature11356. Epub 2012 Aug 22.

Abstract

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.

摘要

SCN1A 基因编码电压门控钠离子通道 Na(V)1.1 的单倍不足导致 Dravet 综合征,这是一种儿童神经精神疾病,包括反复发作的难治性癫痫、认知缺陷和自闭症谱系行为。导致 Dravet 综合征认知缺陷和自闭症谱系行为的神经机制尚未完全了解。在这里,我们报告说 Scn1a 单倍不足的小鼠表现出过度活跃、刻板行为、社交互动缺陷和情景依赖性空间记忆受损。嗅觉敏感性保留,但新型食物气味和社交气味对 Scn1a(+/-) 小鼠具有厌恶感。这种突变特异性损害 GABA 能神经传递,并且选择性删除前脑中间神经元中的 Na(V)1.1 通道足以引起这些行为和认知损伤。值得注意的是,用低剂量氯硝西泮(GABA(A) 受体的正变构调节剂)治疗完全挽救了 Dravet 综合征小鼠模型中的异常社交行为和恐惧记忆缺陷,表明这些异常是由 GABA 能神经传递受损引起的,而不是由反复癫痫发作引起的神经元损伤引起的。这些结果表明 Na(V)1.1 通道在神经精神功能中的关键作用,并为 Dravet 综合征中的认知缺陷和自闭症谱系行为提供了一种潜在的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f82/3448848/c00fe7c78b3b/nihms-389654-f0001.jpg

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