Enhancement of inhibitory neurotransmission by GABAA receptors having α2,3-subunits ameliorates behavioral deficits in a mouse model of autism.
Enhancement of inhibitory neurotransmission by GABAA receptors having α2,3-subunits ameliorates behavioral deficits in a mouse model of autism.
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DOI：
10.1016/j.neuron.2014.01.016
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发表时间：
2014-03-19
期刊：
影响因子：
16.2
通讯作者：
Catterall WA
中科院分区：
文献类型：
--
作者：
Han S;Tai C;Jones CJ;Scheuer T;Catterall WA
自闭症谱系障碍(ASD)可能是由于大脑兴奋性神经传递与抑制性神经传递比例增加引起的。许多药物治疗已经在ASD中进行了测试，但只取得了有限的成功。在这里，我们报道了BTBR T+Itpr3tf/J(BTBR)小鼠，一个特发性自闭症的模型，减少了自发的GABA能神经传递。低剂量非镇静/非抗焦虑的苯二氮卓类药物治疗，通过突触后GABAA受体的正变构调节增加抑制性神经传递，改善社交、重复行为和空间学习的缺陷。此外，GABAA受体的负变构调节损害了C57BL/6J和129SvJ野生型小鼠的社会行为，表明抑制性神经传递减少可能是导致社会和认知障碍的原因之一。小剂量苯二氮类药物治疗后的显著行为改善是亚单位特异性的-α2，3亚单位选择性正变构调节剂L-838,417是有效的，但α1亚单位选择性药物唑吡坦加剧了社会缺陷。GABA能神经传递功能受损可能参与ASD的发生，α2，3亚单位选择性正向GABA受体调节可能是一种有效的治疗方法。
Autism spectrum disorder (ASD) may arise from increased ratio of excitatory to inhibitory neurotransmission in the brain. Many pharmacological treatments have been tested in ASD, but only limited success has been achieved. Here we report that BTBR T+ Itpr3tf/J (BTBR) mice, a model of idiopathic autism, have reduced spontaneous GABAergic neurotransmission. Treatment with low non-sedating/non-anxiolytic doses of benzodiazepines, which increase inhibitory neurotransmission through positive allosteric modulation of postsynaptic GABAA receptors, improved deficits in social interaction, repetitive behavior, and spatial learning. Moreover, negative allosteric modulation of GABAA receptors impaired social behavior in C57BL/6J and 129SvJ wild-type mice, suggesting reduced inhibitory neurotransmission may contribute to social and cognitive deficits. The dramatic behavioral improvement after low-dose benzodiazepine treatment was subunit-specific—the α2,3-subunit-selective positive allosteric modulator L-838,417 was effective, but the α1-subunit-selective drug zolpidem exacerbated social deficits. Impaired GABAergic neurotransmission may contribute to ASD, and α2,3-subunit-selective positive GABAA receptor modulation may be an effective treatment.
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影响因子：
14.9
作者：
Harmar AJ;Hills RA;Rosser EM;Jones M;Buneman OP;Dunbar DR;Greenhill SD;Hale VA;Sharman JL;Bonner TI;Catterall WA;Davenport AP;Delagrange P;Dollery CT;Foord SM;Gutman GA;Laudet V;Neubig RR;Ohlstein EH;Olsen RW;Peters J;Pin JP;Ruffolo RR;Searls DB;Wright MW;Spedding M
通讯作者：
Spedding M
影响因子：
3.7
作者：
Gatto CL;Broadie K
通讯作者：
Broadie K
影响因子：
2.9
作者：
Markram, Kamila;Markram, Henry
通讯作者：
Markram, Henry
影响因子：
2.5
作者：
McFarlane, H. G.;Kusek, G. K.;Crawley, J. N.
通讯作者：
Crawley, J. N.
影响因子：
3.4
作者：
GALPERN, WR;LUMPKIN, M;MILLER, LG
通讯作者：
MILLER, LG