Rescue of deficient amygdala tonic γ-aminobutyric acidergic currents in the Fmr-/y mouse model of fragile X syndrome by a novel γ-aminobutyric acid type A receptor-positive allosteric modulator.
Rescue of deficient amygdala tonic γ-aminobutyric acidergic currents in the Fmr-/y mouse model of fragile X syndrome by a novel γ-aminobutyric acid type A receptor-positive allosteric modulator.
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DOI：
10.1002/jnr.23632
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发表时间：
2016-06
影响因子：
4.2
通讯作者：
Corbin JG
中科院分区：
文献类型：
--
作者：
Martin BS;Martinez-Botella G;Loya CM;Salituro FG;Robichaud AJ;Huntsman MM;Ackley MA;Doherty JJ;Corbin JG
兴奋性传递与抑制性传递比率的改变正在成为许多神经系统疾病的常见组成部分，包括自闭症谱系障碍(ASDS)。由突触周围和突触外的γ-A型受体提供的强直的GABA-氨基丁酸(GABA)能传递有效地控制神经元的兴奋性和可塑性，因此为包括ASD在内的各种疾病的过度兴奋网络的正常化提供了一个合理的治疗靶点。我们以前的研究发现，在Fmr1−/y基因敲除(KO)小鼠模型脆性X综合征中，杏仁基底外侧核(BLA)的主要兴奋性神经元存在紧张性GABA能缺陷。为了纠正Fmr1−/y KO小鼠强直性GABA能神经传递中杏仁核的缺陷，我们开发了一种基于内源性活性神经类固醇的新型GABA受体正性变构调节剂SGE-872。这项研究表明，SGE-872在正向调节GABAA受体方面几乎与其母分子别孕酮一样有效，并且是其母体分子别孕酮的两倍。此外，在亚微摩尔浓度(≤1µM)下，SGE-872对突触外强直的α4β3δ受体具有选择性，而不是典型的突触α1β2γ2受体。我们进一步发现，SGE-872显著地挽救了Fmr1−/y KO BLA中主要兴奋性神经元的紧张性GABA能传递缺陷，这一结构与ASD的神经病理密切相关。因此，SGE-872对含有α4亚单位的紧张性GABA受体的有效和选择性作用可能是治疗ASD和相关神经网络高兴奋性疾病的一种新的、高度有用的途径。
Alterations in the ratio of excitatory to inhibitory transmission are emerging as a common component of many nervous system disorders, including autism spectrum disorders (ASDs). Tonic γ-aminobutyric acidergic (GABAergic) transmission provided by peri- and extrasynaptic GABA type A (GABAA) receptors powerfully controls neuronal excitability and plasticity and, therefore, provides a rational therapeutic target for normalizing hyperexcitable networks across a variety of disorders, including ASDs. Our previous studies revealed tonic GABAergic deficits in principal excitatory neurons in the basolateral amygdala (BLA) in the Fmr1−/y knockout (KO) mouse model fragile X syndrome. To correct amygdala deficits in tonic GABAergic neurotransmission in Fmr1−/y KO mice, we developed a novel positive allosteric modulator of GABAA receptors, SGE-872, based on endogenously active neurosteroids. This study shows that SGE-872 is nearly as potent and twice as efficacious for positively modulating GABAA receptors as its parent molecule, allopregnanolone. Furthermore, at submicromolar concentrations (≤1 µM), SGE-872 is selective for tonic, extrasynaptic α4β3δ-containing GABAA receptors over typical synaptic α1β2γ2 receptors. We further find that SGE-872 strikingly rescues the tonic GABAergic transmission deficit in principal excitatory neurons in the Fmr1−/y KO BLA, a structure heavily implicated in the neuropathology of ASDs. Therefore, the potent and selective action of SGE-872 on tonic GABAA receptors containing α4 subunits may represent a novel and highly useful therapeutic avenue for ASDs and related disorders involving hyperexcitability of neuronal networks.
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影响因子：
4.8
作者：
Dalby, B;Cates, S;Ciccarone, VC
通讯作者：
Ciccarone, VC
影响因子：
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作者：
Goncalves, J. Tiago;Anstey, James E.;Golshani, Peyman;Portera-Cailliau, Carlos
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Portera-Cailliau, Carlos
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Wafford, KA
影响因子：
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作者：
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