GABAergic signaling as therapeutic target for autism spectrum disorders.
GABAergic signaling as therapeutic target for autism spectrum disorders.
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DOI：
10.3389/fped.2014.00070
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发表时间：
2014
影响因子：
2.6
通讯作者：
Cherubini E
中科院分区：
文献类型：
--
作者：
Cellot G;Cherubini E
γ-氨基丁酸(GABA)是成人大脑中主要的抑制性神经递质，在出生后早期具有去极化和兴奋作用。这依赖于细胞内通过阳离子氯进口体NKCC1积累的氯，而氯输出体KCC2在出生时的表达非常低。KCC2的发育调控表达导致氯离子随着年龄的增加而排出，GABA从去极化方向向超极化方向移动。GABA的去极化作用通过电压依赖性钙通道和/或N-甲基-d-天冬氨酸受体导致细胞内钙升高。GABA介导的钙信号调控细胞增殖、迁移、分化、突触成熟和神经元连接等多种发育过程。因此，某些形式的神经发育障碍，如自闭症谱系障碍(ASDS)，与GABA能信号的改变和选择性神经元回路中兴奋/抑制平衡的损害有关，这并不令人惊讶。在这篇综述中，我们将讨论GABAA介导的神经传递的变化如何影响几种形式的ASDS，包括脆性X综合征、Angelman综合征和Rett综合征。然后，我们将描述各种具有GABA能功能障碍的ASD动物模型，强调它们的行为缺陷以及通过靶向GABA能突触的选择性成分来拯救它们的可能性。特别是，我们将讨论在某些情况下，用NKCC1的选择性阻滞剂利尿剂布美他尼将GABA反应的极性从去极化恢复到超极化方向，如何对ASD产生有益的影响，从而为这些破坏性疾病的治疗开辟新的治疗视角。
γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter in the adult brain, early in postnatal life exerts a depolarizing and excitatory action. This depends on accumulation of chloride inside the cell via the cation–chloride importer NKCC1, being the expression of the chloride exporter KCC2 very low at birth. The developmentally regulated expression of KCC2 results in extrusion of chloride with age and a shift of GABA from the depolarizing to the hyperpolarizing direction. The depolarizing action of GABA leads to intracellular calcium rise through voltage-dependent calcium channels and/or N-methyl-d-aspartate receptors. GABA-mediated calcium signals regulate a variety of developmental processes from cell proliferation migration, differentiation, synapse maturation, and neuronal wiring. Therefore, it is not surprising that some forms of neuro-developmental disorders such as autism spectrum disorders (ASDs) are associated with alterations of GABAergic signaling and impairment of the excitatory/inhibitory balance in selective neuronal circuits. In this review, we will discuss how changes of GABAA-mediated neurotransmission affect several forms of ASDs including the Fragile X, the Angelman, and Rett syndromes. Then, we will describe various animal models of ASDs with GABAergic dysfunctions, highlighting their behavioral deficits and the possibility to rescue them by targeting selective components of the GABAergic synapse. In particular, we will discuss how in some cases, reverting the polarity of GABA responses from the depolarizing to the hyperpolarizing direction with the diuretic bumetanide, a selective blocker of NKCC1, may have beneficial effects on ASDs, thus opening new therapeutic perspectives for the treatment of these devastating disorders.
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DOI：
10.1017/s1461145712001216
发表时间：
2013-07
期刊：
The international journal of neuropsychopharmacology
影响因子：
--
作者：
Banerjee A;García-Oscos F;Roychowdhury S;Galindo LC;Hall S;Kilgard MP;Atzori M
通讯作者：
Atzori M
影响因子：
9.9
作者：
Casanova, MF;Buxhoeveden, DP;Roy, E
通讯作者：
Roy, E
影响因子：
5.1
作者：
Cherubini, Enrico;Griguoli, Marilena;Lagostena, Laura
通讯作者：
Lagostena, Laura
影响因子：
5.3
作者：
Cancedda, Laura;Fiumelli, Hubert;Poo, Mu-ming
通讯作者：
Poo, Mu-ming
影响因子：
2.9
作者：
Cheh, Michelle A.;Millonig, James H.;Wagner, George C.
通讯作者：
Wagner, George C.