GABA_A receptors containing the α6 subunit are highly expressed in cerebellar granule cells and less abundantly in many other neuronal and peripheral tissues. Here, we for the first time summarize their importance for the functions of the cerebellum and the nervous system. The cerebellum is not only involved in motor control but also in cognitive, emotional, and social behaviors. α6βγ2 GABA_A receptors located at cerebellar Golgi cell/granule cell synapses enhance the precision of inputs required for cerebellar timing of motor activity and are thus involved in cognitive processing and adequate responses to our environment. Extrasynaptic α6βδ GABA_A receptors regulate the amount of information entering the cerebellum by their tonic inhibition of granule cells, and their optimal functioning enhances input filtering or contrast. The complex roles of the cerebellum in multiple brain functions can be compromised by genetic or neurodevelopmental causes that lead to a hypofunction of cerebellar α6-containing GABA_A receptors. Animal models mimicking neuropsychiatric phenotypes suggest that compounds selectively activating or positively modulating cerebellar α6-containing GABA_A receptors can alleviate essential tremor and motor disturbances in Angelman and Down syndrome as well as impaired prepulse inhibition in neuropsychiatric disorders and reduce migraine and trigeminal-related pain via α6-containing GABA_A receptors in trigeminal ganglia. Genetic studies in humans suggest an association of the human GABA_A receptor α6 subunit gene with stress-associated disorders. Animal studies support this conclusion. Neuroimaging and post-mortem studies in humans further support an involvement of α6-containing GABA_A receptors in various neuropsychiatric disorders, pointing to a broad therapeutic potential of drugs modulating α6-containing GABA_A receptors.

中文翻译：

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含 α6 GABAA 受体：功能作用和治疗潜力


含有α 6 亚基的 GABA _A受体在小脑颗粒细胞中高度表达，而在许多其他神经元和外周组织中表达量较低。在这里，我们首次总结了它们对小脑和神经系统功能的重要性。小脑不仅参与运动控制，还参与认知、情感和社会行为。位于小脑高尔基体细胞/颗粒细胞突触的α 6 βγ 2 GABA _A受体可增强小脑运动活动计时所需的输入精度，从而参与认知处理和对环境的充分反应。突触外α 6 βδ GABA _A受体通过对颗粒细胞的强直抑制来调节进入小脑的信息量，其最佳功能可增强输入过滤或对比度。小脑在多种大脑功能中的复杂作用可能会受到遗传或神经发育原因的影响，导致小脑α 6 含有 GABA _A受体功能减退。模拟神经精神表型的动物模型表明，选择性激活或正向调节小脑α 6 的 GABA _A受体的化合物可以减轻天使和唐氏综合症的原发性震颤和运动障碍，以及神经精神疾病中前脉冲抑制受损，并减轻偏头痛和三叉神经相关的疼痛通过三叉神经节中含有α 6 的 GABA _A受体。 人类遗传学研究表明，人类 GABA _A受体α 6 亚基基因与压力相关疾病存在关联。动物研究支持这一结论。人类神经影像学和尸检研究进一步支持含α 6 GABA _A受体参与各种神经精神疾病，表明调节含α 6 GABA _A受体的药物具有广泛的治疗潜力。