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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A schizophrenia-related sensorimotor deficit links alpha3-containing GABAA receptors to a dopamine hyperfunction.
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A schizophrenia-related sensorimotor deficit links alpha3-containing GABAA receptors to a dopamine hyperfunction.

机译：精神分裂症相关的感觉运动缺陷将含α3的GABAA受体与多巴胺功能亢进联系起来。

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Overactivity of the dopaminergic system in the brain is considered to be a contributing factor to the development and symptomatology of schizophrenia. Therefore, the GABAergic control of dopamine functions was assessed by disrupting the gene encoding the alpha3 subunit of the GABA(A) receptor. alpha3 knockout (alpha3KO) mice exhibited neither an obvious developmental defect nor apparent morphological brain abnormalities, and there was no evidence for compensatory up-regulation of other major GABA(A)-receptor subunits. Anxiety-related behavior in the elevated-plus-maze test was undisturbed, and the anxiolytic-like effect of diazepam, which is mediated by alpha2-containing GABA(A) receptors, was preserved. As a result of the loss of alpha3 GABA(A) receptors, the GABA-induced whole-cell current recorded from midbrain dopamine neurons was significantly reduced. Spontaneous locomotor activity was slightly elevated in alpha3KO mice. Most notably, prepulse inhibition of the acoustic startle reflex was markedly attenuated in the alpha3KO mice, pointing to a deficit in sensorimotor information processing. This deficit was completely normalized by treatment with the antipsychotic D2-receptor antagonist haloperidol. The amphetamine-induced hyperlocomotion was not altered in alpha3KO mice compared with WT mice. These results suggest that the absence of alpha3-subunit-containing GABA(A) receptors induces a hyperdopaminergic phenotype, including a severe deficit in sensorimotor gating, a common feature among psychiatric conditions, including schizophrenia. Hence, agonists acting at alpha3-containing GABA(A) receptors may constitute an avenue for an effective treatment of sensorimotor-gating deficits in various psychiatric conditions.
机译：脑中多巴胺能系统的过度活跃被认为是精神分裂症的发展和症状学的一个促成因素。因此，通过破坏编码GABA（A）受体的alpha3亚基的基因来评估多巴胺功能的GABA能控制。 alpha3基因敲除（alpha3KO）小鼠既没有表现出明显的发育缺陷，也没有表现出明显的脑形态学异常，也没有其他主要GABA（A）受体亚基的补偿性上调的证据。高迷宫测试中与焦虑相关的行为不受干扰，地西epa的抗焦虑样作用得以保留，该作用由含α2的GABA（A）受体介导。由于丢失了alpha3 GABA（A）受体，中脑多巴胺神经元记录的GABA诱导的全细胞电流显着降低。在alpha3KO小鼠中，自发运动能力略有升高。最值得注意的是，α3KO小鼠的听觉惊吓反射的前脉冲抑制作用明显减弱，表明感觉运动信息处理不足。通过用抗精神病药D2受体拮抗剂氟哌啶醇治疗，这种缺陷完全得以恢复。与野生型小鼠相比，alpha3KO小鼠中苯丙胺诱导的运动亢进没有改变。这些结果表明，不存在含α3-亚基的GABA（A）受体会引起高多巴胺能表型，包括感觉运动门控的严重缺陷，这是包括精神分裂症在内的精神疾病的常见特征。因此，作用于含α3的GABA（A）受体的激动剂可能构成有效治疗各种精神病状态下感觉运动门控缺陷的途径。

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