Valenzuela C Fernando, Jotty Karick
Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA,
Cerebellum. 2015 Aug;14(4):438-46. doi: 10.1007/s12311-014-0639-3.
Studies from several laboratories have shown that ethanol impairs cerebellar function, in part, by altering GABAergic transmission. Here, we discuss recent advances in our understanding of the acute effects of ethanol on GABA(A) receptor-mediated neurotransmission at cerebellar cortical circuits, mainly focusing on electrophysiological studies with slices from laboratory animals. These studies have shown that acute ethanol exposure increases GABA release at molecular layer interneuron-to-Purkinje cell synapses and also at reciprocal synapses between molecular layer interneurons. In granule cells, studies with rat cerebellar slices have consistently shown that acute ethanol exposure both potentiates tonic currents mediated by extrasynaptic GABA(A) receptors and also increases the frequency of spontaneous inhibitory postsynaptic currents mediated by synaptic GABA(A) receptors. These effects have been also documented in some granule cells from mice and nonhuman primates. Currently, there are two distinct models on how ethanol produces these effects. In one model, ethanol primarily acts by directly potentiating extrasynaptic GABA(A) receptors, including a population that excites granule cell axons and stimulates glutamate release onto Golgi cells. In the other model, ethanol acts indirectly by increasing spontaneous Golgi cell firing via inhibition of the Na(+)/K(+) ATPase, a quinidine-sensitive K(+) channel, and neuronal nitric oxide synthase. It was also demonstrated that a direct inhibitory effect of ethanol on tonic currents can be unmasked under conditions of low protein kinase C activity. In the last section, we briefly discuss studies on the chronic effect of ethanol on cerebellar GABA(A) receptor-mediated transmission and highlight potential areas where future research is needed.
多个实验室的研究表明，乙醇会损害小脑功能，部分原因是其改变了γ-氨基丁酸（GABA）能传递。在此，我们讨论近期在理解乙醇对小脑皮质回路中GABA(A)受体介导的神经传递的急性作用方面取得的进展，主要聚焦于对实验动物脑片进行的电生理研究。这些研究表明，急性乙醇暴露会增加分子层中间神经元与浦肯野细胞突触处以及分子层中间神经元之间相互突触处的GABA释放。在颗粒细胞中，对大鼠小脑脑片的研究一致表明，急性乙醇暴露既增强了由突触外GABA(A)受体介导的强直电流，也增加了由突触GABA(A)受体介导的自发抑制性突触后电流的频率。在小鼠和非人类灵长类动物的一些颗粒细胞中也记录到了这些效应。目前，关于乙醇如何产生这些效应有两种不同的模型。在一种模型中，乙醇主要通过直接增强突触外GABA(A)受体起作用，包括一群能兴奋颗粒细胞轴突并刺激谷氨酸释放到高尔基细胞上的受体。在另一种模型中，乙醇通过抑制钠/钾ATP酶、一种奎尼丁敏感的钾通道和神经元型一氧化氮合酶来增加高尔基细胞的自发放电，从而间接起作用。还证明了在低蛋白激酶C活性条件下，乙醇对强直电流的直接抑制作用会被揭示出来。在最后一部分，我们简要讨论了乙醇对小脑GABA(A)受体介导的传递的慢性作用的研究，并强调了未来需要研究的潜在领域。
