Department of Information Physiology, National Institute for Physiological Sciences (NIPS), Myodaiji-cho, Okazaki, Japan.
Eur J Neurosci. 2010 Dec;32(11):1843-53. doi: 10.1111/j.1460-9568.2010.07469.x. Epub 2010 Nov 11.
Neurotransmitters diffuse out of the synaptic cleft and act on adjacent synapses to exert concerted control of the synaptic strength within neural pathways that converge on single target neurons. The excitatory transmitter released from climbing fibers (CFs), presumably glutamate, is shown to inhibit γ-aminobutyric acid (GABA) release at basket cell (BC)-Purkinje cell (PC) synapses in the rat cerebellar cortex through its extrasynaptic diffusion and activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on BC axon terminals. This study aimed at examining how the CF transmitter-diffusion-mediated presynaptic inhibition is controlled by glutamate transporters. Pharmacological blockade of the PC-selective neuronal transporter EAAT4 markedly enhanced CF-induced inhibition of GABAergic transmission. Tetanic CF-stimulation elicited long-term potentiation of glutamate transporters in PCs, and thereby attenuated the CF-induced inhibition. Combined use of electrophysiology and immunohistochemistry revealed a significant inverse relationship between the level of EAAT4 expression and the inhibitory action of CF-stimulation on the GABA release at different cerebellar lobules - the CF-induced inhibition was profound in lobule III, where the EAAT4 expression level was low, whereas it was minimal in lobule X, where EAAT4 was abundant. The findings clearly demonstrate that the neuronal glutamate transporter EAAT4 in PCs plays a critical role in the extrasynaptic diffusion of CF transmitter - it appears not only to retrogradely determine the degree of CF-mediated inhibition of GABAergic inputs to the PC by controlling the glutamate concentration for intersynaptic diffusion, but also regulate synaptic information processing in the cerebellar cortex depending on its differential regional distribution as well as use-dependent plasticity of uptake efficacy.
神经递质从突触间隙扩散出来，作用于相邻的突触，协同控制会聚到单个靶神经元的神经通路中的突触强度。从 climbing fibers (CFs) 释放的兴奋性递质（推测是谷氨酸）通过其在 basket cell (BC) - Purkinje cell (PC) 突触中的 extrasynaptic 扩散和激活 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) 受体，抑制了 GABA 的释放。本研究旨在探讨 CF 递质扩散介导的 presynaptic 抑制是如何被谷氨酸转运体控制的。药理学阻断 PC 选择性神经元转运体 EAAT4 显著增强了 CF 诱导的 GABA 能传递抑制。CF 刺激引起的谷氨酸转运体长期增强作用，从而减弱了 CF 诱导的抑制。电生理学和免疫组织化学的联合使用表明，EAAT4 的表达水平与 CF 刺激对不同小脑叶 GABA 释放的抑制作用之间存在显著的负相关关系 - 在 EAAT4 表达水平较低的 III 小叶中，CF 诱导的抑制作用很深，而在 EAAT4 丰富的 X 小叶中，抑制作用最小。这些发现清楚地表明，PC 中的神经元谷氨酸转运体 EAAT4 在 CF 递质的 extrasynaptic 扩散中起着关键作用 - 它不仅通过控制突触间扩散的谷氨酸浓度来反向决定 CF 对 GABA 输入到 PC 的抑制程度，而且还根据其差异分布以及摄取效率的使用依赖性可塑性，调节小脑皮层的突触信息处理。
