Differential Roles of Glial and Neuronal Glutamate Transporters in Purkinje Cell Synapses
Differential Roles of Glial and Neuronal Glutamate Transporters in Purkinje Cell Synapses
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DOI：
10.1523/jneurosci.1020-05.2005
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发表时间：
2005-09
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通讯作者：
Y. Takayasu;M. Iino;W. Kakegawa;H. Maeno;K. Watase;K. Wada;D. Yanagihara;T. Miyazaki;O. Komine;Masahiko Watanabe;Kohichi Tanaka;S. Ozawa
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作者：
Y. Takayasu;M. Iino;W. Kakegawa;H. Maeno;K. Watase;K. Wada;D. Yanagihara;T. Miyazaki;O. Komine;Masahiko Watanabe;Kohichi Tanaka;S. Ozawa
谷氨酸转运体是终止兴奋性神经传递所必需的。两种不同的谷氨酸转运蛋白，谷氨酸-天冬氨酸转运蛋白（GLAST）和兴奋性氨基酸转运蛋白4 (EAAT4)，在小脑皮层的分子层中表达最丰富。GLAST在浦肯野细胞树突棘兴奋性突触周围的Bergmann胶质突中表达，而EAAT4则集中在浦肯野细胞棘膜的突触外区域。为了阐明这些转运体共存的功能意义，我们分析了缺乏GLAST或EAAT4的小鼠浦肯野细胞中EPSCs的动力学。野生型和eaat4缺陷小鼠在攀爬纤维和平行纤维刺激下EPSCs的上升期和初始衰减期的振幅和动力学均无差异。然而，在eaat4缺陷小鼠的大多数浦肯野细胞中，EPSCs的长时间尾电流表现出年龄依赖性。这些尾电流在缺乏GLAST的小鼠中从未出现过。然而，在glast缺陷小鼠中，与野生型和eaat4缺陷小鼠相比，降低AMPA受体脱敏的环噻嗪类药物的应用增加了EPSC的峰值幅度，并延长了其衰减时间。结果表明，这些转运蛋白在突触释放谷氨酸的清除中起着不同的作用。GLAST主要参与谷氨酸的摄取，谷氨酸在递质释放后早期从突触间隙涌出。相反，EAAT4的主要作用是去除在后期从胶质转运体摄取中逃脱的低浓度谷氨酸，从而防止递质溢出到邻近的突触。
Glutamate transporters are essential for terminating excitatory neurotransmission. Two distinct glutamate transporters, glutamate–aspartate transporter (GLAST) and excitatory amino acid transporter 4 (EAAT4), are expressed most abundantly in the molecular layer of the cerebellar cortex. GLAST is expressed in Bergmann glial processes surrounding excitatory synapses on Purkinje cell dendritic spines, whereas EAAT4 is concentrated on the extrasynaptic regions of Purkinje cell spine membranes. To clarify the functional significance of the coexistence of these transporters, we analyzed the kinetics of EPSCs in Purkinje cells of mice lacking either GLAST or EAAT4. There was no difference in the amplitude or the kinetics of the rising and initial decay phase of EPSCs evoked by stimulations of climbing fibers and parallel fibers between wild-type and EAAT4-deficient mice. However, long-lasting tail currents of the EPSCs appeared age dependently in most of Purkinje cells in EAAT4-deficient mice. These tail currents were never seen in mice lacking GLAST. In the GLAST-deficient mice, however, the application of cyclothiazide that reduces desensitization of AMPA receptors increased the peak amplitude of the EPSC and prolonged its decay more markedly than in both wild-type and EAAT4-deficient mice. The results indicate that these transporters play differential roles in the removal of synaptically released glutamate. GLAST contributes mainly to uptake of glutamate that floods out of the synaptic cleft at early times after transmitter release. In contrast, the main role of EAAT4 is to remove low concentrations of glutamate that escape from the uptake by glial transporters at late times and thus prevents the transmitter from spilling over to neighboring synapses.