State-dependent changes in astrocyte regulation of extrasynaptic NMDA receptor signalling in neurosecretory neurons
State-dependent changes in astrocyte regulation of extrasynaptic NMDA receptor signalling in neurosecretory neurons
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DOI：
10.1113/jphysiol.2011.207340
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发表时间：
2011-08-15
影响因子：
5.5
通讯作者：
Stern, Javier E.
中科院分区：
文献类型：
--
作者：
Fleming, Tiffany M.;Scott, Victoria;Stern, Javier E.
尽管谷氨酸 NMDA 受体 (eNMDAR) 长期以来一直存在于突触外位点，但它们的功能作用仍然知之甚少。影响突触外空间谷氨酸浓度和时间过程的因素，例如神经元-胶质微环境的拓扑结构以及胶质谷氨酸转运蛋白，预计会影响 eNMDAR 介导的信号强度。在这项研究中，我们使用体外和体内电生理记录来评估下丘脑视上核（SON）神经元中 eNMDAR 激活介导的持续兴奋电流的特性、功能相关性和调节。我们发现非突触来源的环境谷氨酸激活 eNMDAR 介导持续的兴奋性电流（称为强直性 I-NMDA），从而强直性刺激神经元活动。药理学阻断 GLT1 星形胶质细胞谷氨酸转运蛋白以及胶霉毒素 α-氨基达二酸，增强强直 I-NMDA 和神经元活性，支持星形胶质细胞对强直 I-NMDA 强度的调节。脱水是一种生理挑战，已知会增加 SON 放电活性并诱导神经胶质细胞重塑，包括星形胶质细胞过程减少神经元鞘，导致 GLT1 功效减弱、强直 I-NMDA 强度增强和神经元活性增加。综上所述，我们的研究支持这样的观点：神经胶质对强直性 IMDA 激活的调节有助于调节 SON 神经元活动，进而有助于生理挑战期间的神经元稳态反应。
Despite the long-established presence of glutamate NMDA receptors at extrasynaptic sites (eNMDARs), their functional roles remain poorly understood. Factors influencing the concentration and time course of glutamate in the extrasynaptic space, such as the topography of the neuronal-glial microenvironment, as well as glial glutamate transporters, are expected to affect eNMDAR-mediated signalling strength. In this study, we used in vitro and in vivo electrophysiological recordings to assess the properties, functional relevance and modulation of a persistent excitatory current mediated by activation of eNMDARs in hypothalamic supraoptic nucleus (SON) neurons. We found that ambient glutamate of a non-synaptic origin activates eNMDARs to mediate a persistent excitatory current (termed tonic I-NMDA), which tonically stimulates neuronal activity. Pharmacological blockade of GLT1 astrocyte glutamate transporters, as well as the gliotoxin alpha-aminodadipic acid, enhanced tonic I-NMDA and neuronal activity, supporting an astrocyte regulation of tonic I-NMDA strength. Dehydration, a physiological challenge known to increase SON firing activity and to induce neuroglial remodelling, including reduced neuronal ensheathment by astrocyte processes, resulted in blunted GLT1 efficacy, enhanced tonic I-NMDA strength, and increased neuronal activity. Taken together, our studies support the view that glial modulation of tonic INMDA activation contributes to regulation of SON neuronal activity, contributing in turn to neuronal homeostatic responses during a physiological challenge.