Vesicular GABA release delays the onset of the Purkinje cell terminal depolarization without affecting tissue swelling in cerebellar slices during simulated ischemia.
Vesicular GABA release delays the onset of the Purkinje cell terminal depolarization without affecting tissue swelling in cerebellar slices during simulated ischemia.
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DOI：
10.1016/j.neuroscience.2010.03.009
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发表时间：
2010-06-16
期刊：
影响因子：
3.3
通讯作者：
Rossi, D. J.
中科院分区：
文献类型：
--
作者：
Brady, J. D.;Mohr, C.;Rossi, D. J.
神经甾体可以增强GABAA受体的敏感性，保护小脑浦肯野细胞对短暂发作的全脑缺血，但很少有人知道缺血如何影响GABA能传递到浦肯野细胞。在这里，我们使用膜片钳记录浦肯野细胞在急性制备的大鼠小脑切片，以确定缺血如何影响GABA能信号浦肯野细胞。在电压钳位浦肯野细胞中，将切片暴露于旨在模拟脑缺血的溶液中导致自发抑制性突触后电流（sIPSC）频率的早期部分抑制，但5-8分钟后，GABA在浦肯野细胞周围的细胞外空间中积累，产生大的（~17 nS），持续的GABAA受体介导的电导。持续的GABAA电导与更大（~117 nS）的谷氨酸受体介导的电导平行发生，但阻断GABAA受体并不影响谷氨酸电导的时间或幅度，阻断谷氨酸受体并不影响GABAA电导的时间或幅度。尽管缺乏GABA和谷氨酸之间的相互作用，阻断GABAA受体显着加速了浦肯野细胞的“缺血性”去极化（ID）的发病，评估与电流钳记录从浦肯野细胞或场电位记录在浦肯野细胞的树突状领域。在对照条件下，浦肯野细胞ID发生在持续谷氨酸释放之前约2分钟，并且当GABAA受体被阻断时，浦肯野细胞ID发生在另外1-2分钟之前。组织肿胀，通过监测透过切片的透光率进行评估，在持续谷氨酸释放之前，在ID后达到峰值，但不受阻断GABAA受体的影响。这些数据表明，缺血诱导浦肯野细胞ID和组织肿胀之前，谷氨酸释放，并阻断GABAA受体加速ID的发作，而不影响组织肿胀。综合这些数据可以解释为什么浦肯野细胞是大脑中最缺血敏感的神经元之一，尽管缺乏NMDA受体，以及为什么增强GABAA受体功能的神经类固醇保护浦肯野细胞免受短暂的全脑缺血发作。
Neurosteroids that can enhance GABAA receptor sensitivity protect cerebellar Purkinje cells against transient episodes of global brain ischemia, but little is known about how ischemia affects GABAergic transmission onto Purkinje cells. Here we use patch-clamp recording from Purkinje cells in acutely prepared slices of rat cerebellum to determine how ischemia affects GABAergic signaling to Purkinje cells. In voltage-clamped Purkinje cells, exposing slices to solutions designed to simulate brain ischemia caused an early, partial suppression of the frequency of spontaneous inhibitory post synaptic currents (sIPSCs), but after 5-8 minutes GABA accumulated in the extracellular space around Purkinje cells, generating a large (~17 nS), sustained GABAA receptor-mediated conductance. The sustained GABAA conductance occurred in parallel with an even larger (~117 nS) glutamate receptor-mediated conductance, but blocking GABAA receptors did not affect the timing or magnitude of the glutamate conductance, and blocking glutamate receptors did not affect the timing or magnitude of the GABAA conductance. Despite the lack of interaction between GABA and glutamate, blocking GABAA receptors significantly accelerated the onset of the Purkinje cell “ischemic” depolarization (ID), as assessed with current-clamp recordings from Purkinje cells or field potential recordings in the dendritic field of the Purkinje cells. The Purkinje cell ID occurred ~2 minutes prior to the sustained glutamate release under control conditions and a further 1-2 minutes earlier when GABAA receptors were blocked. Tissue swelling, as assessed by monitoring light transmittance through the slice, peaked just after the ID, prior to the sustained glutamate release, but was not affected by blocking GABAA receptors. These data indicate that ischemia induces the Purkinje cell ID and tissue swelling prior to glutamate release, and that blocking GABAA receptors accelerates the onset of the ID without affecting tissue swelling. Taken together these data may explain why Purkinje cells are one of the most ischemia sensitive neurons in the brain despite lacking NMDA receptors, and why neurosteroids that enhance GABAA receptor function protect Purkinje cells against transient episodes of global brain ischemia.
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