GABA转运体通过控制突触间隙的GABA浓度及其受体GABA（A）介导的抑制性效应，调节海马脑区theta节律刺激（TBS）诱导的LTP以及theta振荡
12月16日，美国《神经科学杂志》（Journal of Neuroscience）在线发表了中国科学院上海生命科学研究院神经科学研究所徐天乐研究组的最新研究成果――“GABA Transporter-1 Activity Modulates Hippocampal Theta Oscillation and Theta Burst Stimulation-Induced Long-Term Potentiation”。大脑的网络振荡活动和突触可塑性被认为与学习记忆的形成密切相关。近年来，脑内最主要的抑制性神经递质GABA以及GABA能中间神经元在神经网络活动中的作用一直是神经科学热点课题之一。GABA转运体主要负责突触释放的GABA的重摄取，进而控制细胞外GABA的浓度。几年前同济大学费俭研究组成功制备出了1型GABA转运体（GAT1）基因敲除小鼠，该动物模型为研究脑内GABA及其受体在学习记忆等脑认知活动中的作用提供了一个重要工具。徐天乐研究员指导的博士后龚能及合作者利用GAT1敲除小鼠和GAT1特异性抑制剂No711，发现在小鼠海马CA1区，GABA通过作用于其受体GABA(A)调节theta节律刺激（theta burst stimulation，TBS）诱导的长时程增强（LTP）形式的突触可塑性。这种theta节律性的刺激模式来源于脑电中观察到的theta振荡（theta oscillation）。通过在活体动物观察GAT1敲除后海马区的theta振荡，发现GAT1敲除显著降低theta节律的振荡频率。在观察到网络振荡和可塑性发生改变的同时，还发现GAT1敲除小鼠海马依赖的空间学习记忆能力明显受损。这项研究进一步证实了GABA及其受体在节律性神经网络活动（特别是theta振荡），突触可塑性以及学习记忆等脑认知行为中重要作用。同时，由于抑制GABA(A)受体可逆转GAT1敲除小鼠受损的海马突触可塑性，这一研究也为开发针对学习记忆受损的脑认知相关疾病的有效药物提供了新线索。（生物谷Bioon.com）
生物谷推荐原始出处：
The Journal of Neuroscience, December 16, 2009, 29(50):15836-15845; doi:10.1523/JNEUROSCI.4643-09.2009
GABA Transporter-1 Activity Modulates Hippocampal Theta Oscillation and Theta Burst Stimulation-Induced Long-Term Potentiation
Neng Gong,1 Yong Li,2 Guo-Qiang Cai,3 Rui-Fang Niu,4 Qi Fang,1,5 Kun Wu,1,6 Zhong Chen,5 Long-Nian Lin,4 Lin Xu,1,6 Jian Fei,3 and Tian-Le Xu1
1Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, 2Department of Neurobiology, Institutes of Medical Sciences, Shanghai Jiaotong University, Shanghai 200025, China, 3School of Life Science and Technology, Tongji University, Shanghai 200092, China, 4Shanghai Institute of Brain Functional Genomics, East China Normal University, Shanghai 200062, 5College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China, and 6Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
The network oscillation and synaptic plasticity are known to be regulated by GABAergic inhibition, but how they are affected by changes in the GABA transporter activity remains unclear. Here we show that in the CA1 region of mouse hippocampus, pharmacological blockade or genetic deletion of GABA transporter-1 (GAT1) specifically impaired long-term potentiation (LTP) induced by theta burst stimulation, but had no effect on LTP induced by high-frequency stimulation or long-term depression induced by low-frequency stimulation. The extent of LTP impairment depended on the precise burst frequency, with significant impairment at 3–7 Hz that correlated with the time course of elevated GABAergic inhibition caused by GAT1 disruption. Furthermore, in vivo electrophysiological recordings showed that GAT1 gene deletion reduced the frequency of hippocampal theta oscillation. Moreover, behavioral studies showed that GAT1 knock-out mice also exhibited impaired hippocampus-dependent learning and memory. Together, these results have highlighted the important link between GABAergic inhibition and hippocampal theta oscillation, both of which are critical for synaptic plasticity and learning behaviors.
