Wu Yan-Jiao, Yi Xin, Gu Xue, Wang Qi, Jiang Qin, Li Ying, Zhu Michael X, Ding Jianqing, Li Wei-Guang, Xu Tian-Le
Songjiang Hospital and Songjiang Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China.
Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
iScience. 2023 Mar 3;26(4):106322. doi: 10.1016/j.isci.2023.106322. eCollection 2023 Apr 21.
Homeostatic synaptic scaling entails adjustment of synaptic strength on a cell to prolonged changes of neuronal activity, which is postulated to participate in neuropsychiatric disorders . Here, we find that sustained elevation in ambient GABA levels, by either genetic deletion or pharmacological blockade of GABA transporter-1 (GAT1), leads to synaptic scaling up of corticostriatal pathways, which underlies locomotor hyperactivity. Meanwhile, medium spiny neurons of the dorsal striatum exhibit an aberrant increase in excitatory synaptic transmission and corresponding structural changes in dendritic spines. Mechanistically, GAT1 deficiency dampens the expression and function of metabotropic glutamate receptors (mGluRs) and endocannabinoid (eCB)-dependent long-term depression of excitatory transmission. Conversely, restoring mGluR function in GAT1 deficient mice rescues excitatory transmission. Lastly, pharmacological potentiation of mGluR-eCB signaling or inhibition of homomeric-GluA1 AMPA receptors eliminates locomotor hyperactivity in the GAT1 deficient mice. Together, these results reveal a synaptic scaling mechanism in corticostriatal pathways that regulate locomotor activity.
稳态突触缩放需要根据神经元活动的长期变化来调整细胞上的突触强度，据推测这参与了神经精神疾病。在这里，我们发现，通过基因缺失或对γ-氨基丁酸转运体-1（GAT1）进行药理学阻断，使周围γ-氨基丁酸水平持续升高，会导致皮质纹状体通路的突触放大，这是运动亢进的基础。同时，背侧纹状体的中等棘状神经元表现出兴奋性突触传递异常增加以及树突棘的相应结构变化。从机制上讲，GAT1缺乏会抑制代谢型谷氨酸受体（mGluRs）的表达和功能以及内源性大麻素（eCB）依赖性兴奋性传递的长期抑制。相反，恢复GAT1缺陷小鼠的mGluR功能可挽救兴奋性传递。最后，mGluR-eCB信号的药理学增强或同源性GluA1 AMPA受体的抑制可消除GAT1缺陷小鼠的运动亢进。总之，这些结果揭示了皮质纹状体通路中调节运动活动的突触缩放机制。
