Synaptic scaling of corticostriatal circuits underlies hyperactivity in GABA Transporter-1 deficient mice

Yan-Jiao Wu; Xin Yi; Xue Gu; Qi Wang; Qin Jiang; Ying Li; Michael X Zhu; Jianqing Ding; Wei-Guang Li; Tian-Le Xu

doi:10.1016/j.isci.2023.106322

Synaptic scaling of corticostriatal circuits underlies hyperactivity in GABA Transporter-1 deficient mice

iScience. 2023 Mar 3;26(4):106322. doi: 10.1016/j.isci.2023.106322. eCollection 2023 Apr 21.

Authors

Yan-Jiao Wu^{1

2}, Xin Yi^{1

2

3}, Xue Gu^{1

2}, Qi Wang^{1

2}, Qin Jiang^{1

2}, Ying Li^{1

2}, Michael X Zhu⁴, Jianqing Ding⁵, Wei-Guang Li^{2

3

6}, Tian-Le Xu^{1

2

6}

Affiliations

¹ Songjiang Hospital and Songjiang Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China.
² Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
³ Department of Rehabilitation Medicine, Huashan Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China.
⁴ Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁵ Institute of Aging and Tissue Repair, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
⁶ Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai 201210, China.

Abstract

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 in vivo. 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.

Keywords: Genetics; Molecular biology; Neuroscience.