Synaptic Scaling of Corticostriatal Circuits Underlies Hyperactivity in Gaba Transporter-1 Deficient Mice

Authors

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

Publication Date

4-21-2023

Journal

iScience

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

DOI

10.1016/j.isci.2023.106322

PMID

36968092

PMCID

PMC10031039

PubMedCentral® Posted Date

3-3-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes