Thrombospondin1 mimics rapidly relieve depression via Shank3 dependent uncoupling between dopamine D1 and D2 receptors

Shuang-Qi Gao; Jun-Quan Chen; Hai-Yun Zhou; Lun Luo; Bao-Yu Zhang; Man-Ting Li; Hai-Yong He; Chuan Chen; Ying Guo

doi:10.1016/j.isci.2023.106488

Thrombospondin1 mimics rapidly relieve depression via Shank3 dependent uncoupling between dopamine D1 and D2 receptors

iScience. 2023 Mar 22;26(4):106488. doi: 10.1016/j.isci.2023.106488. eCollection 2023 Apr 21.

Authors

Shuang-Qi Gao¹, Jun-Quan Chen¹, Hai-Yun Zhou², Lun Luo¹, Bao-Yu Zhang¹, Man-Ting Li¹, Hai-Yong He¹, Chuan Chen¹, Ying Guo¹

Affiliations

¹ Departments of Neurosurgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province 510630, China.
² Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

Abstract

Deficits in astrocyte function contribute to major depressive disorder (MDD) and suicide, but the therapeutic effect of directly reactivating astrocytes for depression remains unclear. Here, specific gains and losses of astrocytic cell functions in the medial prefrontal cortex (mPFC) bidirectionally regulate depression-like symptoms. Remarkably, recombinant human Thrombospondin-1 (rhTSP1), an astrocyte-secreted protein, exerted rapidly antidepressant-like actions through tyrosine hydroxylase (Th)/dopamine (DA)/dopamine D2 receptors (D2Rs) pathways, but not dopamine D1 receptors (D1Rs), which was dependent on SH3 and multiple ankyrin repeat domains 3 (Shank3) in the mPFC. TSP1 in the mPFC might have potential as a target for treating clinical depression.

Keywords: Biological sciences; Neuroscience; Proteomics; Transcriptomics.