Shared GABA transmission pathology in dopamine agonist- and antagonist-induced dyskinesia
☆ Watchresearch · published 2023-10-17 · by Abe Y, Dantsuji M, Hata J, Inoue T, Matsumoto M, Mochizuki A, Nambu A, Ohno N, Okano H, Sano H, Suematsu M, Sugiura Y, Suzuki T, Taira S, Takeuchi H, Tanaka KF, Watanabe M, Yagishita S, Yoshimaru D
Cell reports. Medicine · 2023 Oct 17
Abstract
Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat Parkinson's disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we search for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identify the enlarged axon terminals of striatal medium spiny neurons in LID and TD model mice. Striatal overexpression of the vesicular gamma-aminobutyric acid transporter (VGAT) is necessary and sufficient for modeling these structural changes; VGAT levels gate the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation.
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