Shared GABA transmission pathology in dopamine agonist- and antagonist-induced dyskinesia

Abstract

SummaryDyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist, 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 searched for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identified the enlarged axon terminals of striatal medium spiny neurons in both LID and TD model mice. The striatal overexpression of vesicular gamma-aminobutyric acid transporter (VGAT) was necessary and sufficient for modeling these structural changes; VGAT levels gated 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.HighlightsEnhancement of GABAergic transmission is a shared mechanism between LID and TD.VGAT levels in MSNs govern the structure and function of MSN presynaptic terminals.Gain and loss of VGAT function in MSNs exacerbates and ameliorates dyskinesia.Lowered D2 signaling with repetitive DA fluctuations causes VGAT overexpression.Graphical abstract