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bioRxiv · 10.1101/2023.07.26.550763

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

Abe, Y.·Yagishita, S.·Sano, H.·Sugiura, Y.·Dantsuji, M.·Suzuki, T.·Mochizuki, A.·Yoshimaru, D.·Hata, J.·Matsumoto, M.·Taira, S.·Takeuchi, H.·Okano, H.·Ohno, N.·Suematsu, M.·Inoue, T.·Nambu, A.·Watanabe, M.·Tanaka, K. F. F.
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Abstract

Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist, L-DOPA, to treat Parkinsons 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. HighlightsO_LIEnhancement of GABAergic transmission is a shared mechanism between LID and TD. C_LIO_LIVGAT levels in MSNs govern the structure and function of MSN presynaptic terminals. C_LIO_LIGain and loss of VGAT function in MSNs exacerbates and ameliorates dyskinesia. C_LIO_LILowered D2 signaling with repetitive DA fluctuations causes VGAT overexpression. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=188 HEIGHT=200 SRC="FIGDIR/small/550763v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@15041b4org.highwire.dtl.DTLVardef@9bf41org.highwire.dtl.DTLVardef@1eb7ee4org.highwire.dtl.DTLVardef@1d7dae8_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Abe, Y., Yagishita, S., Sano, H., Sugiura, Y., Dantsuji, M., Suzuki, T., Mochizuki, A., Yoshimaru, D., Hata, J., Matsumoto, M., Taira, S., Takeuchi, H., Okano, H., Ohno, N., Suematsu, M., Inoue, T., Nambu, A., Watanabe, M., Tanaka, K. F. F.. 2023-07-28. Shared GABA transmission pathology in dopamine agonist- and antagonist-induced dyskinesia. https://doi.org/10.1101/2023.07.26.550763

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