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<p>In Parkinson’s disease (PD), long-term 3,4-dihydroxy-L-phenylalanine (L-dopa) therapy leads to the development of motor complications, including L-dopa-induced dyskinesia (LID). Increased numbers of reactive astrocytes in the brains of patients with PD are a key feature of this disease. Astrocytes are involved in the development of LID; however, whether the regulation of astrocytic activity influences LID development remains unclear. Therefore, this study aimed to determine the effect of the direct modulation of glial fibrillary acidic protein (GFAP)-expressing glia on LID development during L-dopa therapy in PD using chemogenetic tools. Adeno-associated viruses (AAVs) were used to target designer receptors exclusively activated by designer drugs (DREADDs) in GFAP-expressing cells to modulate Gq- or Gi-mediated signaling and regulate astrocytic activity in the brain. AAVs were injected into the dorsal striatum, and 6-hydroxydopamine (6-OHDA) was injected into the substantia nigra of mice. Clozapine N-oxide was co-administered with L-dopa. Chemogenetic activation of astrocytes in the dopamine-depleted striatum affected the early development of LID in 6-OHDA-lesioned mice. Furthermore, astrocyte suppression through Gi-mediated DREADD reduced abnormal involuntary movement scores in mice. These results suggest that regulating astrocytic activity in the dorsal striatum could be a therapeutic option for LID in PD.</p>

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Regulating astrocytic activity in the dorsal striatum mitigates L-dopa-induced dyskinesia in Parkinson’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月22日

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  • Young-Kyoung Ryu,
  • Hye-Yeon Park,
  • Ju-Eun Kim,
  • Hyun-Hee Seo,
  • Chul-Ho Lee,
  • Kyoung-Shim Kim

摘要

In Parkinson’s disease (PD), long-term 3,4-dihydroxy-L-phenylalanine (L-dopa) therapy leads to the development of motor complications, including L-dopa-induced dyskinesia (LID). Increased numbers of reactive astrocytes in the brains of patients with PD are a key feature of this disease. Astrocytes are involved in the development of LID; however, whether the regulation of astrocytic activity influences LID development remains unclear. Therefore, this study aimed to determine the effect of the direct modulation of glial fibrillary acidic protein (GFAP)-expressing glia on LID development during L-dopa therapy in PD using chemogenetic tools. Adeno-associated viruses (AAVs) were used to target designer receptors exclusively activated by designer drugs (DREADDs) in GFAP-expressing cells to modulate Gq- or Gi-mediated signaling and regulate astrocytic activity in the brain. AAVs were injected into the dorsal striatum, and 6-hydroxydopamine (6-OHDA) was injected into the substantia nigra of mice. Clozapine N-oxide was co-administered with L-dopa. Chemogenetic activation of astrocytes in the dopamine-depleted striatum affected the early development of LID in 6-OHDA-lesioned mice. Furthermore, astrocyte suppression through Gi-mediated DREADD reduced abnormal involuntary movement scores in mice. These results suggest that regulating astrocytic activity in the dorsal striatum could be a therapeutic option for LID in PD.