Regulating astrocytic activity in the dorsal striatum mitigates L-dopa-induced dyskinesia in Parkinson’s disease
Abstract 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. Ast...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-12104-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849234639655272448 |
|---|---|
| author | Young-Kyoung Ryu Hye-Yeon Park Ju-Eun Kim Hyun-Hee Seo Chul-Ho Lee Kyoung-Shim Kim |
| author_facet | Young-Kyoung Ryu Hye-Yeon Park Ju-Eun Kim Hyun-Hee Seo Chul-Ho Lee Kyoung-Shim Kim |
| author_sort | Young-Kyoung Ryu |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-9d4b8d8a59e741849054d9f1e7f8d54a |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-9d4b8d8a59e741849054d9f1e7f8d54a2025-08-20T04:03:06ZengNature PortfolioScientific Reports2045-23222025-07-0115111210.1038/s41598-025-12104-5Regulating astrocytic activity in the dorsal striatum mitigates L-dopa-induced dyskinesia in Parkinson’s diseaseYoung-Kyoung Ryu0Hye-Yeon Park1Ju-Eun Kim2Hyun-Hee Seo3Chul-Ho Lee4Kyoung-Shim Kim5Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Abstract 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.https://doi.org/10.1038/s41598-025-12104-5Abnormal involuntary movementsStriatumAAV-GFAP-hM3D(Gq)AAV-GFAP-hM4D(Gi)Clozapine N-oxide (CNO)6-hydroxydopamine-induced mouse model |
| spellingShingle | Young-Kyoung Ryu Hye-Yeon Park Ju-Eun Kim Hyun-Hee Seo Chul-Ho Lee Kyoung-Shim Kim Regulating astrocytic activity in the dorsal striatum mitigates L-dopa-induced dyskinesia in Parkinson’s disease Scientific Reports Abnormal involuntary movements Striatum AAV-GFAP-hM3D(Gq) AAV-GFAP-hM4D(Gi) Clozapine N-oxide (CNO) 6-hydroxydopamine-induced mouse model |
| title | Regulating astrocytic activity in the dorsal striatum mitigates L-dopa-induced dyskinesia in Parkinson’s disease |
| title_full | Regulating astrocytic activity in the dorsal striatum mitigates L-dopa-induced dyskinesia in Parkinson’s disease |
| title_fullStr | Regulating astrocytic activity in the dorsal striatum mitigates L-dopa-induced dyskinesia in Parkinson’s disease |
| title_full_unstemmed | Regulating astrocytic activity in the dorsal striatum mitigates L-dopa-induced dyskinesia in Parkinson’s disease |
| title_short | Regulating astrocytic activity in the dorsal striatum mitigates L-dopa-induced dyskinesia in Parkinson’s disease |
| title_sort | regulating astrocytic activity in the dorsal striatum mitigates l dopa induced dyskinesia in parkinson s disease |
| topic | Abnormal involuntary movements Striatum AAV-GFAP-hM3D(Gq) AAV-GFAP-hM4D(Gi) Clozapine N-oxide (CNO) 6-hydroxydopamine-induced mouse model |
| url | https://doi.org/10.1038/s41598-025-12104-5 |
| work_keys_str_mv | AT youngkyoungryu regulatingastrocyticactivityinthedorsalstriatummitigatesldopainduceddyskinesiainparkinsonsdisease AT hyeyeonpark regulatingastrocyticactivityinthedorsalstriatummitigatesldopainduceddyskinesiainparkinsonsdisease AT jueunkim regulatingastrocyticactivityinthedorsalstriatummitigatesldopainduceddyskinesiainparkinsonsdisease AT hyunheeseo regulatingastrocyticactivityinthedorsalstriatummitigatesldopainduceddyskinesiainparkinsonsdisease AT chulholee regulatingastrocyticactivityinthedorsalstriatummitigatesldopainduceddyskinesiainparkinsonsdisease AT kyoungshimkim regulatingastrocyticactivityinthedorsalstriatummitigatesldopainduceddyskinesiainparkinsonsdisease |