Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson’s Disease
Open accessAbstract
Current pharmacological treatments for Parkinson's disease (PD) are focused on symptomatic relief, but not on disease modification, based on the strong belief that PD is caused by irreversible dopaminergic neuronal death. Thus, the concept of the presence of dormant dopaminergic neurons and its possibility as the disease-modifying therapeutic target against PD have not been explored. Here we show that optogenetic activation of substantia nigra pars compacta (SNpc) neurons alleviates parkinsonism in acute PD animal models by recovering tyrosine hydroxylase (TH) from the TH-negative dormant dopaminergic neurons, some of which still express DOPA decarboxylase (DDC). The TH loss depends on reduced dopaminergic neuronal firing under aberrant tonic inhibition, which is attributed to excessive astrocytic GABA. Blocking the astrocytic GABA synthesis recapitulates the therapeutic effect of optogenetic activation. Consistently, SNpc of postmortem PD patients shows a significant population of TH-negative/DDC-positive dormant neurons surrounded by numerous GABA-positive astrocytes. We propose that disinhibiting dormant dopaminergic neurons by blocking excessive astrocytic GABA could be an effective therapeutic strategy against PD.
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Excessive release of GABA by reactive astrocytes in AD and Parkinson's disease may be a case of gain of detrimental function.
“The excessive release of GABA by reactive astrocytes in AD63 and Parkinson’s disease64 may be a case of gain of detrimental function.”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [64]
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Neurotoxic reactive astrocytes are induced by activated microglia
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“As previously demonstrated [13, 14], we found that astrocytes in the SNpc became dramatically reactive in the A53T, 6-OHDA, and MPTP models as evidenced by increased GFAP expression, hypertrophy, and marked increase in GABA, while the protein expression of TH was significantly decreased compared to the control groups…”
BackgroundGlial reactions in Parkinson's disease
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Toll‐like receptor 4 is required for α‐synuclein dependent activation of microglia and astroglia
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Reactive astrocyte nomenclature, definitions, and future directions
Escartin, C., Galea, E., Lakatos, A., O’Callaghan, J. P., Petzold, G. C., Serrano-Pozo, A., Steinhäuser, C., Volterra, A., Carmignoto, G., Agarwal, A., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00783-4 · Cited by 2,533 · see citing works
Self-citationBeyond the GFAP-Astrocyte Protein Markers in the Brain
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- Authors
- Heo, J. Y., Nam, M.-H., Yoon, H. H., Kim, J., Hwang, Y. J., Won, W., Woo, D. H., Lee, J. A., Park, H.-J., Jo, S., Lee, M. J., Kim, S., Shim, J.-E., Jang, D.-P., Kim, K. I., Huh, S. H., Jeong, J. Y., Kowall, N. W., Lee, J., Im, H., Park, J. H., Jang, B. K., Park, K. D., Lee, H. J., Shin, H., Cho, I.-J., Hwang, E. M., Kim, Y., Kim, H. Y., Oh, S.-J., Lee, S. E., Paek, S. H., Yoon, J. H., Jin, B. K., Kweon, G. R., Shim, I., Hwang, O., Ryu, H., Jeon, S. R., & Lee, C. J.
- Affiliations
- Chungnam National University (KR)
- Kyung Hee University (KR)
- Asan Medical Center (KR)
- Korea Brain Research Institute (KR)
- Korea Institute of Science and Technology (KR)
- Korea University (KR)
- Boston University (US)
- Korea Advanced Institute of Science and Technology (KR)
- Hanyang University (KR)
- Convergence Research Center for Diagnosis Treatment and Care System of Dementia (KR)
- Yonsei University (KR)
- Seoul National University (KR)
- University of Ulsan (KR)
- Corresponding author
- Ryu, Hoon
- Jeon, Sang Ryong
- Lee, C. Justin
- ORCID
- Heo, Jun Young
- Nam, Min-Ho
- Yoon, Hyung Ho
- Kim, Jeongyeon
- Won, Woojin
- Woo, Dong Ho
- Lee, Ji Ae
- Park, Hyun-Jung
- Jo, Seonmi
- Lee, Min Joung
- Kim, Sunpil
- Jang, Dong-Pyo
- Jeong, Jae Y.
- Kowall, Neil W.
- Park, Jong Hyun
- Jang, Bo Ko
- Park, Ki Duk
- Lee, Hyunjoo J.
- Shin, Hyogeun
- Cho, Il-Joo
- Hwang, Eun Mi
- Kim, Hye Yun
- Oh, Soo-Jin
- Lee, Seung Eun
- Paek, Sun Ha
- Yoon, Jong Hyuk
- Jin, Byung K.
- Kweon, Gi Ryang
- Shim, Insop
- Hwang, Onyou
- Ryu, Hoon
- Jeon, Sang Ryong
- Lee, C. Justin
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2020-01
- Volume
- 30
- Issue
- 2
- Pages
- 276-291.e9
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2999816645
- Cited by
- 135
- References
- 6
- Citations by year
- 2026: 15 · 2025: 21 · 2024: 33 · 2023: 24 · 2022: 19 · 2021: 19 · 2020: 4
- FWCI
- 7.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Science and ICT, South Korea
- Asan Institute for Life Sciences, Asan Medical Center
- Institute for Basic Science
- National Research Foundation of Korea
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Parkinson's disease, parkinsonism, substantia nigra pars compacta, dopaminergic neurons, tyrosine hydroxylase, aromatic L-amino acid decarboxylase, tonic inhibition, optogenetic stimulation, disease modification, GABA synthesis inhibition
- MeSH terms
- Aged, Aged, 80 and over, Animals, Astrocytes, Disease Models, Animal, Female, gamma-Aminobutyric Acid, Humans, Male, Mice, Inbred C57BL, Mice, Inbred ICR, Middle Aged, Nerve Degeneration, Parkinson Disease, Tyrosine 3-Monooxygenase, Down-Regulation, Rats, Wistar, Immobility Response, Tonic, Mice, Rats, Dopaminergic Neurons
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