Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson's Disease.,Current Biology

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Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson's Disease.
Current Biology ( IF 8.1 ) Pub Date : 2020-01-09 , DOI: 10.1016/j.cub.2019.11.079
Jun Young Heo ₁ , Min-Ho Nam ₂ , Hyung Ho Yoon ₃ , Jeongyeon Kim ₄ , Yu Jin Hwang ₅ , Woojin Won ₆ , Dong Ho Woo ₇ , Ji Ae Lee ₈ , Hyun-Jung Park ₉ , Seonmi Jo ₁₀ , Min Joung Lee ₁₁ , Sunpil Kim ₆ , Jeong-Eun Shim ₁₂ , Dong-Pyo Jang ₁₂ , Kyoung I Kim ₁₃ , Sue H Huh ₁₃ , Jae Y Jeong ₁₃ , Neil W Kowall ₁₄ , Junghee Lee ₁₄ , Hyeonjoo Im ₁₅ , Jong Hyun Park ₁₆ , Bo Ko Jang ₁₆ , Ki Duk Park ₁₆ , Hyunjoo J Lee ₁₇ , Hyogeun Shin ₁₇ , Il-Joo Cho ₁₇ , Eun Mi Hwang ₁₈ , YoungSoo Kim ₁₉ , Hye Yun Kim ₂₀ , Soo-Jin Oh ₂₁ , Seung Eun Lee ₂₂ , Sun Ha Paek ₂₃ , Jong Hyuk Yoon ₂₄ , Byung K Jin ₁₃ , Gi Ryang Kweon ₁₁ , Insop Shim ₉ , Onyou Hwang ₈ , Hoon Ryu ₂₅ , Sang Ryong Jeon ₃ , C Justin Lee ₂₆

Affiliation

Center for Neuroscience, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Korea; Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon 35015, Korea.
Center for Neuroscience, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Korea.
Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
Center for Neuroscience, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; Emotion, Cognition and Behavior Research Group, Korea Brain Research Institute, Daegu 41062, Korea.
Center for Neuro-Medicine, Brain Science Institute, KIST, Seoul 02792, Korea.
Center for Neuroscience, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; KU-KIST Graduate School of Converging Science of Technology, Korea University, Seoul 02841, Korea.
Center for Neuroscience, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 05505, Korea.
Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul 02447, Korea.
Center for Neuroscience, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea; Department of Genetic Resources Research, National Marine Biodiversity Institute of Korea, Seocheon 33662, Korea.
Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Korea; Infection Control Convergence Research Center, College of Medicine, Chungnam National University, Daejeon 35015, Korea.
Department of Biomedical Engineering, Hanyang University, Seoul 04763, Korea.
Department of Biochemistry & Molecular Biology, Department of Neuroscience, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul 02447, Korea.
Boston University Alzheimer's Disease Center, Boston University School of Medicine, Boston, MA 02118, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA; VA Boston Healthcare System, Boston, MA 02132, USA.
Center for Neuroscience, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; Center for Neuro-Medicine, Brain Science Institute, KIST, Seoul 02792, Korea.
Convergence Research Center for Dementia, KIST, Seoul 02792, Korea.
Center for BioMicrosystems, Brain Science Institute, KIST, Seoul 02792, Korea.
Center for Functional Connectomics, KIST, Seoul 02792, Korea.
Center for Neuro-Medicine, Brain Science Institute, KIST, Seoul 02792, Korea; Department of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, and Integrated Science and Engineering Division, Yonsei University, Incheon 21983, Korea.
Department of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, and Integrated Science and Engineering Division, Yonsei University, Incheon 21983, Korea.
Center for Neuroscience, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; Convergence Research Center for Dementia, KIST, Seoul 02792, Korea.
Virus Facility, Research Animal Resource Center, KIST, Seoul 02792, Korea.
Department of Neurosurgery, Seoul National University Hospital, Seoul 03080, Korea.
Neurodegenerative Diseases Research Group, Korea Brain Research Institute, Daegu 41062, Korea.
Center for Neuroscience, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; Center for Neuro-Medicine, Brain Science Institute, KIST, Seoul 02792, Korea; Boston University Alzheimer's Disease Center, Boston University School of Medicine, Boston, MA 02118, USA; Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA; VA Boston Healthcare System, Boston, MA 02132, USA.
Center for Neuroscience, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea; KU-KIST Graduate School of Converging Science of Technology, Korea University, Seoul 02841, Korea; Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34126, Korea.

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.

中文翻译：

多巴胺能神经元活动的异常补品抑制导致帕金森氏病动物模型中的运动症状。

基于帕金森氏病（PD）是由不可逆的多巴胺能神经元死亡引起的坚信，目前针对帕金森氏病（PD）的药物治疗主要集中在症状缓解上，而不是疾病改变上。因此，尚未探索休眠的多巴胺能神经元的存在的概念及其作为针对PD的疾病改良治疗靶标的可能性。在这里我们显示，黑质致密部（SNpc）神经元的光遗传激活可通过从TH阴性的多巴胺能神经元中恢复酪氨酸羟化酶（TH）来缓解急性PD动物模型中的帕金森氏病，其中一些仍表达DOPA脱羧酶（DDC）。TH的丧失取决于在异常的补药抑制下多巴胺能神经元放电的减少，这归因于过多的星形细胞GABA。阻断星形细胞GABA的合成概括了光遗传激活的治疗作用。一致地，死后PD患者的SNpc显示大量被许多GABA阳性星形胶质细胞包围的TH阴性/ DDC阳性休眠神经元。我们建议通过阻止过量的星形细胞GABA抑制休眠的多巴胺能神经元可能是针对PD的有效治疗策略。

更新日期：2020-01-09

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