Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson’s Disease

Title
Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson’s Disease
Authors
오수진이창준조일주박기덕황은미박종현남민호이승은류훈장보고신효근허준영임현주윤형호김정연황유진원우진우동호이지애박현정조선미이민정김선필심정은장동표김경인허수희정재영Neil W. Kowall이정희이현주김영수김혜연백선하윤종혁진병관권기량심인섭황온유전상용
Issue Date
2020-01
Publisher
Current biology : CB
Abstract
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.
URI
http://pubs.kist.re.kr/handle/201004/63090
ISSN
0960-9822
Appears in Collections:
KIST Publication > Article
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