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인지 및 사회성 연구단
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Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson's Disease

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Title
Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson's Disease
Author(s)
C. Justin Lee; Park, KD; Kweon, GR; Kim, J; Hwang, O; Shim, JE; Cho, IJ; Hwang, YJ; Jeong, JY; Woo, DH; Oh, SJ; Lee, SE; Shin, H; Lee, HJ; Kim, S; Kowall, NW; Kim, HY; Jeon, SR; Kim, Y; Jang, BK; Park, JH; Lee, JA; Yoon, HH; Heo, JY; Won, W; Jin, BK; Nam, MH; Lee, MJ; Kim, KI; Yoon, JH; Paek, SH; Jo, S; Park, HJ; Huh, SH; Ryu, H; Lee, J; Shim, I
Subject
MONOAMINE-OXIDASE-B, ; REVERSIBLE PARKINSONISM, ; TYROSINE-HYDROXYLASE, ; REACTIVE ASTROCYTES, ; SUBSTANTIA-NIGRA, ; ALPHA-SYNUCLEIN, ; RAT MODEL, ; INFLAMMATORY RESPONSES, ; GABA RELEASE, ; NEURODEGENERATION
Publication Date
2020-01
Journal
CURRENT BIOLOGY, v.30, no.2, pp.276 - 291
Publisher
CELL PRESS
Abstract
ª 2019 Elsevier Ltd. 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
https://pr.ibs.re.kr/handle/8788114/8734
DOI
10.1016/j.cub.2019.11.079
ISSN
0960-9822
Appears in Collections:
Center for Cognition and Sociality(인지 및 사회성 연구단) > 1. Journal Papers (저널논문)
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