Details

Autor(en) / Beteiligte

• Heo, Jun Young
• Nam, Min-Ho
• Yoon, Hyung Ho
• Kim, Jeongyeon
• Hwang, Yu Jin
• Won, Woojin
• Woo, Dong Ho
• Lee, Ji Ae
• Park, Hyun-Jung
• Jo, Seonmi
• Lee, Min Joung
• Kim, Sunpil
• Shim, Jeong-Eun
• Jang, Dong-Pyo
• Kim, Kyoung I.
• Huh, Sue H.
• Jeong, Jae Y.
• Kowall, Neil W.
• Lee, Junghee
• Im, Hyeonjoo
• Park, Jong Hyun
• Jang, Bo Ko
• Park, Ki Duk
• Lee, Hyunjoo J.
• Shin, Hyogeun
• Cho, Il-Joo
• Hwang, Eun Mi
• Kim, YoungSoo
• 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

Titel

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

Ist Teil von

• Current biology, 2020-01, Vol.30 (2), p.276-291.e9

Ort / Verlag

England: Elsevier Inc

Erscheinungsjahr

2020

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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. [Display omitted] •Reactive astrocytes in SNpc produce excessive GABA via MAO-B in animal models of PD•Aberrant tonic inhibition causes reduced DA production in neurons and motor deficits•Dormant neurons are rescued by MAO-B inhibition or optogenetic neuronal activation Heo et al. report that astrocytic GABA-mediated aberrant tonic inhibition of DA neurons leads to a reduction in TH expression and dopamine production, causing dormant DA neurons and motor deficits. Blocking astrocytic GABA synthesis by MAO-B inhibition or optogenetic activation of dormant DA neurons reverses PD pathology.