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

Jun Young Heo, Min Ho Nam, Hyung Ho Yoon, Jeongyeon Kim, Yu Jin Hwang, Woojin Won, Dong Ho Woo, Ji Ae Lee, Hyun Jung Park, Seonmi Jo, Min Joung Lee, Sunpil Kim, Jeong Eun Shim, Dong Pyo Jang, Kyoung I. Kim, Sue H. Huh, Jae Y. Jeong, Neil W. Kowall, Junghee Lee, Hyeonjoo ImJong Hyun Park, Bo Ko Jang, Ki Duk Park, Hyunjoo J. Lee, Hyogeun Shin, Il Joo Cho, Eun Mi Hwang, Young Soo Kim, Hye Yun Kim, Soo Jin Oh, Seung Eun Lee, Sun Ha Paek, Jong Hyuk Yoon, Byung K. Jin, Gi Ryang Kweon, Insop Shim, Onyou Hwang, Hoon Ryu, Sang Ryong Jeon, C. Justin Lee

Research output: Contribution to journalArticle

1 Citation (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)276-291.e9
JournalCurrent Biology
Volume30
Issue number2
DOIs
Publication statusPublished - 2020 Jan 20

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Fingerprint Dive into the research topics of 'Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson's Disease'. Together they form a unique fingerprint.

  • Cite this

    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., ... Lee, C. J. (2020). Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson's Disease. Current Biology, 30(2), 276-291.e9. https://doi.org/10.1016/j.cub.2019.11.079