Control of motor coordination by astrocytic tonic GABA release through modulation of excitation/inhibition balance in cerebellum

Junsung Woo, Joo Ok Min, Dae Si Kang, Yoo Sung Kim, Guk Hwa Jung, Hyun Jung Park, Sunpil Kim, Heeyoung An, Jea Known, Jeongyeon Kim, Insop Shim, Hyung Gun Kim, C. Justin Lee, Bo Eun Yoon

Research output: Contribution to journalArticlepeer-review

65 Citations (Scopus)

Abstract

Tonic inhibition in the brain is mediated through an activation of extrasynaptic GABAA receptors by the tonically released GABA, resulting in a persistent GABAergic inhibitory action. It is one of the key regulators for neuronal excitability, exerting a powerful action on excitation/inhibition balance. We have previously reported that astrocytic GABA, synthesized by monoamine oxidase B (MAOB), mediates tonic inhibition via GABA-permeable bestrophin 1 (Best1) channel in the cerebellum. However, the role of astrocytic GABA in regulating neuronal excitability, synaptic transmission, and cerebellar brain function has remained elusive. Here, we report that a reduction of tonic GABA release by genetic removal or pharmacological inhibition of Best1 or MAOB caused an enhanced neuronal excitability in cerebellar granule cells (GCs), synaptic transmission at the parallel fiber-Purkinje cell (PF-PC) synapses, and motor performance on the rotarod test, whereas an augmentation of tonic GABA release by astrocyte-specific overexpression of MAOB resulted in a reduced neuronal excitability, synaptic transmission, and motor performance. The bidirectional modulation of astrocytic GABA by genetic alteration of Best1 or MAOB was confirmed by immunostaining and in vivo microdialysis. These findings indicate that astrocytes are the key player in motor coordination through tonic GABA release by modulating neuronal excitability and could be a good therapeutic target for various movement and psychiatric disorders, which show a disturbed excitation/inhibition balance.

Original languageEnglish
Pages (from-to)5004-5009
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number19
DOIs
Publication statusPublished - 2018 May 8

Bibliographical note

Funding Information:
This study was supported by the Creative Research Initiative Program through the National Research Foundation (NRF) of Korea (Grant 2015R1A3A2066619); the Korea Institute of Science and Technology (KIST) Institutional Grant 2E26662; and the Korea University (KU)-KIST Graduate School of Science and Technology program (Grant R1435281) (to C.J.L.). This research was also supported by the Brain Research Program through the NRF of Korea, funded by the Ministry of Science, ICT, & Future Planning (Grant NRF-2016M3C7A1905074); and the Small Grant for Exploratory Research Program (Grant NRF-2016R1D1A1A02937398) (to B.-E.Y.).

Funding Information:
ACKNOWLEDGMENTS. This study was supported by the Creative Research Initiative Program through the National Research Foundation (NRF) of Korea (Grant 2015R1A3A2066619); the Korea Institute of Science and Technology (KIST) Institutional Grant 2E26662; and the Korea University (KU)-KIST Graduate School of Science and Technology program (Grant R1435281) (to C.J.L.). This research was also supported by the Brain Research Program through the NRF of Korea, funded by the Ministry of Science, ICT, & Future Planning (Grant NRF-2016M3C7A1905074); and the Small Grant for Exploratory Research Program (Grant NRF-2016R1D1A1A02937398) (to B.-E.Y.).

Publisher Copyright:
© 2018 National Academy of Sciences. All rights reserved.

Keywords

  • Astrocyte
  • Cerebellum
  • Motor coordination
  • Neuronal excitability
  • Tonic GABA

ASJC Scopus subject areas

  • General

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