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, Changjoon Lee, Bo Eun Yoon

Research output: Contribution to journalArticle

13 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

Keywords

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

ASJC Scopus subject areas

  • General

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  • Cite this

    Woo, J., Min, J. O., Kang, D. S., Kim, Y. S., Jung, G. H., Park, H. J., Kim, S., An, H., Known, J., Kim, J., Shim, I., Kim, H. G., Lee, C., & Yoon, B. E. (2018). Control of motor coordination by astrocytic tonic GABA release through modulation of excitation/inhibition balance in cerebellum. Proceedings of the National Academy of Sciences of the United States of America, 115(19), 5004-5009. https://doi.org/10.1073/pnas.1721187115