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

Abstract

Tonic inhibition in the brain is mediated through an activation of extrasynaptic GABA 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.

Bestrophin1‐mediated tonic GABA release from reactive astrocytes prevents the development of seizure‐prone network in kainate‐injected hippocampi

“…We have recently reported that astrocytic GABA, synthesized by monoamine oxidase‐B and released by Best1 channel, mediates tonic inhibition in various brain regions including the cerebellum, hippocampus, and striatum (Jo et al, ; Lee et al, ; Yoon et al, ). This astrocytic tonic GABA modulates brain function in physiological and pathological conditions through the tight regulation of E/I balance (Jo et al, ; Kim, Woo, Lee, & Yoon, ; Woo et al, ). In the Alzheimer disease model, we have reported that an aberrant GABA synthesis and release in reactive astrocytes causes memory impairment and proposed that a similar mechanism should be involved in other brain diseases where reactive astrocytes are present including Parkinson's disease, stroke, and epilepsy (Jo et al, ; Sofroniew, ).…”

GABAergic‐astrocyte signaling: A refinement of inhibitory brain networks

“…Astrocytes can release GABA via the Best1 channel which tonically activates both GABAARs and GABABRs, contributing to depression of excitatory synaptic transmission in hippocampal (Lee et al, ) and cerebellar networks (Jo et al, ; Yoon et al, ; Yoon & Lee, ), controlling motor coordination (Woo et al, ). A relevant feature of Best1 is its significant permeability to Cl in conjunction with GABA and glutamate in astrocytes (Lee et al, ; Park et al, ).…”

“…Astrocytes can release GABA via the Best1 channel which tonically activates both GABAARs and GABABRs, contributing to depression of excitatory synaptic transmission in hippocampal (Lee et al, 2010) and cerebellar networks , controlling motor coordination (Woo et al, 2018).…”

Spinal dorsal horn astrocytes release GABA in response to synaptic activation

“…It is now widely accepted that astrocytes release glutamate, ATP, D-serine or S100β (Zhang et al 2003;Perea & Araque, 2007;Henneberger et al 2010;Araque et al 2014;Morquette et al 2015). A few studies also suggest that GABA is released from astrocytes (Lee et al 2010(Lee et al , 2011Le Meur et al 2012;Jo et al 2014;Woo et al 2018). This idea is supported by the fact that astrocytes store GABA, as shown by immunohistochemistry (Blomqvist & Broman, 1988;Bull & Blomqvist, 1991;Gonzalo-Ruiz et al 1993).…”

“…; Woo et al . ). This idea is supported by the fact that astrocytes store GABA, as shown by immunohistochemistry (Blomqvist & Broman, ; Bull & Blomqvist, ; Gonzalo‐Ruiz et al .…”