GABA Release from Astrocytes in Health and Disease

Abstract

Astrocytes are the most abundant glial cells in the central nervous system (CNS) mediating a variety of homeostatic functions, such as spatial K+ buffering or neurotransmitter reuptake. In addition, astrocytes are capable of releasing several biologically active substances, including glutamate and GABA. Astrocyte-mediated GABA release has been a matter of debate because the expression level of the main GABA synthesizing enzyme glutamate decarboxylase is quite low in astrocytes, suggesting that low intracellular GABA concentration ([GABA]i) might be insufficient to support a non-vesicular GABA release. However, recent studies demonstrated that, at least in some regions of the CNS, [GABA]i in astrocytes might reach several millimoles both under physiological and especially pathophysiological conditions, thereby enabling GABA release from astrocytes via GABA-permeable anion channels and/or via GABA transporters operating in reverse mode. In this review, we summarize experimental data supporting both forms of GABA release from astrocytes in health and disease, paying special attention to possible feedback mechanisms that might govern the fine-tuning of astrocytic GABA release and, in turn, the tonic GABAA receptor-mediated inhibition in the CNS.

Tonic activation of GABAB receptors via GAT-3 mediated GABA release reduces network activity in the developing somatosensory cortex in GAD67-GFP mice

“…While GABA transporters like GAT-1 are localized predominantly on neurons, GAT-3 is expressed by astrocytes ( Minelli et al, 1995 ; Minelli et al, 1996 ). GAT-3-mediated GABA release from astrocytes has been shown in several brain regions (for review see: Kilb and Kirischuk, 2022 ), and it was shown to have neuroprotective effects in animal models of brain injury ( Cho et al, 2022 ). Elevation of intra-astrocytic Na + leads to switching GAT-3 into GABA efflux mode ( Heja et al, 2009 ; Heja et al, 2012 ).…”

Astrocytic GABAergic Regulation in Alcohol Use and Major Depressive Disorders

“…Each process responds to various pathophysiological stimuli to maintain GABA homeostasis. These processes are multifaceted, with distinct mechanisms operating in different cell types and regions of the brain [30,[51][52][53][54][55]. Due to their close association with neurons and ability to engage in GABA synthesis, release, and reuptake, astrocytes are now considered pivotal contributors to the intricate task of regulating GABA homeostasis within the CNS [56].…”

“…The release of GABA from astrocytes occurs through three distinct mechanisms: calcium-dependent vesicular exocytosis, direct release into the extracellular space via GABA transporters (GATs) in reverse mode, or through GABA-permeable channels [51,60,61]. GATs function as secondary active electrogenic transporters and utilize sodium and chloride ion exchange with GABA uptake.…”

“…Furthermore, astrocytic GABA release is facilitated by permeable membrane channels, such as BEST1, which is a calcium-dependent anion channel and is considered a vital mechanism of astrocytic GABA release [51]. Astrocytic GABA is known to interact with mainly surrounding neurons [50].…”

“…Interestingly, the genetic ablation of GAT3 is lethal in mice, suggesting its critical role in GABA homeostasis during early embryogenesis and development [67]. Furthermore, astrocytic GABA release is facilitated by permeable membrane channels, such as BEST1, which is a calcium-dependent anion channel and is considered a vital mechanism of astrocytic GABA release [51]. Astrocytic GABA is known to interact with mainly surrounding neurons [50].…”