Diagnostic and therapeutic potential of tonic gamma‐aminobutyric acid from reactive astrocytes in brain diseases

Abstract

Diagnostic and therapeutic potential of tonic gamma-aminobutyric acid from reactive astrocytes in brain diseasesDear Editor, Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain, serves as a cornerstone in modulating neuronal activity and maintaining cognitive functions. Its role extends beyond fast-acting phasic inhibition, as slow-acting tonic GABA inhibition, mediated by extrasynaptic GABA A receptors, responds to ambient GABA levels (i.e. GABA tone), significantly influencing synaptic plasticity, learning and memory, and sensory processing. 1 Dysregulation of tonic GABA inhibition in a range of neurological and psychiatric diseases is associated with cognitive decline, motor symptoms, and other functional impairments, highlighting the potentially broad impact of GABA tone across various diseases. One of the common cellular responses in pathological conditions is the emergence of reactive astrocytes, 2 often accompanied by upregulation of monoamine oxidase B (MAO-B) expression and increased GABA synthesis (Figure 1A), thus affecting neighbouring neurons through tonic inhibition. 3 Here, we present the impact of pathological GABA tone and propose its therapeutic and diagnostic targets for clinical applications.Astrocytes once thought to be mere support cells, emerge as key players in the regulation of GABA tone through various mechanisms of GABA synthesis, release, and clearance. 1 These cells are strategically positioned to interface closely with neurons, allowing them to effectively regulate GABA tone in the extrasynaptic space. This role becomes particularly crucial in a range of pathological conditions, such as Alzheimer's 3-5 and Parkinson's diseases. 6,7 In these conditions, astrocytes become reactive, exhibiting increased MAO-B expression and enhanced GABA synthesis, which contributes to an elevated GABA tone and leads to pathological symptoms. This phenomenon is not limited to Alzheimer's and Parkinson's disease but is also observed in stroke, 8 depression, 9 obesity, 10 and potentially extends to conditions like post-traumatic stress disorderThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.