Glial-neuronal crosstalk via GABA signaling: mechanistic insights into neuropsychiatric and neurological pathophysiology.

Glial cells-including astrocytes, microglia, oligodendrocytes (OLs), and oligodendrocyte progenitor cells (OPCs)- are essential for maintaining central nervous system (CNS) homeostasis, shaping neural circuits, supporting neuronal function, and regulating immune responses and myelination. These cells engage in dynamic and reciprocal interactions with neurons, which are frequently disrupted under pathological conditions. Emerging evidence identifies γ-aminobutyric acid (GABA), classically known as the principal inhibitory neurotransmitter, as a key mediator of glia-neuron communication. Glial cells express diverse GABA receptor subtypes, enabling them to sense and respond to neuronal GABA release. Beyond sensing, glia also synthesize, uptake, and release GABA, thereby modulating neuronal excitability and network activity. Notably, GABA metabolism occurs primarily within mitochondria, linking neurotransmitter signaling to cellular bioenergetics. Perturbations in GABA metabolic pathways-commonly observed in disease states-can impair mitochondrial function, trigger glial state transitions, and disrupt circuit homeostasis. These alterations contribute to disease pathogenesis and exacerbate progression. In this review, we summarize current findings on GABA-mediated glial-neuronal crosstalk, with emphasis on its roles in CNS physiology and its multifaceted regulation in neurological and neuropsychiatric disorders. We further highlight recent advances linking GABA metabolism to mitochondrial homeostasis in glial cells, offering mechanistic insights into how GABAergic signaling shapes brain health and pathology.