GABA Signaling in Glioma: Paradoxes and Therapeutic Perspectives

Glioma is the most common primary malignant brain tumor in adults and is characterized by an extremely poor prognosis. A distinctive feature of glioma is its profound dependence on the unique brain microenvironment. Gamma-Aminobutyric Acid (GABA), the principal inhibitory neurotransmitter in the central nervous system, has been implicated in the regulation of glioma pathophysiology. However, evidence regarding its influence on tumor progression remains highly contradictory. Current findings indicate that GABA can exert either tumor-suppressive or tumor-promoting effects depending on multiple interconnected factors, including Isocitrate Dehydrogenase 1 (IDH1) mutation status, intracellular chloride ion concentration governed by Na+-K+-Cl- Cotransporter 1 (NKCC1) and K+-Cl- Cotransporter 2 (KCC2) transporters, heterogeneous GABAA and GABAB receptor expression patterns, and dynamic glioma-neuron synaptic interactions. Among these, the NKCC1/KCC2 balance emerges as a central molecular switch governing intracellular chloride homeostasis and, consequently, the functional polarity of GABAA receptor activation. This review provides a comprehensive overview of the complex and paradoxical roles of GABA signaling in glioma biology, with particular emphasis on dysregulated GABA synthesis and catabolism as well as divergent GABA receptor-mediated mechanisms. Furthermore, we discuss potential explanations for the conflicting findings reported in the literature and highlight promising therapeutic targets within the GABAergic system, including metabolic enzymes, chloride cotransporters, and specific receptor antagonists that may be exploited for clinical intervention.