GABA_B Receptors Mediate Intracellular Calcium Release in Astrocytes of the Prefrontal Cortex

The prefrontal cortex (PFC) is a cortical brain region whose multifaceted functions are based on a complex interplay between excitatory pyramidal neurons, inhibitory GABAergic interneurons, and astrocytes maintaining a fine-tuned excitation/inhibition balance (E/I balance). The regulation of the E/I balance in cortical networks is crucial as the disruption leads to impairments in PFC-associated behavior and pathologies. Astrocytes express specific GABA receptors that mediate intracellular Ca²⁺ signaling upon stimulation by γ-aminobutyric acid (GABA), resulting in the release of gliotransmitters. GABA-mediated Ca²⁺ signaling in astrocytes has been of great interest in the past; however, especially, the signaling pathway greatly varies across brain regions and from development to adulthood. Here we took advantage of GLAST-promoter driven GCaMP6s expression in astrocytes to study GABAergic Ca²⁺ signaling, especially in young adult astrocytes of the PFC by confocal microscopy. The results show that GABA induces Ca²⁺ signaling via the stimulation of the metabotropic GABA_B receptor in astrocytes. GABA_B receptor-mediated Ca²⁺ signals greatly depend on intracellular Ca²⁺ stores rather than on extracellular Ca²⁺. Additionally, antagonists of the PLC/IP₃-signaling cascade significantly reduced GABA_B receptor-mediated Ca²⁺ signaling in astrocytes. Moreover, inhibition of the G_i/o signaling cascade did not have an effect on GABA_Breceptor-mediated Ca²⁺ transients, suggesting that astrocytic GABA_B receptors in the PFC of adolescent mice are coupled to the G_q-GPCR signaling pathway exclusively.