Gi/o protein-coupled receptors inhibit neurons but activate astrocytes and stimulate gliotransmission

G protein-coupled receptors (GPCRs) play key roles in intercellular signaling in the brain. Their effects on cellular function have been largely studied in neurons, but their functional consequences on astrocytes are less known. Using both endogenous and chemogenetic approaches with DREADDs, we have investigated the effects of G_q and G_i/o GPCR activation on astroglial Ca²⁺-based activity, gliotransmitter release, and the functional consequences on neuronal electrical activity. We found that while G_qGPCR activation led to cellular activation in both neurons and astrocytes, G_i/oGPCR activation led to cellular inhibition in neurons and cellular activation in astrocytes. Astroglial activation by either G_q or G_i/o protein-mediated signaling stimulated gliotransmitter release, which increased neuronal excitability. Additionally, activation of G_q and G_i/o DREADDs in vivo increased astrocyte Ca²⁺ activity and modified neuronal network electrical activity. Present results reveal additional complexity of the signaling consequences of excitatory and inhibitory neurotransmitters in astroglia-neuron network operation and brain function.