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GABAergic network activity has been established to be involved in numerous physiological processes and pathological conditions. Extensive studies have corroborated that GABAergic network activity regulates excitatory synaptic networks by activating presynaptic GABAB receptors (GABABRs). It is well documented that astrocytes express GABABRs and respond to GABAergic network activity. However, little is known about whether astrocytic GABABRs regulate excitatory synaptic transmission mediated by GABAergic network activity. To address this issue, we combined whole‐cell recordings, optogenetics, calcium imaging, and pharmacological approaches to specifically activate hippocampal somatostatin‐expressing interneurons (SOM‐INs), a type of interneuron that targets pyramidal cell dendrites, while monitoring excitatory synaptic transmission in CA1 pyramidal cells. We found that optogenetic stimulation of SOM‐INs increases astrocyte Ca2+ signaling via the activation of astrocytic GABABRs and GAT‐3. SOM‐INs depress excitatory neurotransmission by activating presynaptic GABABRs and astrocytic GABABRs, the latter inducing the release of ATP/adenosine. In turn, adenosine inhibits excitatory synaptic transmission by activating presynaptic adenosine A1 receptors (A1Rs). Overall, our results reveal a novel mechanism that SOM‐INs activation‐induced synaptic depression is partially mediated by the activation of astrocytic GABABRs.

No abstract