GABAergic signaling to astrocytes in the prefrontal cortex sustains goal-directed behaviors

GABA interneurons play a critical role in higher brain functions. Astrocytic glial cells interact with synapses throughout the whole brain and are recognized as regulatory elements of excitatory synaptic transmission. However, it is largely unknown how GABAergic interneurons and astrocytes interact and contribute to stable performance of complex behaviors. Here, we found that genetic ablation of GABA receptors in medial prefrontal cortex astrocytes altered low-gamma oscillations and firing properties of cortical neurons, which affected goal-directed behaviors. Remarkably, working memory deficits were restored by optogenetic stimulation of astrocytes with melanopsin. Furthermore, melanopsin-activated astrocytes in wild-type mice enhanced the firing rate of cortical neurons and gamma oscillations, as well as improved cognition. Therefore, our work identifies astrocytes as a hub for controlling inhibition in cortical circuits, providing a novel pathway for the behaviorally relevant midrange time-scale regulation of cortical information processing and consistent goal-directed behaviors.We thank the T. Korotkova Lab, C. González-Arias and C. Heikenfeld for technical support; the Molecular and Cellular Biology Unit from the Cajal Institute for technical assistance; B. Bettler, A. Araque, M. Navarrete, E. D. Martín and A. Fernández-Ruiz for critical review of the manuscript; and Buzsáki Lab members for valuable suggestions. This work was supported by the MCIU/AEI/FEDER, UE (BES-2014-067594) to S.M.; a European Molecular Biology Organization (EMBO) postdoctoral fellowship (EMBO ALTF 1161-2017) and a Human Frontiers Science Program (HFSP) postdoctoral fellowship (LT0000717/2018) to M.V.; the Deutsche Forschungsgemeinschaft (DFG: SPP1665, 1799/1-2 and Heisenberg Program 1799/2-1 and 1799/3-1) to A.P.; the MCIU/AEI/FEDER, UE (BFU2016-75107-P), and MCIU/AEI/FEDER, UE (PID2019- 106579RB-I00), 202020E073 from the CSIC, and the Cajal Blue Brain Project (C080020- 09; the Spanish partner of the Blue Brain Project initiat