Astrocytes convert network excitation to tonic inhibition of neurons

Here we present evidence that glutamate uptake-induced release of GABA from astrocytes has a direct impact on the excitability of pyramidal neurons in the hippocampus. We demonstrate that GABA, synthesized from the polyamine putrescine, is released from astrocytes by the reverse action of glial GABA transporter (GAT) subtypes GAT-2 or GAT-3. GABA release can be prevented by blocking glutamate uptake with the non-transportable inhibitor DHK, confirming that it is the glutamate transporter activity that triggers the reversal of GABA transporters, conceivably by elevating the intracellular Na+ concentration in astrocytes. The released GABA significantly contributes to the tonic inhibition of neurons in a network activity-dependent manner. Blockade of the Glu/GABA exchange mechanism increases the duration of seizure-like events in the low-[Mg2+] in vitro model of epilepsy. Under in vivo conditions the increased GABA release modulates the power of gamma range oscillation in the CA1 region, suggesting that the Glu/GABA exchange mechanism is also functioning in the intact hippocampus under physiological conditions.The results suggest the existence of a novel molecular mechanism by which astrocytes transform glutamatergic excitation into GABAergic inhibition providing an adjustable, in situ negative feedback on the excitability of neurons.Glial cells have long been considered to have only a supporting role in the central nervous system. Substantial advances in the past two decades, however, shed light on the various physiological functions they perform and led to the current view that they are active participants of the tripartite synapse [1,2], consisting of the presynaptic and postsynaptic neurons as well as the glial cells, in particular astrocytes. Several studies demonstrated the ability of astrocytes to sense, respond to and regulate neuronal function. Importantly, astrocytes possess the complete set of membrane proteins to detect γ-aminobutyric acid (GABA) and glutam