Inhibition of Astrocytic Glutamate Transporter and Stimulation of Glutamate Release from Astrocytes Mediated via an A_<2a> Adenosine Receptor/PKA Signaling Pathway

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A low concentration(10nM) of adenosine facilitated hippocampal neurotransmission via an A_<2a> adenosine receptor/protein kinase A(PKA) signaling pathway, and a similar effect was obtained with mice lacking the astrocytic glutamate transporter GLT-1. Adenosine had no effect on transmitter release from presynaptic terminals or postsynaptic membrane conductances. Adenosine inhibited GLT-1 function, i.e., uptake of glutamate into astrocytes, as mediated via an A_<2a> adenosine receptor/PKA signaling pathway. Furthermore, adenosine stimulated vesicular glutamate release from astrocytes via an A_<2a> adenosine receptor/PKA signaling pathway, independently of reverse transport of glutamate by glutamate transporters. Adenosine also enhanced intracellular Ca^<2+> concentrations in astrocytes via A_<2a> adenosine receptors involving PKA activation, perhaps by vesicular Ca^<2+> release from an unknown intracellular calcium store, which may trigger glutamate release. The effects of adenosine on astrocytic glutamate transporters and astrocytic glutamate release would cause an increase in glutamate concentrations in the synaptic clefts, responsible for the facilitatory action on hippocampal neurotransmission. The results of the present study, thus, may represent a new neuromodulatory pathway with an astrocytic contribution mediated via an A_<2a> adenosine receptor/PKA signaling pathway.