CALCIUM ELEVATION IN ASTROCYTES CAUSES AN NMDA RECEPTOR-DEPENDENT INCREASE IN THE FREQUENCY OF MINIATURE SYNAPTIC CURRENTS IN CULTURED HIPPOCAMPAL-NEURONS

Astrocytes exhibit a form of excitability and communication on the bas is of intracellular Ca2+ variations (Cornell-Bell et al., 1990; Charle s et al., 1991) that can be initiated by neuronal activity (Dani et al ., 1992; Porter and McCarthy, 1996). A Ca2+ elevation in astrocytes in duces the release of glutamate (Parpura et al., 1994; Pasti et al., 19 97; Araque et al., 1998; Bezzi et al., 1998), which evokes a slow inwa rd current in neurons and modulates action potential-evoked synaptic t ransmission between cultured hippocampal cells (Araque et al., 1998), suggesting that astrocytes and neurons may function as a network with bidirectional communication. Here we show that a Ca2+ elevation in ast rocytes increases the frequency of excitatory as well as inhibitory mi niature postsynaptic currents (mPSCs), without modifying their amplitu des. Thapsigargin incubation, microinjection of the Ca2+ chelator BAPT A, and photolysis of the Ca2+ cage NP-EGTA demonstrate that a Ca2+ ele vation in astrocytes is both necessary and sufficient to modulate spon taneous transmitter release. This Ca2+-dependent release of glutamate from astrocytes enhances mPSC frequency by acting on NMDA glutamate re ceptors, because it is antagonized by D-2-amino-5-phosphonopentanoic a cid (AP5) or extracellular Mg2+. These NMDA receptors are located extr asynaptically, because blockage specifically of synaptic NMDA receptor s by synaptic activation in the presence of the open channel blocker M K-801 did not impair the AP5-sensitive astrocyte-induced increase of m PSC frequency. Therefore, astrocytes modulate spontaneous excitatory a nd inhibitory synaptic transmission by increasing the probability of t ransmitter release via the activation of NMDA receptors.