ABSTRACT An accumulating amount of data suggests that Ca 2+ -dependent gliotransmitter release plays a key role in the modulation of neuronal networks. Here, we tested the hypothesis that in response to agonist exposure, astrocytes release lipid modulators through activation of Ca 2+ -independent phospholipase A 2 (iPLA 2 ) activity. We found that cultured rat astrocytes treated with selective ATP and glutamatergic agonists released arachidonic acid (AA) and/or its derivatives, including the endogenous cannabinoid 2-arachidonoyl-sn-glycerol (2AG) and prostaglandin E2 (PGE 2 ). Surprisingly, the buffering of cytosolic Ca 2+ resulted in a sharp increase in agonist-induced lipid release by astrocytes. In addition, the astrocytic release of PGE 2 increased miniature excitatory postsynaptic potentials (mEPSPs) by inhibiting the opening of neuronal Kv channels in brain slices. This study provides the first evidence showing that a Ca 2+ -independent pathway regulates the release of PGE 2 from astrocytes and further demonstrates the functional role of astrocytic lipid release in the modulation of synaptic activity. SIGNIFICANCE Until now, most studies that implicate astrocytes in the modulation of synaptic activity have focused on Ca 2+ -dependent release of traditional gliotransmitters such as D-serine, ATP, and glutamate. Mobilization of intracellular stores of Ca 2+ occurs within a matter of seconds, but this novel Ca 2+ -independent lipid pathway in astrocytes could occur on a faster time scale and thus play a role in the rapid signaling processes involved in synaptic potentiation, attention, and neurovascular coupling.
