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Calcium-independent astrocytic lipid release modulates neuronal excitability

Accumulating data point to a key role of Ca2+-dependent gliotransmitter release as a modulator of neuronal networks. Here, we tested the hypothesis that astrocytes in response to agonist exposure also release lipid modulators through activation of Ca2+-independent phospholipase A2 (iPLA2) 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 (PGE2). Surprisingly, buffering of cytosolic Ca2+ resulted in a sharp increase in agonist-induced astrocytic lipid release. In addition, astrocytic release of PGE2 enhanced miniature excitatory post-synaptic potentials (mEPSPs) by inhibiting the opening of neuronal Kv channels in brain slices. This study provides the first evidence for the existence of a Ca2+-independent pathway regulating the release of PGE2 from astrocytes, and furthermore demonstrates a functional role for astrocytic lipid release in the modulation of synaptic activity. Significance Statement Until now, the majority of studies implicating astrocytes in modulating synaptic activity have focused on Ca2+-dependent release of traditional gliotransmitters such as D-serine, ATP, and glutamate. Mobilization of intracellular stores of Ca2+ occurs within a matter of seconds, but this novel Ca2+-independent lipid pathway in astrocytes could potentially occur on a still faster time scale and thus participate in the rapid signaling processes involved in synaptic potentiation, attention, and neurovascular coupling.