Astrocytes are crucial for synaptic plasticity and memory formation. Astrocyte-derived factors, such as D-serine and lactate, have been suggested to enhance learning and memory likely via modulating NMDA receptor functions in neurons. However, the intracellular mechanisms of astrocytes that release these factors are not fully clarified. Here we adopted an optogenetic approach to regulate the intracellular cyclic AMP (cAMP), a major second messenger, specifically in astrocytes in vivo. We developed a transgenic mouse line in which astrocytes express photoactivated adenylyl cyclase (PAC), a protein that rapidly changes its conformation and synthesizes cAMP from ATP in response to blue light. In these mice, we optogenecically modulated the intracellular levels of cAMP in hippocampal astrocytes and investigated the effect of a prolonged cAMP elevation on spatial memory. We found that a long-term cAMP elevation in astrocytes after training session facilitated the memory fading, whereas a short-term cAMP elevation enhanced memory formation. We also found that astrocytic cAMP facilitates synaptic plasticity through activating NMDA receptors, which may underlie both memory fading and enhanced memory formation. Thus, our results suggest that astrocytic cAMP signaling modulates hippocampus-dependent learning and memory.
