Graphical Abstract Highlights d MIA causes behavioral and synaptic abnormalities in the offspring d Microglia-dependent synaptic engulfment is impaired by MIA d Voluntary running in adulthood ameliorates MIA-induced abnormalities d Voluntary running stimulates microglia-mediated engulfment of surplus synapses

Astrocytes play a key role in brain homeostasis and functions such as memory. Specifically, astrocytes express multiple receptors that transduce signals via the second messenger cAMP. However, the involvement of astrocytic cAMP in animal behavior and the underlying glial–neuronal interactions remains largely unknown. Here, we show that an increase in astrocytic cAMP is sufficient to induce synaptic plasticity and modulate memory. We developed a method to increase astrocytic cAMP levels in vivo using photoactivated adenylyl cyclase and found that increased cAMP in hippocampal astrocytes at different time points facilitated memory formation but interrupted memory retention via NMDA receptor–dependent plasticity. Furthermore, we found that the cAMP-induced modulation of memory was mediated by the astrocyte–neuron lactate shuttle. Thus, our study unveils a role of astrocytic cAMP in brain function by providing a tool to modulate astrocytic cAMP in vivo.

Brain‐derived neurotrophic factor (BDNF), a main member of the neurotrophin family that is active in the brain, supports neuronal survival and growth. Microglial BDNF affects both the structural and functional properties of neurons. In contrast, whether and how neuronal BDNF affects microglial dynamics remain largely undetermined. Here, we examined the effects of BDNF on the properties of microglia in the CA3 region of the hippocampus. We chose this site because the axonal boutons of hippocampal mossy fibers, which are mostly formed in the CA3 region, contain the highest levels of BDNF in the rodent brain. We transfected mouse dentate granule cells with an adeno‐associated virus that encodes both a BDNF short hairpin RNA (shRNA) and red fluorescent protein to examine the effects of mossy fiber‐derived BDNF on microglia. Based on immunohistochemistry, BDNF knockdown with an shRNA resulted in an increase in microglial density in the mossy fiber pathway and increased engulfment of mossy fiber axons by microglia. In addition, we performed time‐lapse imaging of microglial processes in hippocampal slice cultures to examine the effects of BDNF on microglial motility. Time‐lapse imaging revealed increases in the motility of microglial processes and the engulfment of mossy fiber synapses by microglia when BDNF signaling was pharmacologically blocked. Thus, neuronal BDNF prevents microglia from engulfing mossy fiber synapses in the hippocampus.

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.