Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus

Significance Synaptic plasticity in the hippocampus is important for learning and memory formation. In particular, homeostatic synaptic plasticity enables neurons to restore their activity levels in response to chronic neuronal activity changes. While astrocytes modulate synaptic functions via the secretion of factors, the underlying molecular mechanisms remain unclear. Here, we show that suppression of hippocampal neuronal activity increases cytokine IL-33 release from astrocytes in the CA1 region. Activation of IL-33 and its neuronal ST2 receptor complex promotes functional excitatory synapse formation. Moreover, IL-33/ST2 signaling is important for the neuronal activity blockade-induced increase of CA1 excitatory synapses in vivo and spatial memory formation. This study suggests that astrocyte-secreted IL-33 acts as a negative feedback control signal to regulate hippocampal homeostatic synaptic plasticity.