Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity

Synapse remodeling is essential to encode experiences into neuronal circuits. Here, we define a molecular interaction between neurons and microglia that drives experience-dependent synapse remodeling in the hippocampus. We find that the cytokine interleukin-33 (IL-33) is expressed by adult hippocampal neurons in an experience-dependent manner and defines a neuronal subset primed for synaptic plasticity. Loss of neuronal IL-33 or the microglial IL-33 receptor leads to impaired spine plasticity, reduced newborn neuron integration, and diminished precision of remote fear memories. Memory precision and neuronal IL-33 are decreased in aged mice, and IL-33 gain of function mitigates age-related decreases in spine plasticity. We find that neuronal IL-33 instructs microglial engulfment of the extracellular matrix (ECM) and that its loss leads to impaired ECM engulfment and a concomitant accumulation of ECM proteins in contact with synapses. These data define a cellular mechanism through which microglia regulate experience-dependent synapse remodeling and promote memory consolidation. [Display omitted] •IL-33 is expressed by subsets of hippocampal neurons and is modulated by experience•Microglia drive dendritic spine plasticity and memory precision via neuronal IL-33•IL-33 gain of function mitigates some age-related decreases in spine plasticity•Neuronal IL-33 induces microglial remodeling of the extracellular matrix A form of experience-dependent neuron-microglial communication is mediated by IL-33, which promotes hippocampal dendritic spine formation, synapse plasticity, and ECM engulfment and is required for memory consolidation.