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.

突触重塑对于将经验编码到神经元回路中至关重要。在这里，我们定义了神经元和小胶质细胞之间的分子相互作用，该相互作用驱动了海马中依赖经验的突触重塑。我们发现细胞因子白介素33（IL-33）由成年海马神经元以经验依赖的方式表达，并定义了引发突触可塑性的神经元子集。神经元IL-33或小胶质细胞IL-33受体的丧失会导致脊柱可塑性受损，新生儿神经元整合减少以及远程恐惧记忆的准确性降低。衰老小鼠的记忆精确度和神经元IL-33降低，IL-33功能的获得减轻了与年龄相关的脊柱可塑性下降。我们发现，神经元IL-33指示细胞外基质（ECM）的小胶质细胞吞噬，并且其损失导致受损的ECM吞噬和伴随突触的ECM蛋白伴随积累。这些数据定义了一种细胞机制，小胶质细胞通过该机制调节经验依赖的突触重塑并促进记忆巩固。