Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
Cell. 2020 Jul 23;182(2):388-403.e15. doi: 10.1016/j.cell.2020.05.050. Epub 2020 Jul 1.
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.
突触重构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，该作用驱动海马体中经验依赖性的突触重构。我们发现细胞因子白细胞介素-33（IL-33）以经验依赖性的方式由成年海马神经元表达，并定义了一个预先准备好进行突触可塑性的神经元亚群。神经元 IL-33 或小胶质细胞 IL-33 受体的缺失会导致脊柱可塑性受损、新生神经元整合减少以及远程恐惧记忆的精度降低。在老年小鼠中，记忆精度和神经元 IL-33 减少，而 IL-33 的功能获得可减轻与年龄相关的脊柱可塑性下降。我们发现神经元 IL-33 指示小胶质细胞吞噬细胞外基质（ECM），而其缺失会导致 ECM 吞噬作用受损，并且与突触接触的 ECM 蛋白随之积累。这些数据定义了一种细胞机制，通过该机制，小胶质细胞调节经验依赖性的突触重构并促进记忆巩固。
