Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity

Phi T Nguyen; Leah C Dorman; Simon Pan; Ilia D Vainchtein; Rafael T Han; Hiromi Nakao-Inoue; Sunrae E Taloma; Jerika J Barron; Ari B Molofsky; Mazen A Kheirbek; Anna V Molofsky

doi:10.1016/j.cell.2020.05.050

Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity

Cell. 2020 Jul 23;182(2):388-403.e15. doi: 10.1016/j.cell.2020.05.050. Epub 2020 Jul 1.

Authors

Affiliations

¹ 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.
² 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.
³ Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
⁴ Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁵ Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA, USA.
⁶ Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA, USA. Electronic address: anna.molofsky@ucsf.edu.

Abstract

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.

Keywords: microglia, hippocampus, extracellular matrix, aging, memory, dendrite remodeling, interleukin-33.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aging
Animals
Extracellular Matrix / metabolism*
Fear
Gene Expression Regulation
Hippocampus / metabolism
Interleukin-1 Receptor-Like 1 Protein / genetics
Interleukin-1 Receptor-Like 1 Protein / metabolism
Interleukin-33 / genetics
Interleukin-33 / metabolism
Memory
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microglia / physiology*
Neuronal Plasticity / physiology*
Neurons / metabolism
Signal Transduction

Substances

Interleukin-1 Receptor-Like 1 Protein
Interleukin-33

Abstract

Publication types

MeSH terms

Substances

Grants and funding