Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity
Authors: Leah C Dorman
Ari B Molofsky
Sunrae E Taloma
Jerika J Barron
Phi T Nguyen
Ilia D Vainchtein
Mazen A Kheirbek
Simon Pan
Anna V Molofsky
Rafael T Han
Hiromi Nakao-Inoue
Journal: Cell (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: microglia, hippocampus, extracellular matrix, aging, memory, dendrite remodeling, interleukin-33.
Affiliations: 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., Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA., Department of Laboratory Medicine, 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; Kavli Institute for Fundamental Neuroscience, 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; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA, USA. Electronic address: .

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. 

Retracted: No

PubPeer comments:
 When looking at Fig.1 J and K, I am puzzled why the standards [controls] are very different (in grey, J bar-1 vs K bar-1: 15% vs 22%; also J bar-3 vs K bar-3). Could the authors explain why IL-33 expression is different in the two controls in the DG? ![file] , 
 #1 Thanks for the question- an important difference between these 2 experiments is the age of the cohorts. For the enrichment group, adult mice (~3 months old) were put into enrichment and analyzed 4 weeks later (4 months old at analysis), which is consistent with our other experiments using enrichment. For the social isolation group, mice were put in isolation immediately after weaning to reduce any further social interactions and analyzed 4 weeks later (2 months old at analysis). We believe this 2 month difference in age accounts for the different baseline values. ,