Loss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice

Katia Monsorno; Kyllian Ginggen; Andranik Ivanov; An Buckinx; Arnaud L. Lalive; Anna Tchenio; Sam Benson; Marc Vendrell; Angelo D’Alessandro; Dieter Beule; Luc Pellerin; Manuel Mameli; Rosa Chiara Paolicelli

doi:10.1038/s41467-023-41502-4

journal article Open Access Sep 16, 2023

Loss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice

Katia Monsorno

Kyllian Ginggen Andranik Ivanov An Buckinx Arnaud L. Lalive Anna Tchenio Sam Benson Marc Vendrell

Rosa Chiara Paolicelli

Nature Communications Vol. 14 No. 1 · Springer Science and Business Media LLC

View at Publisher Save 10.1038/s41467-023-41502-4

Abstract

AbstractMicroglia, the innate immune cells of the central nervous system, actively participate in brain development by supporting neuronal maturation and refining synaptic connections. These cells are emerging as highly metabolically flexible, able to oxidize different energetic substrates to meet their energy demand. Lactate is particularly abundant in the brain, but whether microglia use it as a metabolic fuel has been poorly explored. Here we show that microglia can import lactate, and this is coupled with increased lysosomal acidification. In vitro, loss of the monocarboxylate transporter MCT4 in microglia prevents lactate-induced lysosomal modulation and leads to defective cargo degradation. Microglial depletion of MCT4 in vivo leads to impaired synaptic pruning, associated with increased excitation in hippocampal neurons, enhanced AMPA/GABA ratio, vulnerability to seizures and anxiety-like phenotype. Overall, these findings show that selective disruption of the MCT4 transporter in microglia is sufficient to alter synapse refinement and to induce defects in mouse brain development and adult behavior.

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Details

Published: Sep 16, 2023
Vol/Issue: 14(1)
License: View

Authors

MRC Centre for Inflammation Research; Queen's Medical Research Institute; The University of Edinburgh; EH16 4TJ Edinburgh; UK

A

Angelo D’Alessandro

Department of Biochemical and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA

Rosa Chiara Paolicelli

Funding

French Agence Nationale de la Recherche

ERC Consolidator Grant

Swiss National Science Foundation Dementia Research Switzerland ERC Starting Grant

Cite This Article

Katia Monsorno, Kyllian Ginggen, Andranik Ivanov, et al. (2023). Loss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice. Nature Communications, 14(1). https://doi.org/10.1038/s41467-023-41502-4

Loss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice

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