TY - JOUR
T1 - Loss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice
AU - Monsorno, Katia
AU - Ginggen, Kyllian
AU - Ivanov, Andranik
AU - Buckinx, An
AU - Lalive, Arnaud L
AU - Tchenio, Anna
AU - Benson, Sam
AU - Vendrell, Marc
AU - D'Alessandro, Angelo
AU - Beule, Dieter
AU - Pellerin, Luc
AU - Mameli, Manuel
AU - Paolicelli, Rosa Chiara
N1 - Funding Information:
This work was supported by grants from the Swiss National Science Foundation (SNSF 310030_197940), the Dementia Research Switzerland – Synapsis Foundation, an ERC StGrant (REMIND 804949), and funding from UNIL to RCP; Swiss National Science Foundation (SNSF 310030_212193) to MM; French Agence Nationale de la Recherche (BrainFuel ANR-21-CE44-0023-01) to LP; M.V. acknowledges funds from an ERC Consolidator Grant (DYNAFLUORS, 771443). The authors would like to thank Dr. Hector Gallart-Ayala and Dr. Julijana Ivanisevic at the Metabolomics Unit of the University of Lausanne for their technical support.
Publisher Copyright:
© 2023, Springer Nature Limited.
PY - 2023/9/16
Y1 - 2023/9/16
N2 - Microglia, 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.
AB - Microglia, 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.
U2 - 10.1038/s41467-023-41502-4
DO - 10.1038/s41467-023-41502-4
M3 - Article
SN - 2041-1723
JO - Nature Communications
JF - Nature Communications
ER -