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Published on: December 22, 2008
Loss of microglial MCT4 leads to defective synaptic pruning and anxiety-like behavior in mice
Katia Monsorno1, Kyllian Ginggen1, Andranik Ivanov2
1University of Lausanne, Department of Biomedical Sciences, Lausanne, Switzerland.
Abstract:
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.
Insights
Microglia utilize lactate as fuel, impacting brain development. Disrupting lactate transporter MCT4 in microglia impairs synaptic pruning and causes behavioral deficits in mice.
Area of Science:
- Neuroscience
- Immunology
- Metabolism
Background:
- Microglia are innate immune cells in the central nervous system crucial for brain development and synaptic refinement.
- Microglia exhibit metabolic flexibility, utilizing various substrates for energy, but their use of lactate remains unclear.
- Lactate is abundant in the brain, suggesting a potential role in microglial energy metabolism.
Purpose of the Study:
- To investigate if microglia can utilize lactate as a metabolic fuel source.
- To explore the role of the monocarboxylate transporter 4 (MCT4) in microglial lactate import and lysosomal function.
- To determine the in vivo consequences of microglial MCT4 disruption on synaptic development and behavior.
Main Methods:
- In vitro studies using microglia to assess lactate import and lysosomal acidification.
- Genetic manipulation of monocarboxylate transporter 4 (MCT4) in microglia, both in vitro and in vivo.
- Assessment of synaptic pruning, neuronal activity (AMPA/GABA ratio), seizure susceptibility, and anxiety-like behaviors in mice.
Main Results:
- Microglia import lactate, leading to increased lysosomal acidification.
- Loss of MCT4 in microglia prevents lactate-induced lysosomal changes and impairs cargo degradation.
- In vivo depletion of microglial MCT4 results in defective synaptic pruning, increased neuronal excitation, and behavioral abnormalities including seizures and anxiety.
Conclusions:
- Microglia utilize lactate as an energy substrate, facilitated by MCT4.
- MCT4-mediated lactate transport is essential for microglial function in synaptic refinement during brain development.
- Disruption of microglial MCT4 impacts brain development and adult behavior, highlighting a critical role for microglial metabolism in neural function.
