Lactate metabolism in the control of microglial function Katia Monsorno (1) - Kyllian Ginggen (1)- Arnaud L Lalive (2) - Anna Tchenio (2) - Manuel Mameli (2) - Rosa Chiara Paolicelli (1) (1) University of Lausanne, Department of Biomedical Sciences, Lausanne, Switzerland (2) University of Lausanne, Department of Fundamental Neurosciences, Lausanne, Switzerland Microglia are the tissue-resident macrophages of the brain. Beyond their innate immunity roles, they are implicated in a variety of physiological processes required for proper brain development, including removal of apoptotic neurons and remodeling of synapses. Not surprisingly, dysregulation of microglial function is linked with the onset of neuropathology. Accumulating evidences point towards the involvement of metabolism and differential substrates catabolism in the regulation of immune cells, including microglia. In particular, lactate, which sustains brain energetics and increases in response to neuronal activity, was shown to regulate inflammatory responses in peripheral immune cells. However, the physiological role for lactate in modulating microglial function is still unexplored. In order to address this question, we generated a microglia-specific conditional knock out (cKO) mouse model for the monocarboxylate transporter 4 (MCT4), which we describe to be specifically upregulated in microglia upon lactate exposure and which is known to be implicated in lactate transport. We analyzed key microglia features during postnatal development, and we found alterations in microglial density and in CD68+ phagocytic structures in the hippocampus of two-week-old cKO mice. This was associated with alterations in presynaptic markers and changes in excitatory post-synaptic currents, indicating that microglia-specific depletion of MCT4 is sufficient to considerably affect neuronal development and function. Additionally, adult cKO mice present an anxiety-like phenotype. In summary, this study highlights the importance of microglial metabolism for correct brain maturation, emphasizing how metabolic flexibility, and in particular lactate metabolism, could be functionally coupled to microglial regulation. Given the established role of microglia in neuropathology, a better mechanistic understanding of lactate-dependent modulations may be relevant for targeting microglia in neurodevelopmental diseases.