Microglial Trem2 shapes neuronal bioenergetics during development

Triggering receptor expressed on myeloid cells 2 (Trem2) is a myeloid cell-specific gene expressed in microglia, whose variants are associated with multiple neurodegenerative diseases. TREM2 receptor modulates phagocytosis, cytokine production and metabolism, enabling appropriate surveillance of the brain by microglia and ensuring their proper response to damage signals. Here, we demonstrate that TREM2 plays a key role in controlling the bioenergetic profile of pyramidal neurons during development. In the absence of Trem2, developing neurons in hippocampal CA1 -but not in CA3- subfield display compromised energetic metabolism and defective basal, maximal and ATP-dependent respiration, accompanied by reduced mitochondrial mass and abnormal organelle ultrastructure. This is paralleled by a significant transcriptional rearrangement of hippocampal pyramidal neurons at birth, with a pervasive alteration of metabolic, oxidative phosphorylation and mitochondrial signatures. The developmental trajectories of the excitatory lineages indicate that lack of Trem2 causes a delay in the maturation of CA1 neurons, paired with specific alterations in the mitochondrial TOM complex which persist in the mature hippocampus. In addition, the mitochondrial defects and faulty neuronal differentiation are maintained also after neuron isolation from the brain context, suggesting that the lack of TREM2-mediated communication between microglia and neurons at early developmental windows is sufficient to derange the forthcoming maturation of neuronal metabolism. Our results unveil a novel role of TREM2 in controlling neuronal development by regulating the metabolic fitness of neurons in a region-specific manner. Hippocampi of the Trem2 +/+ and -/- mice were dissected at P1, dissociated to single cell suspension and analyzed using scRNAseq.