Microglial TREM2 receptor signaling shapes neuronal bioenergetics during development

Despite the traditional view of the brain as an immunological privileged organ, recent discoveries have revealed that a continuous crosstalk between microglia, the brain residential immune cells, and neurons is required for the maintenance of brain homeostasis and for the sculpting of neuronal connections during development. Indeed, defects in this bidirectional communication have been described in brain diseases, where altered microglia function, synaptic activity and plasticity may produce profound changes in nervous circuits and associated functions.The Triggering receptor expressed on myeloid cells 2 (Trem2) is a myeloid cell-specific gene expressed in brain microglia, with variants that are associated with neurodegenerative diseases, including Alzheimer’s disease. During development, Trem2 is essential for microglia-mediated synaptic refinement, but whether it also contributes in shaping early neuronal development remains unclear. 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 the hippocampal CA1 but not CA3 region, display compromised energetic metabolism, accompanied by a transcriptional rearrangement that include a pervasive alteration of metabolic and synaptic signatures, ultimately leading to a delay in the maturation of CA1 pyramidal neurons. Such early derangement is mantained at later developmental windows, leading to synaptic and circuitry alterations. Altogether, these results unveil a novel role of Trem2 in controlling neuronal development by regulating the metabolic fitness of neurons in a region-specific manner.