Rosa Paolicelli

Synaptic consequences of selective microglial TDP-43 depletion

Microglia are implicated in a variety of functions in the central nervous system, ranging from shaping neural circuits during early brain development, to surveying the brain parenchyma, and providing trophic support to neurons across the entire lifespan. Microglial phagocytic activity is important for mediating synapse elimination, clearing invading pathogens and removing protein aggregates like amyloid deposits. TDP-43, a DNA-RNA binding protein encoded by the Tardbp gene, is a critical regulator of microglial phagocytosis. Mice lacking TDP-43 selectively in microglia (cKO) exhibit drastic synapse loss and enhanced amyloid clearance in a model of Alzheimer's disease (AD). Loss of synapses in Tardbp cKO mice, however, is independent of amyloid deposition. Selective loss of TDP-43 in microglia promotes microglial engulfment of synaptic material, and is associated with decreased spine density in the motor/ somatosensory cortex. Here we show that mice lacking TDP-43 in microglia exhibit motor deficit and clasping behavior, and display altered levels of cytokines expression in the cortex and in the spinal cord. Furthermore, aberrant phagocytic microglia induced by TDP-43 depletion during early brain development leads to selective structural defects in the motor cortex, as revealed by MRI analyses. Overall, our data indicate that dysfunctional microglia significantly affect synapses, thus playing an important role in the pathogenesis of neurodegeneration.