The role of phagocytic activity in brain maintenance

Thousands of new neurons are generated daily during adult life but only a fraction of them survive, mature and incorporate into the neural circuits; the rest die, and their corpses are presumably cleared by other healthy cells. How the dying neurons are removed and how such clearance influences neurogenesis are not well understood.  We identified an unexpected phagocytic role for the doublecortin (DCX)-positive neuronal progenitor cells during adult neurogenesis.  Our in vivo and ex vivo studies demonstrate that DCX⁺ cells comprise of a significant phagocytic population within the neurogenic zones.  Intracellular engulfment protein ELMO1, which promotes Rac activation downstream of phagocytic receptors, was required for phagocytosis by DCX+ cells. Disruption of engulfment in vivo genetically (in Elmo1-null mice) or pharmacologically (in wild type mice) led to reduced uptake by DCX⁺ cells, accumulation of apoptotic nuclei in the neurogenic niches, and impaired neurogenesis. Implication of this phenomenon could be relevant to clinical conditions associated with induced (stroke) or impaired (depression) neurogenesis.

We extended our studies of phagocytic activity to neurodevelopmental diseases, such as autistic spectrum disorders and Rett syndrome, in particular.  We found that myeloid compartment of Rett mice is impaired in phagocytic activity. When myeloid compartment is replaced using bone marrow transplantation from wild-type bone marrow into Mecp2^‒/y mice, the disease is arrested and life expectancy is increased by more than five-fold. Bone marrow transplantation results in engraftment of the brain parenchyma with wild type microglia-like cells, capable of clearing apoptotic debris load, which presumably allows more efficient neuronal function. Our data unexpectedly implicate myeloid cells in Rett pathology, and suggest that these immune cells might offer a feasible target for future therapeutic intervention for this devastating disease.