Disrupted-In-Schizophrenia 1 controls microglial movement and phagocytosis

BACKGROUND: Microglia are the phagocytes of the central nervous system. They survey the micro-environment by migration during early development and by projecting and retracting protrusions at later stages. Appropriate control of microglial movement and phagocytosis is necessary to sculpt and maintain an efficient neuronal network. We study the neurodevelopmental gene Disrupted-In-Schizophrenia 1 (DISC1) as a regulator of microglial functioning. DISC1 disruption is associated with impaired neuronal networks and neurodevelopmental disorders. We hypothesize that loss of DISC1 in microglia impairs cytoskeletal control, disrupts their developmental functions, and contributes to neurodevelopmental disorders. RESULTS: Our results show that DISC1 is highly expressed in mouse and human microglia. DISC1 locus impairment (LI) microglia phagocytose slower but their final synaptosome uptake is increased compared to wildtype (WT) microglia. DISC1 LI microglia migrate slower compared to WT microglia in vitro and in embryonic living brain slices. The relative idling time of in vitro and ex vivo DISC1 LI microglia is increased and the mean active migration speed is decreased. In contrast, we show that the surveyed brain area of DISC1 LI microglia in adolescent living brain slices is increased compared to WT microglia. Process extension towards laser-induced brain damage seems unchanged. The morphology, ramification index and cell size will be investigated and we are currently validating our findings using a DISC1 LI bone marrow transplantation in WT mice to exclude environmental effects of the DISC1 locus impairment on microglial behavior. CONCLUSION: DISC1 is a molecular key controlling microglial movement during phagocytosis, migration, and branch motility.