Disrupted-In-Schizophrenia 1 controls microglial movement and phagocytosis

Abstract

BACKGROUND: Microglia are the phagocytes of the central nervous system and are involved in a broad spectrum of processes that regulate homeostasis in the brain. Synaptic elimination involves phagocytosis of weak synapses, which is essential to sculpt and maintain an efficient neuronal network. Disruption of microglial movement and synaptic elimination gives rise to multiple different pathologies such as autism spectrum disorder and schizophrenia. Here, we push forward the psychiatric risk gene Disrupted-in-schizophrenia 1 (DISC1) as a new molecular key that controls microglial functions in the developing brain. We hypothesize that DISC1 controls microglial movement and phagocytosis through interaction with the cytoskeleton and that impairment of microglial DISC1 contributes to related psychiatric symptoms. We approach this problem starting from molecular control of microglial movement up to behavioral aspects upon DISC1 impairment. RESULTS: Our results show that DISC1 is highly expressed in mouse and human microglia. Using raster image correlation spectroscopy, we found that DISC1 diffuses slower in actin-and tubulin-rich regions of microglial cells, suggesting protein interaction. On the level of cellular dynamics, we show that DISC1 locus impairment (LI) microglia phagocytose slower compared to wildtype (WT) microglia, but their final synaptosome uptake is increased. DISC1 LI microglia migrate slower compared to WT microglia in vitro and in embryonic living brain slices. In contrast, we show that the surveyed brain area of DISC1 LI microglia in adolescent living brain slices is increased compared to WT microglia, whereas their morphological complexity is impaired. Process extension towards laser-induced brain damage is unchanged. We are currently validating our findings using a DISC1 LI bone marrow transplantation in WT mice to study the cell-autonomous effects of DISC1 locus impairment on microglial movement.CONCLUSION: The psychiatric risk gene DISC1 is a molecular key controlling microglial movement during phagocytosis, migration and branch motility.