Lymphatic dysfunction in neurodevelopmental disorders and associated behaviors

PROJECT SUMMARY/ABSTRACT This project aims at understanding the molecular mechanisms governing lymphatic dysfunction in a mouse model of neurodevelopmental disorder, i.e. the fmr1-KO mice, and their involvement in social and behavior. Meningeal lymphatic drainage, an essential system for the maintenance of brain function in adult and aged mice, was recently demonstrated to develop postnatally during a critical window of brain maturation. We found that fmr1, the gene responsible for Fragile X Syndrome, is expressed in lymphatic endothelial cells, and that loss of fmr1 results in altered meningeal lymphatic morphology and function, via regulation of junction protein patterning. Furthermore, we found that altered lymphatic function in fmr1-KO mice results in decrease IFNγ production (essential for neuronal homeostasis) in the meninges, that is rescued upon drainage improvement. Finally, restoring draining function results in improved neuronal activation and social behavior in fmr1-KO mice. We therefore hypothesize that meningeal lymphatic dysfunction, through dysregulation of local immune cells, contributes to behavioral impairments in Fragile X. Guided by our preliminary data, we propose to address our hypothesis using the following aims: Aim1: Determine how fmr1 regulates meningeal lymphatic function. Aim2: Decipher the role of fmr1-induced lymphatic dysfunction in IFNγ T cell maintenance. Aim3: Address the contribution of meningeal lymphatic dysfunction in FXS-associated social behavior Collectively, Our proposed studies will have a broad impact by a) characterizing meningeal lymphatic function in FXS; b) deciphering new molecular regulators of lymphatic function; c) demonstrating the central role of the meningeal lymphatic in the regulation of social behavior d) identifying and characterizing new molecular targets for the treatment of FXS; and e) providing evidence that the meningeal lymphatics represent a novel target for therapeutic strategies in neurodevelopmental disorders.