# Lymphatic dysfunction in neurodevelopmental disorders and associated behaviors

> **NIH NIH R56** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $402,500

## Abstract

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 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
IFNg 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 IFN 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.

## Key facts

- **NIH application ID:** 10916546
- **Project number:** 5R56MH133584-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Antoine Louveau
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2023-09-01 → 2024-12-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916546

## Citation

> US National Institutes of Health, RePORTER application 10916546, Lymphatic dysfunction in neurodevelopmental disorders and associated behaviors (5R56MH133584-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10916546. Licensed CC0.

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