Fingolimod Exerts Therapeutic Effects on Autistic Mice via Improving the Structure and Function of Meningeal Lymphatics.

BACKGROUND: Accumulating evidence suggests a correlation between maternal infection during pregnancy and an increased risk of autism spectrum disorder (ASD) in offspring. Our previous studies have demonstrated that maternal immune activation (MIA) induces autism-like behaviors in offspring mice, accompanied by significant lateral ventricular enlargement and cerebrospinal fluid (CSF) circulation deficits. As a critical pathway for CSF drainage, the role of meningeal lymphatic vessels in the pathophysiology of ASD remains uncharacterized. Fingolimod (FTY720), a clinically used immunomodulator, has been shown to ameliorate autism-like behaviors, but its underlying mechanism remains unclear. METHODS: We utilized an MIA-induced autism-like offspring mouse model. Autism-like behaviors in the mice were assessed using three-chamber social interaction, marble burying, grooming and other related behavioral tests. The size of the lateral ventricles was evaluated by magnetic resonance imaging and hematoxylin and eosin staining. The structure and function of meningeal lymphatic vessels were examined using immunofluorescence and in vivo visible light imaging. Lymphangiogenesis was investigated through techniques such as Western blotting, tube formation assays, sprouting experiments and other relevant methods. RESULTS: FTY720 not only alleviates autism-like behaviors and lateral ventricular dilation, but also significantly restores the structural integrity and drainage function of meningeal lymphatic vessels in MIA offspring. Furthermore, in vitro experiments reveal that FTY720 promotes lymphangiogenesis by targeting the S1PR3 receptor to inhibit the expression of thrombospondin-1 (TSP1), a lymphangiogenesis-related inhibitor. CONCLUSION: FTY720 acts on the S1PR3 receptor to inhibit TSP1, thereby improving the structure and function of meningeal lymphatic vessels and alleviating autism-like behaviors and lateral ventricular dilation.