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. 2025 May 15;188(10):2705-2719.e23.
doi: 10.1016/j.cell.2025.02.022. Epub 2025 Mar 21.

Meningeal lymphatics-microglia axis regulates synaptic physiology

Kyungdeok Kim  1 , Daviti Abramishvili  2 , Siling Du  2 , Zachary Papadopoulos  3 , Jay Cao  2 , Jasmin Herz  2 , Igor Smirnov  2 , Jean-Leon Thomas  4 , Marco Colonna  5 , Jonathan Kipnis  6
Affiliations

Meningeal lymphatics-microglia axis regulates synaptic physiology

Kyungdeok Kim et al. Cell. .

Abstract

Meningeal lymphatics serve as an outlet for cerebrospinal fluid, and their dysfunction is associated with various neurodegenerative conditions. Previous studies have demonstrated that dysfunctional meningeal lymphatics evoke behavioral changes, but the neural mechanisms underlying these changes have remained elusive. Here, we show that prolonged impairment of meningeal lymphatics alters the balance of cortical excitatory and inhibitory synaptic inputs, accompanied by deficits in memory tasks. These synaptic and behavioral alterations induced by lymphatic dysfunction are mediated by microglia, leading to increased expression of the interleukin 6 gene (Il6). IL-6 drives inhibitory synapse phenotypes via a combination of trans- and classical IL-6 signaling. Restoring meningeal lymphatic function in aged mice reverses age-associated synaptic and behavioral alterations. Our findings suggest that dysfunctional meningeal lymphatics adversely impact cortical circuitry through an IL-6-dependent mechanism and identify a potential target for treating aging-associated cognitive decline.

Keywords: E/I balance; IL-6; VEGF-C; VEGFR3; aging; meningeal lymphatics; meningeas; microglia; neuroimmunology; synapse.

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Conflict of interest statement

Declaration of interests J.K. is a co-founder of Rho Bio and holds patents and provisional applications related to the work presented here.

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