Meningeal lymphatics-microglia axis regulates synaptic physiology, 2025, Kim et al.

Meningeal lymphatics-microglia axis regulates synaptic physiology
Kyungdeok Kim; Daviti Abramishvili; Siling Du; Zachary Papadopoulos; Jay Cao; Jasmin Herz; Igor Smirnov; Jean-Leon Thomas; Marco Colonna; Jonathan Kipnis

SUMMARY
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.

HIGHLIGHTS
• Meningeal lymphatic dysfunction disrupts cortical E/I balance and impairs memory

• Impaired meningeal lymphatics reshape microglial properties and functions

• Microglia-dependent excessive IL-6 mediates synaptic and behavioral alterations

• Enhancing meningeal lymphatics alleviates age-related neural and cognitive decline


Link | PDF (Cell) [Open Access]