Profilin 1 controls a microglial cytoskeleton checkpoint to prevent senescence and premature synaptic decline.

Profilin 1 (Pfn1) expression decreases significantly in aged human microglia, suggesting that loss of cytoskeletal integrity may trigger microglial senescence and increased synaptic vulnerability. To test this hypothesis, we used an inducible, microglia-specific Pfn1 knockout in adult mice, a strategy designed to isolate the direct effects of acute Pfn1 loss at the cellular and circuit levels, avoiding confounding factors from development or chronic aging. Using a multi-omics approach combined with intravital two-photon imaging, we found that Pfn1 ablation disrupts actin–microtubule coupling, leading to a collapse of microglial morphodynamics and a complete failure to respond to focal brain injury. This cytoskeletal disruption triggers a cell-autonomous, senescence-associated secretory phenotype (SASP), driven by the ERK/NF-κB signaling axis. SASP factors secreted by Pfn1-deficient microglia reprogram the synaptic environment, resulting in significant deficits in mitochondrial energy production and a selective reduction in the frequency of GABAergic inhibitory postsynaptic currents in the prefrontal cortex. These circuit-level disturbances lead to behaviors characterized by altered anxiety and risk assessment. Our findings identify Pfn1 as a critical checkpoint against microglial senescence and show that its loss is sufficient to drive circuit-specific synaptic decline, highlighting the Pfn1-cytoskeleton axis as a potential therapeutic target to enhance brain resilience.