Sex-specific roles of neuronal TNFR1 in synaptic remodeling and stroke recovery

excitatory neurons and examined behavior, ischemic injury, inflammatory responses, and molecular markers of synaptic function. Under naïve conditions, neuronal TNFR1 ablation did not alter locomotor or anxiety-like behavior and produced only minor effects on spatial learning and memory. These behavioral outcomes were accompanied by sex-dependent differences in selected synaptic proteins, including reduced PSD-95 levels in females. Following permanent middle cerebral artery occlusion, neuronal TNFR1 deletion produced marked neuroprotection in females, reflected by reduced infarct volume, preserved sensorimotor function, and strongly attenuated early pro-inflammatory cytokine signaling. In males, neuronal TNFR1 ablation did not influence acute lesion development, but was associated with modest differences in long-term cognitive outcome and distinct patterns of synaptic protein regulation after stroke. Complementary analysis of cerebrospinal fluid from individuals with ischemic stroke revealed sex-specific increases in soluble TNFR1, elevated across stroke severities in females. Together, these findings identify TNFR1 as a sex-dependent modulator of neuroinflammatory injury and synaptic function, highlighting its potential as a cell-type-specific therapeutic target in ischemic brain injury.