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

Tumor necrosis factor receptor 1 (TNFR1) regulates inflammatory and synaptic signaling in the CNS, but its neuron-specific and sex-dependent roles remain unclear. To define the function of neuronal TNFR1, we used mice with conditional deletion of TNFR1 in Nex + 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. • Neuronal TNFR1 ablation reduced infarct volume in female mice after MCAO. • Female conditional knockouts lacked early post-stroke cytokine induction. • Male conditional knockouts showed unchanged acute infarcts but improved 14-day spatial memory. • TNFR1 deletion produced sex-specific PSD-95 alterations at baseline and post-stroke. • Stroke patient CSF showed sex-dependent increases in soluble TNFR1 levels.