90 - solTNF/TNFR1 Activity Regulates Hippocampal Synaptic Plasticity following TBI in Mice

Abstract Text: Traumatic brain injury (TBI) induces inflammations that lead to secondary damage. The pathological cascade of secondary injury processes, including inflammation, can lead to hippocampal-associated functional impairments, including cognitive deficits, depression, and pain. Inflammatory-induced alterations in synaptic plasticity are thought to underly these outcomes (Larson et al., 2022 PMID 35692164). Tumor Necrosis Factor (TNF) is a major inflammatory cytokine, and the soluble form of TNF (solTNF) preferentially binds TNFR1, which under physiological conditions regulates homeostatic synaptic plasticity, but at pathological levels promotes aberrant synaptic plasticity. This study aimed to investigate how solTNF/TNFR1 activity may regulate hippocampal neurotransmitter expression and translocation following TBI in mice. Adult C57Bl/6J mice underwent either single moderate TBI (CCI model) or sham-injury and treated with either XPro1595 (10 mg/kg, S.C.) or vehicle 30 minutes post-injury. At 30 minutes post-injury, the mice were treated with the biologic XPro1595, which neutralizes the soluble form of TNF, thus inhibiting solTNF/TNFR1 activity. At 3 days post-injury hippocampal tissue was collected, and Western blotting was performed on either whole hippocampal tissue or synaptoneurosome fractions from the ipsilateral hemisphere. Within the whole hippocampal tissue, we observed reductions in postsynaptic density-95 (PSD-95) protein expression, which was prevented in the injured mice treated with XPro1595. Next, within the hippocampal synaptoneurosome fraction, we quantitated α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPAR1), and N-methyl-D-aspartate receptor 1 (NMDAR1) levels. At 3 days post-injury, we also observed reductions in AMPAR1 and NMDAR1 levels, which was again prevented by treating the injured mice with XPro1595. Overall our findings suggest that injury-induced solTNF/TNFR1 activity down-regulates PSD-95 expression that prevents translocation of AMPA and NMDA receptors into the synaptic membrane, which likely underlies the development of hippocampal-associated functional impairments previously observed.

Keywords: Soluble TNF, Tumor necrosis factor receptor 1, Synaptoneurosome, PSD-95, AMPA receptors, NMDA receptors, XPro1595