Rationale:
Status epilepticus (SE), induced by diisopropylfluorophosphate (DFP) or other seizurogenic agents, can lead to neurodegeneration, neuroinflammation, epilepsy, and behavioral comorbidities. Evidence from the kainate model and human epilepsy suggest that tauopathy is a key mechanism driving SE-induced brain pathogenesis and epilepsy (PMID:39355003). In this study, we hypothesized that tau and its interacting proteins Fyn, CDK5, and PSD95 are also dysregulated in the DFP model, contributing to SE-induced brain pathogenesis.
Methods:
A mixed-sex cohort of 7-8-week-old Sprague Dawley rats (n=40) was exposed to DFP (4mg/kg-s.c.) and treated with 2-PAM (25mg/kg-i.m.), atropine (2mg/kg-i.m.) immediately and with midazolam (3mg/kg-i.m.) 1h post-DFP. Animals were euthanized at 24h or 8 days. Brains were collected and the hippocampus, prefrontal cortex, and piriform cortex were analyzed with Western blot and co-immunoprecipitation to assess differential changes in Fyn-tau interacting molecules and CDK5 expression.
Results:
DFP exposure significantly altered tau interacting proteins in the hippocampal PSD fraction with a PSD95 reduction at both time points, and Src family kinase (SFK) activation (pSFK, Fyn, and pSFK/Fyn) increased by day 8. A similar trend was observed in the piriform cortex, where pSFK was significantly increased at the 8-day timepoint. While Fyn-tau, PSD95-tau, and NR2B-tau (trending) interactions increased post-DFP, the changes were not significant in the hippocampus. CDK5 and its interacting molecules p25 and p35 were significantly reduced, though p25 recovered by day 8 in the prefrontal cortex.
Conclusions:
Our findings demonstrate that DFP-induced SE alters tau-interacting signaling molecules in the hippocampus and cortex. The reduction of PSD95 and increased SFK activation by day 8 indicate synaptic remodeling. CDK5 and its’ activators were reduced, potentially disrupting tau regulation and neuronal function. These results highlight tau-mediated dysregulation in DFP-induced seizure pathology, suggesting a possible role in epileptogenesis.
Funding:
Funded by the NIH/NINDS CounterACT program (R01-NS133584).