The impact of predator stress on electroshock seizure threshold: insights into GABAergic, glutamatergic, and serotonergic pathways in mice.

Abstract

BACKGROUND: Post-traumatic stress disorder (PTSD) disrupts neural pathways, increasing susceptibility to neurological disorders, including epilepsy. Stress-induced alterations in glutamatergic, GABAergic, and serotonergic systems influence seizure susceptibility. This study investigates seizure thresholds within a PTSD-relevant mouse model, evaluating the roles of these neurotransmitters. METHODS: Male NMRI mice were exposed to predator stress using Wistar rats. Seizure thresholds were assessed via electroshock tests at multiple post-stress intervals. Pharmacological interventions, diazepam, MK-801, and fluoxetine, were administered seven days post-stress. Hippocampal tissues were analyzed for GABAreceptor &#x3b1;subunit, NMDAR1, and 5-HTreceptor expression, as well as nuclear factor &#x3ba;-light-chain-enhancer of activated B cells (NF-&#x3ba;B) and extracellular signal-regulated kinase (ERK) protein levels, utilizing Western blot techniques. RESULTS: Predator stress significantly decreased seizure thresholds in a time-dependent manner, with the highest effect on day 7 (P&#x2009;<&#x2009;0.0001). Treatment with diazepam (P&#x2009;<&#x2009;0.05), MK-801 (P&#x2009;<&#x2009;0.0001), and fluoxetine (P&#x2009;<&#x2009;0.0001) reversed these effects, increasing seizure thresholds. Western blot analysis revealed reduced expression of GABA&#x3b1;, NMDAR1, and 5-HTreceptors (P&#x2009;<&#x2009;0.001). Additionally, NF-&#x3ba;B levels were elevated while ERK levels were reduced (P&#x2009;<&#x2009;0.001). CONCLUSION: This study shows that predator stress is associated with increased seizure susceptibility and with downregulation of hippocampal GABAA&#x3b1;1R and 5-HT1AR expression, together with enhanced NF-&#x3ba;B activation and reduced ERK signaling. Pharmacological modulation of GABAergic, glutamatergic, and serotonergic pathways reversed the stress-induced reduction in seizure threshold in this model, suggesting that these systems may contribute to stress-related seizure susceptibility.