Insulin signaling disruption exacerbates memory impairment and seizure susceptibility in an epilepsy model with Alzheimer's disease-like pathology.

Abstract

Alzheimer's disease (AD) and epilepsy exhibit a complex bidirectional relationship. Curiously, diabetes as a comorbidity increases the risk of epilepsy among AD patients. Recently, we reported that the Wistar audiogenic rat (WAR) strain, a genetic model of epilepsy, displays a partial AD-like phenotype, including brain insulin resistance. We also assessed seizure susceptibility in an AD model created through intracerebroventricular injections of streptozotocin (icv-STZ), which induces AD features via brain insulin resistance. Our goal was to explore how disrupted brain insulin signaling influences AD-like features and seizure susceptibility in the WAR strain. Adult male WARs received a single intracerebroventricular injection of streptozotocin (icv-STZ) (1.5 mg/kg) or vehicle (saline). Two weeks post-injection, spatial memory was assessed using the Barnes Maze (BM) test. Three weeks later, the rats underwent an audiogenic kindling (AuK) protocol (20 acoustic stimuli, 2 per day) to evaluate seizure frequency and severity. Seizures were analyzed using the Categorized Severity Index and Racine's scale and Western blot analysis was performed on hippocampal tissue. Our findings revealed that icv-STZ significantly worsened memory performance, increased seizure frequency, and reduced seizure onset relative to vehicle. Furthermore, icv-STZ decreased Akt activation and increased Glycogen Synthase Kinase-3 (GSK3) phosphorylation, indicating disrupted insulin signaling. Notably, icv-STZ decreased tau phosphorylation without altering amyloid β precursor protein (AβPP) levels. In conclusion, a low-dose icv-STZ injection exacerbates memory deficits and seizure susceptibility in the WAR strain by disturbing downstream proteins involved in insulin signaling. This highlights the implications of brain insulin resistance in both AD and epilepsy.