Effect of rapamycin on reversing post-ictal impairments in trace fear learning following a single brief convulsive seizure in rats.

The postictal period, which immediately follows a seizure, is associated with several incapacitating symptoms or signs, such as psychosis, confusion, paresis, aphasia and memory loss. These symptoms can last from several minutes to even days and can have a negative impact on the quality of life for people living with epilepsy. However, there is a scarcity of data concerning the neurobiological mechanisms that mediate postictal amnesia and behavioural impairments. In the present study, we examined the impact of a single brief, self-limiting convulsive seizure induced by the chemoconvulsant pentylenetetrazol (PTZ) on trace fear learning. We found that PTZ administration produced a rapid but transient increase in hippocampal PI3K-Akt-mTOR signalling, with phosphorylation of Akt, mTOR, and ribosomal protein S6 peaking between 2 and 6 h post-seizure and returning to baseline by 24 h. This activation coincided with increased expression of plasticity-related markers, including Egr1 and PSD-95, and was associated with impaired memory in a hippocampus-dependent trace fear conditioning task. Administration of the mTORC1 inhibitor rapamycin 30 min post-seizure rescued the memory deficit. These findings suggest that postictal hyperactivation of mTOR signalling disrupts mechanisms of synaptic plasticity through excessive or unregulated protein synthesis, potentially saturating plasticity mechanisms and impairing new memory formation. Taken together, our results identify a critical role for aberrant mTOR signaling in mediating postictal cognitive dysfunction and suggest that targeted inhibition of mTORC1 may represent a therapeutic strategy for preserving memory after seizures.