Influence of Sex And Age on The Development Of Audiogenic Kindling In The Moderate Seizure Severity Strain Of The Genetically Epilepsy-Prone Rats

The genetically epilepsy-prone rat (GEPR) is a long-standing animal model of inherited epilepsy. In these rats, seizures are triggered by acoustic stimulation, making them audiogenic. Specifically, the GEPR-3, which is a moderate seizure severity strain of the GEPRs, a single high-intensity acoustic stimulation triggers generalized tonic-clonic seizures when exposed to a single high-intensity acoustic stimulus. These seizures propagate through a well-characterized network in the brainstem and are called brainstem seizures. With repeated exposure to acoustic stimuli, the GEPR-3s can develop brainstem-triggered limbic seizures associated with cortical epileptiform activity; this phenomenon is known as audiogenic kindling (AK). Although the GEPR strains have been used for over 50 years, how age and sex impact the development of AK in the GEPR-3s remains unknown, and thus we address it here. The present study aimed to assess the effects of age (1, 2, 4, and 6 months old) and sex (male and female) on the development of AK in the GEPR-3s. Male and female GEPR-3s at 1, 2, 4, and 6 months old were exposed to acoustically evoked seizures once daily for 30 days. The acoustic stimulation (105-110 dB pure tones or 120 dB mixed sounds) was presented to the GEPR-3s until either the onset of a seizure or 60 seconds passed with no seizure activity. Seizure latency, duration of seizure components, and behavioral seizure score were analyzed as a function of age and number of stimulations. The results of this study indicated that the development of AK in the GEPR-3s was significantly influenced by sex and age. Brainstem-triggered motor limbic seizures were only observed in 4- and 6-month-old GEPR-3s, with females experiencing AK at a faster rate than males. Additionally, an increase in the severity of brainstem seizures was observed in 4-month-old GEPR-3s compared to those at 1, 2, and 6 months old. Furthermore, a subset of male and female 4- and 6-month-old GEPR-3s exhibited forelimb and hindlimb extension. These findings confirm the ability of brainstem seizures to trigger limbic seizures and provide more specific information about the role of sex and age in the development of AK. While the mechanisms underlying age- and sex-related changes during the development of AK are unknown, our findings demonstrate previously unknown sex differences in epileptogenesis between male and female GEPRs. NIH grants R01AA027660 (PN) and R01NS097762 (PAF). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.