Influence of sex and age on the development of audiogenic kindling in the moderate seizure severity strain of the genetically epilepsy-prone rats.

Abstract

The genetically epilepsy-prone rat (GEPR) is a long-standing animal model for inherited epilepsy, with seizures triggered by high-intensity acoustic stimulation (audiogenic seizures), leading to generalized tonic-clonic seizures, which propagate through a well-characterized brainstem network and are known as brainstem seizures. Repeated exposure to acoustic stimuli can lead to the development of brainstem-triggered limbic seizures accompanied by cortical epileptiform activity, a process called audiogenic kindling (AK). Although the GEPR-3 strain has been in use for over 50 years, the influences of age and sex on the development of AK in GEPR-3s remain unknown; thus, this study aims to address this knowledge gap. Male and female GEPR-3s, aged 1, 2, 4, and 6 months, were exposed to acoustically evoked seizures once daily for 30 consecutive days. Seizure latency, duration, and severity were analyzed in relation to age and number of stimulations. The findings revealed that AK was age-dependent, with limbic motor seizures occurring exclusively in 4- and 6-month-old GEPR-3s, while younger GEPR-3s showed no limbic seizures. Female GEPR-3s developed AK more rapidly and experienced more severe seizures than males. Furthermore, as AK developed, brainstem seizures became more severe in the GEPR-3s. A subset of 4- and 6-month-old male and female GEPR-3s exhibited forelimb and hindlimb extensions or spontaneous limbic seizures. The results indicate that age and sex impact AK development in GEPR-3s, highlighting the need for further studies to understand their significance in advancing our understanding of epileptogenesis and developing more effective treatments.