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Sex differences in the developing brain impact stress-induced epileptogenicity following hyperthermia-induced
Daniele C Wolf1, Sébastien Desgent1, Nathalie T Sanon2
1Centre de Recherche, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Département de Pédiatrie, Université de Montréal, Québec, Canada; Département de Neurosciences, Université de Montréal, Québec, Canada.
Insights
Early life stress, simulated by corticosterone injections in rat pups, increases seizure susceptibility. Males showed more severe responses than females, suggesting sex differences in stress-related epilepsy development.
Area of Science:
- Neuroscience
- Endocrinology
- Developmental Biology
Background:
- Febrile seizures (FS) affect 2-5% of children, with complex FS linked to mesial temporal lobe epilepsy.
- Sex hormones influence seizure susceptibility, but the role of early life stress and sex differences in epileptogenesis remains unclear.
Purpose of the Study:
- To investigate sex differences in hypothalamic-pituitary-adrenal (HPA) axis activity following chronic stress.
- To determine the contribution of gonadal hormones to hyperthermia-induced seizure (HS) susceptibility in rat pups.
Main Methods:
- Rat pups received daily corticosterone (CORT) or vehicle injections from postnatal day 1-9, followed by HS at P10.
- Evaluated body mass, plasma CORT, HS temperature threshold, seizure characteristics, and electroencephalographic recordings.
- In vitro recordings in juvenile males examined neuronal circuits.
Main Results:
- CORT injections reduced weight gain and HS temperature threshold in both sexes.
- CORT increased seizure duration and number while decreasing latency to generalized convulsions.
- Males exhibited greater HPA axis activation, longer seizure recovery, and more severe seizure phenotypes compared to females, both at baseline and after CORT treatment.
Conclusions:
- Chronic early-life stress via CORT administration is a valid model for investigating seizure susceptibility.
- Significant sex differences exist in response to stress and baseline seizure susceptibility, with males showing a more severe phenotype.
- These findings highlight the importance of studying biological underpinnings of sex differences in neurological disorders for developing targeted therapies.
Abstract:
Febrile seizures (FS) are common, affecting 2-5% of children between the ages of 3 months and 6 years. Complex FS occur in 10% of patients with FS and are strongly associated with mesial temporal lobe epilepsy. Current research suggests that predisposing factors, such as genetic and anatomic abnormalities, may be necessary for complex FS to translate to mesial temporal lobe epilepsy. Sex hormones are known to influence seizure susceptibility and epileptogenesis, but whether sex-specific effects of early life stress play a role in epileptogenesis is unclear. Here, we investigate sex differences in the activity of the hypothalamic-pituitary-adrenal (HPA) axis following chronic stress and the underlying contributions of gonadal hormones to the susceptibility of hyperthermia-induced seizures (HS) in rat pups. Chronic stress consisted of daily injections of 40 mg/kg of corticosterone (CORT) subcutaneously from postnatal day (P) 1 to P9 in male and female rat pups followed by HS at P10. Body mass, plasma CORT levels, temperature threshold to HS, seizure characteristics, and electroencephalographic in vivo recordings were compared between CORT- and vehicle (VEH)-injected littermates during and after HS at P10. In juvenile rats (P18-P22), in vitro CA1 pyramidal cell recordings were recorded in males to investigate excitatory and inhibitory neuronal circuits. Results show that daily CORT injections increased basal plasma CORT levels before HS and significantly reduced weight gain and body temperature threshold of HS in both males and females. CORT also significantly lowered the generalized convulsions (GC) latency while increasing recovery time and the number of electrographic seizures (>10s), which had longer duration. Furthermore, sex-specific differences were found in response to chronic CORT injections. Compared to females, male pups had increased basal plasma CORT levels after HS, longer recovery time and a higher number of electrographic seizures (>10s), which also had longer duration. Sex-specific differences were also found at baseline conditions with lower latency to generalized convulsions and longer duration of electrographic seizures in males but not in females. In juvenile male rats, the amplitude of evoked excitatory postsynaptic potentials, as well as the amplitude of inhibitory postsynaptic currents, were significantly greater in CORT rats when compared to VEH littermates. These findings not only validate CORT injections as a stress model, but also show a sex difference in baseline conditions as well as a response to chronic CORT and an impact on seizure susceptibility, supporting a potential link between sustained early-life stress and complex FS. Overall, these effects also indicate a putatively less severe phenotype in female than male pups. Ultimately, studies investigating the biological underpinnings of sex differences as a determining factor in mental and neurologic problems are necessary to develop better diagnostic, preventative, and therapeutic approaches for all patients regardless of their sex.
