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Early-life stress is associated with gender-based vulnerability to epileptogenesis in rat pups
Sébastien Desgent1, Sandra Duss, Nathalie T Sanon
1Centre de Recherche du Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, Québec, Canada. lionel.carmant@umontreal.ca
Insights
Early life brain insults increase epilepsy risk. This study found males developed mesial temporal lobe epilepsy (MTLE) after two insults, while females did not, suggesting gender-specific vulnerability.
Area of Science:
- Neuroscience
- Epileptology
- Developmental Biology
Background:
- Mesial temporal lobe epilepsy (MTLE) risk increases with multiple early-life brain insults.
- Early life stressors can cause sexual dimorphism in neurological outcomes.
- A two-hit model is needed to study epileptogenesis influenced by early-life insults and sex differences.
Purpose of the Study:
- To investigate gender-based differences in acute stress response and long-term MTLE risk using a two-hit animal model.
- To determine the role of sex steroids in epileptogenesis following early-life insults.
- To explore the impact of early-life stress on the development of MTLE.
Main Methods:
- A two-hit model of MTLE was established using a cortical malformation (P1) and prolonged hyperthermic seizure (P10).
- Video-electroencephalography (EEG) monitored animals from P90 to P120.
- Plasma corticosterone levels measured stress response; androgenized females were used to assess sex steroid influence.
Main Results:
- Only male pups developed MTLE, correlating with a P1 corticosterone rise after the lesion.
- Androgenized females, exhibiting a similar P1 corticosterone rise, also developed MTLE.
- Cortical lesions decreased seizure latency in both sexes, but adult cortical dysplasia volumes were similar.
Conclusions:
- Sexual dimorphism exists in long-term vulnerability to MTLE in this model.
- Early-life stress response at P1 significantly influences epileptogenesis in a gender-specific manner.
- Sex steroids may play a critical role in mediating this gender-specific vulnerability to MTLE.
Abstract:
During development, the risk of developing mesial temporal lobe epilepsy (MTLE) increases when the developing brain is exposed to more than one insult in early life. Early life insults include abnormalities of cortical development, hypoxic-ischemic injury and prolonged febrile seizures. To study epileptogenesis, we have developed a two-hit model of MTLE characterized by two early-life insults: a freeze lesion-induced cortical malformation at post-natal day 1 (P1), and a prolonged hyperthermic seizure (HS) at P10. As early life stressors lead to sexual dimorphism in both acute response and long-term outcome, we hypothesized that our model could lead to gender-based differences in acute stress response and long-term risk of developing MTLE. Male and female pups underwent a freeze-lesion induced cortical microgyrus at P1 and were exposed to HS at P10. Animals were monitored by video-EEG from P90 to P120. Pre and post-procedure plasma corticosterone levels were used to measure stress response at P1 and P10. To confirm the role of sex steroids, androgenized female pups received daily testosterone injections to the mother pre-natally and post-natally for nine days while undergoing both insults. We demonstrated that after both insults females did not develop MTLE while all males did. This correlated with a rise in corticosterone levels at P1 following the lesion in males only. Interestingly, all androgenized females showed a similar rise in corticosterone at P1, and also developed MTLE. Moreover, we found that the cortical lesion significantly decreased the latency to generalized convulsion during hyperthermia at P10 in both genders. The cortical dysplasia volumes at adulthood were also similar between male and female individuals. Our data demonstrate sexual dimorphism in long-term vulnerability to develop epilepsy in the lesion + hyperthermia animal model of MTLE and suggest that the response to early-life stress at P1 contributes significantly to epileptogenesis in a gender-specific manner.
