Early-Life Stress Is Associated with Gender-Based Vulnerability to Epileptogenesis in Rat Pups

Sébastien Desgent,Rose-Marie Rébillard,Nathalie T Sanon,David Hébert,Maxime Lévesque,Karine Bibeau,Michèle Brochu,Lionel Carmant,Pablo Lema,Sandra Duss,Olivier Baud

doi:10.1371/journal.pone.0042622

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.

Highlights

Mesial temporal lobe epilepsy (MTLE) is the most prevalent form of refractory epilepsy in humans and is characterized by seizures originating in limbic structures [1]
Increased susceptibility to hyperthermia-induced generalized convulsion (GC) in lesioned postnatal day 10 (P10) pups is not influenced by gender
As previously described [3,8,20], arrest of movement associated with head nodding occurred with the rise in core body temperature, followed by jaw myoclonus and a generalized convulsion characterized by tonic–clonic movements of the four limbs and loss of the righting reflex were observed

Summary

Introduction

Mesial temporal lobe epilepsy (MTLE) is the most prevalent form of refractory epilepsy in humans and is characterized by seizures originating in limbic structures [1]. MTLE typically begins in teenage years or even adulthood, the initial insult is thought to occur in early life typically as prolonged febrile seizures. Recent evidence suggests that prolonged febrile seizures themselves could only represent the second insult, occurring mostly in individuals with anatomic or genetic predisposing factors [2]. The rationale of the model is that the presence of a cortical malformation induced at P1, leads to enhanced susceptibility to a second insult, the hyperthermic seizure (HS) at P10. Control pups not exposed to the initial insult only experience brief HS and do not develop spontaneous recurrent seizures (SRS), while all lesioned pups exposed to hyperthermia for a similar period of time develop febrile status epilepticus (LHS pups) followed by MTLE after a latent period of approximately 80 days [2,4,5,7]. Other models of prolonged HS in naıve animals produced by prolonged exposure to high temperature lead to chronic epilepsy in about a third of pups [8,9], while the rats exposed to the freeze lesion alone do not experience SRS [4]

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