A burgeoning literature documents the confluence of ovarian steroids and central serotonergic
systems in the injunction of epileptic seizures and epileptogenesis. Estrogen administration
in animals reduces neuronal death from seizures by up-regulation of the prosurvival molecule i.e.
Bcl-2, anti-oxidant potential and protection of NPY interneurons. Serotonin modulates epileptiform
activity in either direction i.e administration of 5-HT agonists or reuptake inhibitors leads to the
activation of 5-HT3 and 5-HT1A receptors tending to impede focal and generalized seizures, while
depletion of brain 5-HT along with the destruction of serotonergic terminals leads to expanded neuronal
excitability hence abatement of seizure threshold in experimental animal models. Serotonergic
neurotransmission is influenced by the organizational activity of steroid hormones in the growing
brain and the actuation effects of steroids which come in adulthood. It is further established that
ovarian steroids bring induction of dendritic spine proliferation on serotonin neurons thus thawing a
profound effect on serotonergic transmission. This review features 5-HT1A and 5-HT3 receptors as
potential targets for ameliorating seizure-induced neurodegeneration and recurrent hypersynchronous
neuronal activity. Indeed 5-HT3 receptors mediate cross-talk between estrogenic and serotonergic
pathways, and could be well exploited for combinatorial drug therapy against epileptogenesis.
Keywords: Epileptic seizures, epileptogenesis, neuroprotection, estrogen, serotonin, neuronal plasticity.