Seizures are more common early in life than in adulthood. Bidirectional interactions between seizures and normal developmental processes define their expression and outcomes. Several developmentally regulated factors control neuronal excitability. GABAA receptors hold a central role as they control neuronal activity in an age-specific manner. Early in development, GABAA receptors have depolarizing effects, which contribute to the increased susceptibility of immature neurons to seizures but they are also essential for normal brain development. During development, there is a gradual shift to the “adult-type” hyperpolarizing GABAA receptor signaling, creating more efficient inhibition. Seizures may disrupt GABAA receptor signaling by changing the expression of their subunits and by changing the direction of GABAA responses, which, in certain situations, may be detrimental for brain development. Furthermore, subcortical nuclei, such as the substantia nigra, control the expression and propagation of seizures in an age- and sex-dependent manner. These endogenous control centers and signaling pathways are further modified by independent genetic epigenetic, biologic, or other factors, which further increase the heterogeneity in presentation of seizures, their treatment, and their comorbidities. Elucidation of these complex interactions and identification of biomarkers guiding therapeutic interventions will be necessary to improve our ability to treat early-life epilepsies.
