Interneurons, GABAA signaling and their presumptive role in catamenial epilepsy

Catamenial epilepsy is characterized by increased seizure frequency or severity during specific phases of the menstrual cycle, presumably driven by changes in the balance between excitation and inhibition. GABA_A receptor-mediated inhibition, which is involved in focal epileptic disorders rests on the presynaptic release of GABA by interneurons. Work performed in the 1980s identified loss of interneuron function in seizure onset zones and the ability of GABA_A receptor antagonists to induce epileptiform synchronization thus indicating that decreased inhibition leads to seizures. However, in vitro and in vivo findings obtained during the last four decades from animal models and epileptic patients have challenged this view. Here, we will first review such active, though unexpected, contribution of interneurons (and thus of inhibition) in seizure initiation and maintenance. We will then address the blood level changes in the sex hormones progesterone and estrogen occurring in humans and rodents during the ovarian cycles, and their potential involvement in specific types of catamenial epilepsy. Finally, we will discuss the active contribution of parvalbumin (PV)-positive GABAergic interneurons to seizure activity. Due to high estrogen blood levels, these cells become hyperexcitable during periovulation and when ovariectomized females are treated with 17β-estradiol; this estrogen β receptor-mediated mechanism makes seizures last longer during periovulation. Such novel role of PV-positive interneurons in increasing focal seizures during proestrus/estrus may lead to formulate new therapeutic interventions in controlling seizure exacerbation during periovulation.