Excitatory/inhibitory balance in epilepsies and neurodevelopmental disorders: Depolarizing γ-aminobutyric acid as a common mechanism

Epilepsy is one of the most common neurological disorders. Although many factors contribute to epileptogenesis, seizure generation is mostly linked to hyperexcitability due to alterations in excitatory/inhibitory (E/I) balance. The common hypothesis is that reduced inhibition, increased excitation, or both contribute to the etiology of epilepsy. Increasing evidence shows that this view is oversimplistic, and that increased inhibition through depolarizing gamma-aminobutyric acid (GABA) similarly contributes to epileptogenisis. In early development, GABA signaling is depolarizing, inducing outward Cl- currents due to high intracellular Cl- concentrations. During maturation, the mechanisms of GABA action shift from depolarizing to hyperpolarizing, a critical event during brain development. Altered timing of this shift is associated with both neurodevelopmental disorders and epilepsy. Here, we consider the different ways that depolarizing GABA contributes to altered E/I balance and epileptogenesis, and discuss that alterations in depolarizing GABA could be a common denominator underlying seizure generation in neurodevelopmental disorders and epilepsies.

Automated summary

Epilepsy is a common neurological disorder associated with alterations in excitatory/inhibitory balance. While previous studies focused on reduced inhibition or increased excitation as the cause of epilepsy, recent research suggests that depolarizing gamma-aminobutyric acid (GABA) also contributes to epileptogenesis. During brain development, GABA switches from depolarizing to hyperpolarizing, and alterations in the timing of this transition are associated with neurodevelopmental disorders and epilepsy. This article discusses the role of depolarizing GABA in altered excitatory/inhibitory balance and seizure generation, highlighting it as a common factor in neurodevelopmental disorders and epilepsy.