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

Abstract

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 γ‐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.

Dual effects ofARXpoly-alanine mutations in human cortical and interneuron development

“…Our MEA results reveal heightened activity in ARX PAE organoids, characterized by increased spikes and bursts recorded from the extracellular space. This elevated activity occurs (abnormally) synchronously in ARX PAE organoids, resembling a pattern indicative of seizures—a condition typically marked by an imbalanced pattern of action potential generation within a neural network 87,88 . According to our findings, the spontaneous hyper spike/burst generation in ARX PAE organoids initiates at 120 DIV and continues through 365 DIV.…”

Exogenous γ-Aminobutyric Acid (GABA) Enhanced Response to Abiotic Stress in Hypsizygus marmoreus by Improving Mycelial Growth and Antioxidant Capacity

“…It also exhibits immune-modulating functions [7] and anti-cancer effects such as the suppression of the proliferation and metastasis of breast [8] and colon cancer cells [9,10]. GABA is closely associated with the regulation of hypothalamic functions, contributing to memory improvement, hormonal regulation [11], and the alleviation of neuroexcitatory disorders such as epilepsy [12]. Previous studies also confirmed the therapeutic effects of GABA in treating asthma [13] and pancreatic dysfunction [14].…”

Excitation/Inhibition balance relates to cognitive function and gene expression in Temporal Lobe Epilepsy: an hdEEG assessment with aperiodic exponent

“…Importantly, E/I balance is a multifactorial byproduct of neuronal activity, influenced by environmental factors as well as gene expression of channels and receptors 29,30 . Numerous mutations of gene regulating gamma-aminobutyric acid receptors, as well as sodium-potassium channels have been enlisted as etiopathogenic causes of epilepsy 31–34 . The recent release of open transcriptomics datasets such as the Allen Human Brain Atlas (AHBA) has offered opportunities to explore how gene expression patterns in the brain reflect macroscale neurofunctional findings 35,36 .…”