Massive Activation of GABAA Receptors: Rundown, Ionic and Neurodegenerative Consequences

The GABAA receptors, through a short-term interaction with a mediator, induce hyperpolarization of the membrane potential (Vm) via the passive influx of chloride ions (Cl−) into neurons. The massive (or intense) activation of the GABAARs by the agonist could potentially lead to depolarization/excitation of the Vm. Although the ionic mechanisms of GABAA-mediated depolarization remain incompletely understood, a combination of the outward chloride current and the inward bicarbonate current and the resulting pH shift are the main reasons for this event. The GABAA responses are determined by the ionic gradients—neuronal pH/bicarbonate homeostasis is maintained by carbonic anhydrase and electroneutral/electrogenic bicarbonate transporters and the chloride level is maintained by secondary active cation–chloride cotransporters. Massive activation can also induce the rundown effect of the receptor function. This rundown effect partly involves phosphorylation, Ca2+ and the processes of receptor desensitization. In addition, by various methods (including fluorescence and optical genetic methods), it has been shown that massive activation of GABAARs during pathophysiological activity is also associated with an increase in [Cl−]i and a decline in the pH and ATP levels in neurons. Although the relationship between the neuronal changes induced by massive activation of GABAergic signaling and the risk of developing neurodegenerative disease has been extensively studied, the molecular determinants of this process remain somewhat mysterious. The aim of this review is to summarize the data on the relationship between the massive activation of inhibitory signaling and the ionic changes in neurons. The potential role of receptor dysfunction during massive activation and the resulting ionic and metabolic disruption in neurons during the manifestation of network/seizure activity will be considered.