Tonic GABAA Receptor-Mediated Signaling in Epilepsy

Excerpt

GABA_A receptors can mediate a “tonic” form of signaling that is not time-locked to presynaptic action potentials, and which depends upon detection of ambient GABA by extrasynaptic receptors. This form of signaling is cell type specific. In dentate granule cells, it is positively modulated by endogenous neurosteroids, which undergo changes related to hormonal status and stress.

Tonic currents profoundly modulate the input–output relationships of individual neurons. However, tonic currents can have a paradoxical excitatory role, either by depolarizing neurons or via a network effect (because of a dominant effect on interneurons). Tonic currents hyperpolarize thalamocortical neurons and so modulate their firing pattern from regular to burst firing.

Tonic currents are preserved or increased in models of focal epilepsy, even in the face of a loss of synaptic inhibition. This may represent a compensatory change that prevents seizure generation. Tonic currents are increased in animal models of absence epilepsy, and promote the generation of spike-wave discharges. Some substances selectively target tonic currents, including certain anesthetics, neurosteroids and gaboxadol. Drugs that elevate the ambient GABA concentration, including the antiepileptic drugs tiagabine and vigabatrin, also potentiate tonic currents, contributing both to their antiepileptic and to their pro-absence effects.