Epilepsy, E/I Balance and GABA(A) Receptor Plasticity

GABA(A) receptors mediate most of the fast inhibitory transmission in the CNS. They form heteromeric complexes assembled from a large family of subunit genes. The existence of multiple GABA(A) receptor subtypes differing in subunit composition, localization and functional properties underlies their role for fine-tuning of neuronal circuits and genesis of network oscillations. The differential regulation of GABA(A) receptor subtypes represents a major facet of homeostatic synaptic plasticity and contributes to the excitation/inhibition (E/I) balance under physiological conditions and upon pathological challenges. The purpose of this review is to discuss recent findings highlighting the significance of GABA(A) receptor heterogeneity for the concept of E/I balance and its relevance for epilepsy. Specifically, we address the following issues: (1) role for tonic inhibition, mediated by extrasynaptic GABA(A) receptors, for controlling neuronal excitability; (2) significance of chloride ion transport for maintenance of the E/I balance in adult brain; and (3) molecular mechanisms underlying GABA(A) receptor regulation (trafficking, posttranslational modification, gene transcription) that are important for homoeostatic plasticity. Finally, the relevance of these findings is discussed in light of the involvement of GABA(A) receptors in epileptic disorders, based on recent experimental studies of temporal lobe epilepsy (TLE) and absence seizures and on the identification of mutations in GABA(A) receptor subunit genes underlying familial forms of epilepsy.