Epilepsy, E/I balance and GABA_A receptor plasticity

• Main Author: Jean-Marc Fritschy
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2008-03-01
• Series: Frontiers in Molecular Neuroscience
• Subjects: absence epilepsy; homeostatic plasticity; synaptic plasticity; Temporal Lobe Epilepsy; tonic inhibition
• Online Access: http://journal.frontiersin.org/Journal/10.3389/neuro.02.005.2008/full

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 fi ne-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 fi ndings highlighting the signifi cance of GABA_A receptor heterogeneity for the concept of E/I balance and its relevance for epilepsy. Specifi cally, we address the following issues: (1) role for tonic inhibition, mediated by extrasynaptic GABA_A receptors, for controlling neuronal excitability; (2) signifi cance of chloride ion transport for maintenance of the E/I balance in adult brain; and (3) molecular mechanisms underlying GABA_A receptor regulation (traffi cking, posttranslational modifi cation, gene transcription) that are important for homoeostatic plasticity. Finally, the relevance of these fi ndings 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 identifi cation of mutations in GABA_A receptor subunit genes underlying familial forms of epilepsy.