GABAA Receptors, Seizures, and Epilepsy

Excerpt

GABA_A receptors (GABARs), the main inhibitory neurotransmitter receptors in the mammalian brain, exist in a multitude of subtypes, including forms that predominantly mediate fast inhibitory synaptic transmission and other highly GABA-sensitive extrasynaptic forms that mediate tonic inhibition. GABARs are heteropentameric proteins formed by three different, yet homologous, subunits. Synaptic and extrasynaptic GABARs are targets of some medications used clinically in the treatment of seizures and epilepsy, including the barbiturates phenobarbital, primidone, and pentobarbital; propofol, and the neuroactive steroid ganaxolone. Synaptic GABARs are the targets of benzodiazepines, including diazepam, lorazepam, midazolam, and clobazam. Other epilepsy medications may also interact with GABARs in addition to affecting other antiseizure targets. This chapter gives a brief history of the GABAR involvement in the epilepsies and then describes developments since the publication of the last volume in this series in 2012. Greater understanding of the roles of GABAR isoforms has suggested strategies to target subpopulations of GABAR to more effectively treat various types of epilepsy and its comorbidities. Subtype specific GABAR positive modulators that selectively act on α2, α3, and α5 GABAR isoforms, and may have enhanced efficacy and reduced tolerance liability, are under investigation.