A Role for Extrasynaptic GABA Receptors?

Abstract

Proper brain function depends on maintaining an appropriate balance between excitation and inhibition: Tipping the balance too far toward inhibition leads to sedation, whereas tipping it too far toward excitation can trigger a seizure. Although research on the role of γ aminobutyric acid (GABA, the chief inhibitory neurotransmitter) in epilepsy has focused on the synapse, δ subunit-containing GABA A receptors in the dentate gyrus of the hippocampus (a seizure-prone structure) are predominantly located in extrasynaptic sites. In one model of temporal lobe epilepsy, the muscarinic agonist pilocarpine is used to induce status epilepticus, leading to loss of hippocampal neurons and the delayed development of spontaneous seizures. Peng et al. found that, in mice treated with pilocarpine, diffuse immunohistochemical staining for the GABA A δ subunit in the molecular layer of the dentate gyrus decreased during the period prior to the onset of spontaneous seizures and remained low during the period when seizures occurred. However, δ subunit labeling of hippocampal interneurons increased. δ subunit-containing GABA A receptors are highly sensitive to modulation by neurosteroids, which enhance GABAergic inhibition, and the authors further observed increased excitability and decreased sensitivity to tetrahydrodeoxycortisone in the dentate of slices from pilocarpine-treated mice. Thus, the authors propose that changes in the expression of presumably extrasynaptic δ subunit-containing GABA A receptors contribute to temporal lobe epilepsy by decreasing inhibitory input onto dentate granule cells and increasing the inhibition of inhibitory interneurons. Z. Peng, C. S. Huang, B. M. Stell, I. Mody, C. R. Houser, Altered expression of the δ subunit of the GABA A receptor in a mouse model of temporal lobe epilepsy . J. Neurosci . 24 , 8629-8639 (2004). [Abstract] [Full Text]