Impaired function of GABAB receptors in tissues from pharmacoresistant epilepsy patients

Abstract

Purpose: Effects of pre- and postsynaptic γ-aminobutyric acid B (GABAB) receptor activation were characterized in human tissue from epilepsy surgery. Methods: Slices of human cortical tissue were investigated in a submerged-type chamber with intracellular recordings in layers II/III. Parallel experiments were performed in rat neocortical slices with identical methods. Synaptic responses were elicited with single or paired stimulations of incrementing intervals. Results: Neurons in human epileptogenic tissue exhibited usually small inhibitory postsynaptic potentials (IPSP) mediated by GABA B receptor, verified by the sensitivity to the selective antagonist CGP 55845A. The IPSPB conductance averaged 5.8 nS in neurons from epileptogenic tissues and 15.9 nS in neurons from nonepileptogenic tissues (p < 0.0001). Application of baclofen caused small conductance increases in human neurons, which were linearly related to IPSPB conductances. Paired-pulse stimulation revealed constant synaptic responses in human temporal lobe epilepsy (TLE) slices at all interstimulus intervals (ISIs). Pharmacologically isolated IPSPA in the human tissue exhibited a small paired-pulse depression (average 10% at 500 ms ISI). Bicuculline-induced paroxysmal depolarization shifts (PDSs) were transiently depressed by 24% in human TLE tissue; and by 74% in rat neocortical slices (200 ms ISI; p = 0.015). The depressions of bicuculline-induced PDSs were antagonized by CGP 55845A in both species. Staining for GABAB receptors revealed significantly smaller numbers of immunopositive dots in human epileptogenic neurons versus human control neurons. Discussion: The small IPSPB, baclofen-conductances, and paired-pulse depression of PDSs and IPSPs in human TLE tissue indicate a reduced density of post- and presynaptic GABAB receptors. The reduced efficacy of presynaptic GABAB receptors facilitates the occurrence of repetitive synaptic activity. © 2009 International League Against Epilepsy.