Impaired function of GABAB receptors in tissues from pharmacoresistant epilepsy patients

Abstract

Effects of pre- and postsynaptic γ-aminobutyric acid B (GABA(B)) receptor activation were characterized in human tissue from epilepsy surgery. 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. 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 IPSP(B) 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 IPSP(B) conductances. Paired-pulse stimulation revealed constant synaptic responses in human temporal lobe epilepsy (TLE) slices at all interstimulus intervals (ISIs). Pharmacologically isolated IPSP(A) 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 GABA(B) receptors revealed significantly smaller numbers of immunopositive dots in human epileptogenic neurons versus human control neurons. The small IPSP(B), baclofen-conductances, and paired-pulse depression of PDSs and IPSPs in human TLE tissue indicate a reduced density of post- and presynaptic GABA(B) receptors. The reduced efficacy of presynaptic GABA(B) receptors facilitates the occurrence of repetitive synaptic activity.