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Impaired function of GABA B receptors in tissues from pharmacoresistant epilepsy patients
Author(s) -
Teichgräber Laura A.,
Lehmann ThomasNicolas,
Meencke HeinzJoachim,
Weiss Torsten,
Nitsch Robert,
Deisz Rudolf A.
Publication year - 2009
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1167.2009.02094.x
Subject(s) - inhibitory postsynaptic potential , postsynaptic potential , bicuculline , neuroscience , neurotransmission , epilepsy , human brain , chemistry , gaba receptor antagonist , stimulation , gabaa receptor , receptor , baclofen , biology , agonist , biochemistry
Summary Purpose: Effects of pre‐ and postsynaptic γ‐aminobutyric acid B (GABA B ) 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 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. Discussion: 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.