Effects of distinct classes of N-methyl- d-aspartate receptor antagonists on seizures, axonal sprouting and neuronal loss in vitro: suppression by NR2B-selective antagonists

Abstract

Chronic treatment with high-affinity, competitive N-methyl- d-aspartate receptor (NMDAR) antagonists can promote axonal sprouting, induce neuronal loss and exacerbate seizures associated with temporal lobe epilepsy. Whether moderate-affinity uncompetitive and NR2B subunit-selective NMDAR antagonists elicit similar responses remains largely unexplored. We directly compared the effects of distinct classes of NMDAR antagonists on electrographic seizures, axonal sprouting and neuronal survival using electrophysiological recordings and histology in hippocampal slice cultures treated chronically with vehicle, D-APV (high-affinity competitive), Ro 25-6981 or ifenprodil (NR2B-selective), or memantine (moderate-affinity uncompetitive). Granule cell layer field potential recordings revealed multiple spontaneous electrographic seizures in vehicle-treated cultures following GABA A receptor blockade. Compared to vehicle, seizures were dramatically reduced in cultures treated with NR2B selective antagonists and slightly increased in cultures treated with moderate-affinity uncompetitive or high-affinity competitive antagonists. In general, compared to vehicle, cultures treated with NR2B selective antagonists exhibited less sprouting of granule cell mossy fiber axons (MFS) and more granule cell layer neurons. Cultures treated with high-affinity competitive or moderate-affinity uncompetitive NMDAR antagonists showed increased MFS and fewer granule cell layer neurons. These data reveal differential effects of distinct classes of NMDAR antagonists on seizure expression, axonal sprouting and neuronal survival and suggest an association between these responses.