N-methyl-D-aspartic acid-induced and Ca-dependent neuronal swelling and its retardation by brain-derived neurotrophic factor in the epileptic hippocampus.

Dentate granule cell (DGC) swelling was studied by imaging changes in light transmittance from hippocampal slices in the rat pilocarpine model of epilepsy and human epileptic specimens. Brief bath-application of N-methyl-D-aspartic acid (NMDA) induced swelling in the control rat DGC (physiological swelling). Physiological swelling was short-lasting, and rapidly recovered upon removal of NMDA. In contrast, the swelling induced in the pilocarpine-treated rat hippocampus and human epileptic hippocampus (epileptic swelling) was long-lasting, and often recovered slowly over an hour. Both types of swelling were blocked by the NMDA receptor (NMDAR) antagonist, D-APV, suggesting that they shared the same induction mechanism. However, the swellings differed in their sensitivity to a calcium chelator, 1.2-bis(2-aminophenoxy)ethane-N,N,N,N-tetra-acetate (BAPTA), and an endoplasmic reticulum (ER) Ca2+-ATPase inhibitor, thapsigargin (TG). BAPTA and TG affected only epileptic swelling, and physiological swelling was spared. This suggested that the NMDAR-induced epileptic swelling might involve an additional mechanism for its maintenance, likely recruiting ER Ca2+ stores. Brain-derived neurotrophic factor (BDNF) slightly attenuated physiological swelling, and blocked epileptic swelling. The present study suggests a functional link between the activation of NMDAR and a release of Ca2+ from internal stores during the induction of epileptic swelling, and a neuroprotective role of BDNF on the NMDAR-induced swelling in the epileptic hippocampus.