CYCLIC CHANGES IN NMDA RECEPTOR ACTIVATION IN HIPPOCAMPAL CA1 NEURONSAFTER ISCHEMIA

We studied N-methyl-D-aspartate (NMDA) receptor-mediated synaptic pote ntials in CAI pyramidal neurons using hippocampal slices of gerbils af ter transient forebrain ischemia. In the presence of 6-cyano-7-nitroqu inoxaline-2,3-dione (CNQX) and bicuculline, stimulation of Schaffer co llateral/commissural fibers induced field excitatory postsynaptic pote ntials (fEPSP) activated by NMDA receptors. We found that in many slic es after ischemia, prolonged low-frequency stimulation (0.1-10 Hz) cau sed repeated depression and potentiation of the NMDA-mediated fEPSP. C hanges in fEPSP amplitude were dependent on stimulus frequency and the cycle frequency ranged from 0.08 to 2.5 cycles/min. These cyclic chan ges were blocked by application of BAPTA-AM, a membrane-permeable Ca2 chelator, but were little affected by application of verapamil or by lowering the Ca2+. in bathing solution. Intracellular recordings from CA1 neurons revealed that low-frequency stimulation caused periodic de polarizations of membrane potential accompanied by depression of the e xcitatory postsynaptic potentials. The cyclic changes of fEPSPs were b locked by inhibit ors of protein kinase C (PKC) but were unaffected by inhibitors of Ca2+/calmodulin-dependent protein kinase II (CaMKII) or myosin light-chain kinase (MLCK). These results suggest that stimulus -dependent NMDA-receptor activation, mediated by PKC, takes place in t he postischemic CA1 neurons and that the cyclic change may reflect abn ormal intracellular Ca2+ signaling processes leading to neuronal degen eration. (C) 1997 Elsevier Science Ireland Ltd.