Abstracts

Previously we have shown that during periodic synchronized network activation (bursting), a partial block of NMDA receptors by competitive antagonists induces depotentiation of recurrent collateral synapses and thus decreases spontaneous CA3 burst frequency in adult rats. We hypothesize that this method (partially blocking NMDA receptors during bursts) will also reduce the strength of recurrent synapses in rats with kainate-induced epilepsy, providing a potential mechanism for blocking interictal spikes and/or seizures., Extracellular recordings of spontaneous population bursts in hippocampal area CA3 were studied as an in vitro model of interictal spikes. Slices were prepared from rats rendered chronically epileptic ([gt]3 month post treatment) by a prior treatment with kainic acid (multiple low-dose injections, 5mg/kg). Bursts were induced by perfusing slices with a modified ACSF (in mM: 3.3 KCl, 1.3 CaCl2, 0.9 MgCl2) containing 100 microM picrotoxin (GABAA antagonist). Spontaneous burst intervals and durations were recorded and analyzed., In spontaneously bursting slices from saline-treated rats, application of sequentially decreasing concentrations of the competitive NMDA antagonists SDZ (80-40-20 microM, lipophilic) and D-APV (10-5-2.5 microM, hydrophilic) significantly decreased burst probability (wash compared to vehicle-baseline; n=6 and n=4, respectively; ANOVA, P[lt]0.05). However in kainate-treated rats, application of sequentially decreasing concentrations of SDZ and D-APV significantly [underline]increased[/underline] burst probability (wash compared to vehicle-baseline; n=5 and n=4, respectively; ANOVA, P[lt]0.05). To determine whether this decrease in interburst interval in slices from kainate-treated rats is mediated by NR2A- or NR2B-containing NMDAR, we partially blocked NR2B-containing NMDA receptors using Ro25-6981 (0.25-1 microM). In saline-treated rats, sequentially decreasing application of Ro25-6981 induced no change in burst probability (n=5, ANOVA, P=0.12). In contrast, in hippocampi from kainate-treated rats, sequentially decreasing application of Ro25-6981 significantly decreased burst probability (n=5, ANOVA, P[lt]0.001)., In chronically epileptic animals, depotentiation of recurrent collateral synapses can only be induced by partial blockade of NR2B-containing NMDA receptors, while in control animals depotentiation can be induced by nonselective partial block of all NMDA receptors. These results may be due to a change in receptor-subunit expression or membrane trafficking as a consequence of kainate-induced damage and/or changes associated with epileptogenesis., (Supported by NIH.)