Abstracts

Recent CA1 and cortical slice studies have shown that long-term potentiation (LTP) and depotentiation (a type of long-term depression; LTD) require the activation of NR2A-containing NMDA receptors, whereas [italic]de novo [/italic]LTD necessitates the activation of NR2B-containing NMDA receptors. Previously we have shown that a partial block of NMDA receptors by competitive antagonists induces LTD at recurrent collateral synapses and thus decreases CA3 burst frequency. Here we tested whether LTD under these conditions is mediated by NR2A- or NR2B-containing NMDA receptors. We used the CA3 region of the hippocampus as a model of network synchronization to test the effects of Ro25-6981 (an NR2B-subunit selective antagonist) on burst probability. To induce spontaneous bursting, slices were superfused with a modified ACSF (in mM: 3.3 KCl, 1.3 CaCl[sub]2[/sub], 0.9 MgCl[sub]2[/sub]) containing 100 [mu]M picrotoxin (GABA[sub]A[/sub] antagonist). Spontaneous burst intervals and durations were recorded and analyzed. LTP and LTD of recurrent collateral synapses were measured by changes in burst probability. In spontaneously bursting slices, transient partial blockade of NR2B-containing NMDA receptors using Ro25-6981 (0.33-6 [mu]M) induced LTP at recurrent synapses, measured as a long-term increase in burst probability (n=4). In contrast, when D-APV was used to induce transient partial block of NMDA receptors containing either NR2A or NR2B subunits, LTD of recurrent synapses was induced, as measured by a long-term 50% decrease in burst probability (n=15, P[lt]0.05). However when NR2B-containing NMDA receptors were first blocked by 3 [mu]M Ro25-6981, LTP of recurrent synapses was induced during bursting despite transient partial block of NMDA receptors by D-APV (n=4). These data indicate that NR2B-containing NMDA receptors are necessary to produce depotentiation of recurrent collateral synapses in busting CA3 slices. These results suggest that LTD may occur as a result of increased activation of NMDA receptors containing NR2B subunits relative to NMDA receptors containing NR2A subunits. Thus selective NR2A antagonists may be the most effective tool for activity-dependent induction of LTD. (Supported by NIH.)