Modular competition driven by NMDA receptor subtypes in spike-timing-dependent plasticity

N-methyl-D-aspartate receptors (NMDARs) play a critical role in transducing neuronal activity patterns into changes in synaptic strength. However, how they mediate this transduction in response to physiological stimuli has remained elusive. In particular, it has been debated whether different NMDAR subtypes play opposing signaling roles in synaptic plasticity. Using perforated patch-clamp recordings from pairs of synaptically connected glutamatergic neurons in dissociated hippocampal culture, we found that spike-timing-dependent potentiation induced by pairing pre- and postsynaptic spikes required the activation of a fast component of NMDAR current that is likely to be mediated by NR2A-containing NMDARs (NR2A-NRs). In contrast, spike-timing-dependent depression required a slow component of NMDAR current carried by NR2B-containing NMDARs (NR2B-NRs). CV analysis showed that the locus of this depression was primarily presynaptic in pairs of cells making strong synaptic connections, whereas weaker synapses showed no clear preference for pre- or postsynaptic expression. This depression was not significantly reduced by antagonism of the CB1 receptor, in contrast to spike-timing-dependent depression in the neocortex that requires presynaptic CB1 signaling. With blockade of NR2B-NRs, spike triplets that contained both potentiating and depressing spike-timing components induced net potentiation. However, when the putative NR2A-NR population is inhibited, these spike triplets resulted in either depression or no net change, depending on the temporal order of the spike-timing components. These results imply a dynamic competition between signaling modules that can be biased by differentially antagonizing NMDAR subtypes during the induction of spike-timing-dependent plasticity. Using a simple model, we show that such a modular competition recapitulates our observations.