Bidirectional NMDA receptor plasticity controls CA3 output and heterosynaptic metaplasticity

N–methyl–d–aspartate glutamate receptors (NMDARs) are classically known as coincidence detectors for the induction of long–term synaptic plasticity, and have been implicated in hippocampal CA3–dependent spatial memory functions that likely rely on dynamic cellular ensemble encoding of space. The unique functional properties of both NMDARs and mossy fiber (MF) projections to CA3 pyramidal cells place MF–NMDARs in a prime position to influence CA3 ensemble dynamics. By mimicking pre and postsynaptic activity patterns observed in–vivo, we report a burst timing–dependent paradigm for bidirectional long–term NMDAR plasticity at MF–CA3 synapses in rat hippocampal slices. This form of plasticity imparts bimodal control of MF–driven CA3 burst–firing and spike temporal fidelity. Moreover, we show that MF–NMDARs mediate heterosynaptic metaplasticity between MF and associational/commissural synapses. Thus, bidirectional NMDAR plasticity at MF–CA3 synapses could significantly contribute to the formation, storage, and recall of CA3 cell assembly patterns.