The Relative Contribution of NMDARs to Excitatory Postsynaptic Currents is Controlled by Ca2+-Induced Inactivation

Fliza Valiullina, Yulia Zakharova, Marat Mukhtarov, Andreas Draguhn, Nail Burnashev, Andrei Rozov

NMDA receptors (NMDARs) are important mediators of excitatory synaptic transmission and plasticity. A hallmark of these channels is their high permeability to Ca(2+). At the same time, they are themselves inhibited by the elevation of intracellular Ca(2+) concentration. It is unclear however, whether the Ca(2+) entry associated with single NMDAR mediated synaptic events is sufficient to self-inhibit their activation. Such auto-regulation would have important effects on the dynamics of synaptic excitation in several central neuronal networks. Therefore, we studied NMDAR-mediated synaptic currents in mouse hippocampal CA1 pyramidal neurons. Postsynaptic responses to subthreshold Schaffer collateral stimulation depended strongly on the absence or presence of intracellular Ca(2+) buffers. Loading of pyramidal cells with exogenous Ca(2+) buffers increased the amplitude and decay time of NMDAR mediated EPSCs (EPSPs) and prolonged the time window for action potential (AP) generation. Our data indicate that the Ca(2+) influx mediated by unitary synaptic events is sufficient to produce detectable self-inhibition of NMDARs even at a physiological Mg(2+) concentration. Therefore, the contribution of NMDARs to synaptic excitation is strongly controlled by both previous synaptic activity as well as by the Ca(2+) buffer capacity of postsynaptic neurons.