Activity-Dependent Plasticity of the NMDA-Receptor Fractional Ca Current

Ca influx through NMDA receptors (NMDARs) triggers synaptic plasticity, gene transcription, and cytotoxicity, but little is known about the regulation of NMDA-Rs themselves. We used two-photon glutamate uncaging to activate NMDA-Rs on individual dendritic spines in rat CA1 neurons while we measured NMDAR currents at the soma and [Ca] changes in spines. Low-frequency uncaging trains induced Ca-dependent long-term depression of NMDA-R-mediated synaptic currents. Additionally, uncaging trains caused a reduction in the Ca accumulation per unit of NMDA-R current in spines due to a reduction in the fraction of the NMDA-R current carried by Ca. Induction of depression of NMDA-R-mediated Ca influx required activation of NR2B-containing receptors. Receptors in single spines depressed rapidly in an all-or-none manner. These adaptive changes in NMDA-R function likely play a critical role in metaplasticity and in stabilizing activity levels in neuronal networks with Hebbian synapses.