Phosphorylation-State-Dependent Regulation of NMDA Receptor Short-Term Plasticity Modifies Hippocampal Dendritic Ca Transients

Chatterjea D, Hamid E, Leonard JP, Alford S. Phosphorylation-statedependent regulation of NMDA receptor short-term plasticity modifies hippocampal dendritic Ca transients. J Neurophysiol 104: 2203–2213, 2010. First published August 18, 2010; doi:10.1152/jn.01081.2009. Nmethyl-D-aspartate (NMDA) receptor-mediated currents are enhanced by phosphorylation. We have investigated effects of phosphorylationdependent short-term plasticity of NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) on the induction of long-term depression (LTD). We confirmed in whole cell clamped CA1 pyramidal neurons that LTD is induced by pairing stimulus protocols. However, after serine-threonine phosphorylation was modified by postsynaptic introduction of a protein phosphatase-1 (PP1) inhibitor, the same pairing protocol evoked long-term potentiation (LTP). We determined effects of modification of phosphatase activity on evoked NMDA EPSCs during LTD induction protocols. During LTD induction, using a protocol pairing depolarization to –40 mV and 0.5 Hz stimulation, NMDA receptor-mediated EPSCs undergo a short-term enhancement at the start of the protocol. In neurons in which PP1 activity was inhibited, this short-term enhancement was markedly amplified. We then investigated the effect of this enhancement on Ca entry during the start of the LTD induction protocol. Enhancement of NMDA receptor-mediated responses was accompanied by an amplification of induction protocol-evoked Ca transients. Furthermore, this amplification required synaptic activation during the protocol, consistent with an enhancement of Ca entry mediated by NMDA receptor activation. The sign of NMDA receptor-mediated long-term plasticity, whether potentiation or depression depends on the amplitude of the synaptic Ca transient during induction. We conclude that short-term phosphorylation-dependent plasticity of the NMDA receptor-mediated EPSCs contributes significantly to the effect of phosphatase inhibition on the subsequent induction of LTD or LTP.