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Glycine in the hippocampus can exert its effect on both synaptic NMDA receptors (NMDARs) and extrasynaptic functional glycine receptors (GlyRs) via distinct binding sites. Previous studies have reported that glycine induces long-term potentiation (LTP) through the activation of synaptic NMDARs. However, little is known about the potential role of the activated GlyRs that are largely located in extrasynaptic regions. We report here that relatively high levels of glycine achieved either by exogenous glycine application or by the elevation of endogenous glycine accumulation with an antagonist of the glycine transporter induced long-term depression (LTD) of excitatory postsynaptic currents (EPSCs) in hippocampal CA1 pyramidal neurons. The co-application of glycine with the selective GlyR antagonist strychnine changed glycine-induced LTD (Gly-LTD) to LTP. Blocking the postsynaptic GlyR-gated net chloride flux by manipulating intracellular chloride concentrations failed to elicit any changes in EPSCs. These results suggest that GlyRs are involved in Gly-LTD. Furthermore, this new form of chemical LTD was accompanied by the internalization of postsynaptic AMPA receptors and required the activation of NMDARs. Therefore, our present findings reveal an important function of GlyR activation and modulation in gating the direction of synaptic plasticity. [ABSTRACT FROM AUTHOR]

In vivo experience induces changes in synaptic NMDA receptor (NMDAR) subunit components, which are correlated with subsequent modifications of synaptic plasticity. However, little is known about how these subunit changes regulate the induction threshold of subsequent plasticity. At hippocampal Schaffer collateral-CA1 synapses, we first examined whether a recent history of neuronal activity could affect subsequent synaptic plasticity through its actions on NMDAR subunit components. We found that prior activity history produced by priming stimulations (PSs) across a wide range of frequencies (1-100 Hz) could induce bidirectional changes in the NR2A/NR2B ratio, which governs the threshold for subsequent long-term potentiation/long-term depression (LTP/LTD). Manipulating the NR2A/NR2B ratio through partial NR2 subunit blockade mimicked the PS regulation of the LTP/LTD threshold. Our results demonstrate that activity-dependent changes in the NR2A/NR2B ratio can be critical factors in metaplastic regulation of the LTP/LTD threshold. [ABSTRACT FROM AUTHOR]

Regulation of neuronal NMDA receptor (NMDAR) is critical in synaptic transmission and plasticity. Protein kinase C (PKC) promotes NMDAR trafficking to the cell surface via interaction with NMDAR-associated proteins (NAPs). Little is known, however, about the NAPs that are critical to PKC-induced NMDAR trafficking. Here, we showed that calcium/calmodulin-dependent protein kinase II (CaMKII) could be a NAP that mediates the potentiation of NMDAR trafficking by PKC. PKC activation promoted the level of autophosphorylated CaMKII and increased association with NMDARs, accompanied by functional NMDAR insertion, at postsynaptic sites. This potentiation, along with PKC-induced long term potentiation of the AMPA receptor-mediated response, was abolished by CaMI(II antagonist or by disturbing the interaction between CaMI(II and NR2A or NR2B. Further mutual occlusion experiments demonstrated that PKC and CaMKII share a common signaling pathway in the potentiation of NMDAR trafficking and longterm potentiation (LTP) induction. Our results revealed that PKC promotes NMDA receptor trafficking and induces synaptic plasticity through indirectly triggering CaMKII autophosphorylation and subsequent increased association with NMDARs. [ABSTRACT FROM AUTHOR]