A NMDA receptor glycine site partial agonist, GLYX-13, simultaneously enhances LTP and reduces LTD at Schaffer collateral-CA1 synapses in hippocampus

作者：Zhang Xiao lei; Sullivan John A; Moskal Joseph R; Stanton Patric K^*

来源：Neuropharmacology, 2008, 55(7): 1238-1250.

DOI：10.1016/j.neuropharm.2008.08.018

• Glutamate receptor
• Learning
• Memory
• N-methyl-D-aspartate receptor
• Partial agonist
• Glycine
• Synaptic plasticity

N-methyl-D-aspartate glutamate receptors (NMDARs) are a key route for Ca(2+) influx into neurons important to both activity-dependent synaptic plasticity and, when uncontrolled, triggering events that cause neuronal degeneration and death. Among regulatory binding sites on the NMDAR complex is a glycine binding site, distinct from the glutamate binding site, which must be co-activated for NMDAR channel opening. We developed a novel glycine site partial agonist, GLYX-13, which is both nootropic and neuroprotective in vivo. Here, we assessed the effects of GLYX-13 on long-term synaptic plasticity and NMDAR transmission at Schaffer collateral-CA1 synapses in hippocampal slices in vitro. GLYX-13 simultaneously enhanced the magnitude of long-term potentiation (LTP) of synaptic transmission, while reducing long-term depression (LTD). GLYX-13 reduced NMDA receptor-mediated synaptic currents in CA] pyramidal neurons evoked by low frequency Schaffer collateral stimulation, but enhanced NMDAR currents during high frequency bursts of activity, and these actions were occluded by a saturating concentration of the glycine site agonist D-serine. Direct two-photon imaging of Schaffer collateral burst-evoked increases in [Ca(2+)] in individual dendritic spines revealed that GLYX-13 selectively enhanced burst-induced NMDAR-clependent spine Ca(2+) influx. Examining the rate of MK-801 block of synaptic versus extrasynaptic NMDAR-gated channels revealed that GLYX-13 selectively enhanced activation of burst-driven extrasynaptic NMDARs, with an action that was blocked by the NR2B-selective NMDAR antagonist ifenprodil. Our data suggest that GLYX-13 may have unique therapeutic potential as a learning and memory enhancer because of its ability to simultaneously enhance UP and suppress LTD.

• 出版日期2008-12
• 单位西北大学