A NMDA receptor glycine site partial agonist, GLYX-13, simultaneously enhances LTP and reduces LTD at Schaffer collateral-CA1 synapses in hippocampus.
N-methyl-D-aspartate glutamate receptors (NMDARs) are a key route for Ca2+ 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 CA1 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 [Ca2+] in individual dendritic spines revealed that GLYX-13 selectively enhanced burst-induced NMDAR-dependent spine Ca2+ 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 LTP and suppress LTD.
Zhang
Xiao-lei
XL
Department of Cell Biology & Anatomy, New York Medical College, Basic Sciences Building, Room 217, Valhalla, NY 10595, USA.
Sullivan
John A
JA
Moskal
Joseph R
JR
Stanton
Patric K
PK
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D003523:Cycloserine / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D008568:Memory / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000819:agonists*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D012694:Serine / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects*
D000963:Antimetabolites; D009842:Oligopeptides; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; C507283:GLYX-13 peptide; D003523:Cycloserine; D002118:Calcium
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