| Abstract No.: | A-B1039 |
| Country: | Canada |
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| Title: | PDGF RECEPTORS TARGET NR2B-CONTAINING NMDA RECEPTORS IN THE HIPPOCAMPUS |
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| Authors/Affiliations: | 1 Michael Beazely*; 1 Hong Bin Li; 1 Bikram Sidhu; 1 Aeni Lim; 1 John F MacDonald;
1 University of Toronto, ON, Canada
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| Content: | Objectives. N-methyl-D-aspartate (NMDA) receptors are tetrameric ion channels composed of two NR1 subunits and 2 NR2A/B/C/D or NR3 subunits. In hippocampal neurons, synaptic NMDA receptors have relatively more NR2A subunits, whereas NR2B-containing NMDA receptors are more mobile and show relatively more extrasynaptic localization. Excess glutamate release, such as the release observed in focal ischemia, can result in neuronal cell death over-stimulating NMDA receptors. Whereas synaptic, NR2A-containing NMDA receptors are neuroprotective, NR2B-containing NMDA receptors may contribute to excitotoxicity. Pyramidal neurons of the hippocampus express a high density of platelet-derived growth factor receptors (PDGFRs) as well as the PDGF-B isoform of the primary ligand for these receptors. Ischemic events up-regulate neuroprotective proteins such as platelet-derived growth factor (PDGF) receptors and its ligand, PDGF-BB. This growth factor signaling system likely plays compensatory role in CNS responses to ischemia and perhaps acts as modulator of synaptic transmission and plasticity in the hippocampus.
Materials and Methods. Isolated hippocampal neurons and hippocampal slices were used to monitor the effects of PDGF-BB on NMDA-evoked currents or field potentials, respectively. CA1 hippocampal slices and cultured hippocampal neurons were employed for Western blotting, surface receptor biotinylation assays, immunocytochemistry, and cell-death assays.
Results. PDGF-BB depresses NMDA-evoked currents in CA1 pyramidal neurons as well as NMDA synaptic currents at CA3-CA1 synapses. We used NR2B and NR2A antagonists to demonstrate that PDGF-BB preferentially inhibits NR2B-containing NMDA receptor currents in isolated CA1 hippocampal neurons. Consistent with a potential extra-synaptic location we also showed that PDGFβRs are more closely localized with NR2B receptors than they are with PSD-95 or NR2A receptors. Furthermore, treatment of hippocampal slices or cultures with PDGF-BB caused a decrease in the surface express of NR2B but not of NR2A subunits. PDGF-BB treatment protected cultured neurons from NMDA-induced toxicity and also altered its signaling to the transcription factors CREB and ERK1/2. At CA3-CA1 synapses PDGF-BB enhanced long-term depression (LTD) of field EPSPs through depression of the NR2B subtype of NMDAR and elevated the threshold for LTP.
Conclusions. We conclude that PDGFR signaling, by preferentially targeting NR2B receptors, can serves as a modulator of CA1 metaplasticity and also provide a mechanism of neuroprotection.
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