Abstract
A variety of processes limit NMDA (N-methyl-D-aspartate) receptor (NMDAR) activity in response to agonist exposure, including rundown—the decline of peak current with repeated, sustained agonist application1,2,3,4. Here we report that calcium and tyrosine phosphorylation differentially regulate rundown of synaptic versus extrasynaptic NMDAR-mediated current in rat hippocampal pyramidal neurons.
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Acknowledgements
This work was supported by the Heart and Stroke Foundation (Doctoral Research Award, B.L.; operating grant, L.A.R.), Hereditary Disease Foundation (Postdoctoral Fellowship Award, N.C.) and the Canadian Institutes for Health Research (MOP-49586, T.H.M. and L.A.R.).
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Supplementary information
Supplementary Fig. 1.
Rundown of peak current mediated by 2B-subtype differs from that of 2A-containing NMDARs. (GIF 17 kb)
(a) Representative responses evoked by NMDA recorded from neurons at 5 d.i.v. (upper), 14 d.i.v. with 10μM ifenprodil (middle), and 15 d.i.v. following isolation of 2B-subtype current by pre-treatment with 20μM MK-801 and 10μM ifenprodil (lower). (b) Pooled data showing development of rundown. Peak current amplitude was normalized to first response. (c) Responses of representative neurons to NMDA in zero Ca2+e. Recordings at +40 mV were made in external 1 mM Mg2+. (d) Pooled data showing Ca2+-independent rundown. Similar results were obtained using 1mM NMDA/100μM glycine to induce rundown (not shown).
Supplementary Fig. 2.
Immunofluorescence internalization assay of mature neurons. Live neurons (20 d.i.v.) were labeled with antibodies recognizing an extracellular region of NR1 and then treated with either control condition (salt solution), or NMDA (1 mM) + glycine (100 μM), for 10 min (see methods above). Representative neurons from n = 2 different experiments. (JPG 23 kb)
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Li, B., Chen, N., Luo, T. et al. Differential regulation of synaptic and extra-synaptic NMDA receptors. Nat Neurosci 5, 833–834 (2002). https://doi.org/10.1038/nn912
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DOI: https://doi.org/10.1038/nn912
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