Differential Regulation of Evoked and Spontaneous Release by Presynaptic NMDA Receptors

Therése Abrahamsson, Christina You Chien Chou, Si Ying Li, Adamo Mancino, Rui Ponte Costa, Jennifer Anne Brock, Erin Nuro, Katherine Anne Buchanan, Dale Elgar, Arne Vladimir Blackman, Adam Tudor-Jones, Julia Oyrer, William Todd Farmer, Keith Kazuo Murai, Per Jesper Sjöström

Research output: Contribution to journalArticle (Academic Journal)peer-review

66 Citations (Scopus)
1 Downloads (Pure)


Presynaptic NMDA receptors (preNMDARs) control synaptic release, but it is not well understood how. Rab3-interacting molecules (RIMs) provide scaffolding at presynaptic active zones and are involved in vesicle priming. Moreover, c-Jun N-terminal kinase (JNK) has been implicated in regulation of spontaneous release. We demonstrate that, at connected layer 5 pyramidal cell pairs of developing mouse visual cortex, Mg2+-sensitive preNMDAR signaling upregulates replenishment of the readily releasable vesicle pool during high-frequency firing. In conditional RIM1αβ deletion mice, preNMDAR upregulation of vesicle replenishment was abolished, yet preNMDAR control of spontaneous release was unaffected. Conversely, JNK2 blockade prevented Mg2+-insensitive preNMDAR signaling from regulating spontaneous release, but preNMDAR control of evoked release remained intact. We thus discovered that preNMDARs signal differentially to control evoked and spontaneous release by independent and non-overlapping mechanisms. Our findings suggest that preNMDARs may sometimes signal metabotropically and support the emerging principle that evoked and spontaneous release are distinct processes. VIDEO ABSTRACT.

Original languageEnglish
Pages (from-to)839-855.e5
Issue number4
Early online date12 Oct 2017
Publication statusPublished - 15 Nov 2017


  • Animals
  • Excitatory Postsynaptic Potentials/physiology
  • Female
  • GTP-Binding Proteins/physiology
  • Magnesium/physiology
  • Male
  • Mice
  • Mice, Transgenic
  • Miniature Postsynaptic Potentials/physiology
  • Mitogen-Activated Protein Kinase 9/physiology
  • Presynaptic Terminals/physiology
  • Pyramidal Cells/physiology
  • Receptors, N-Methyl-D-Aspartate/physiology
  • Receptors, Presynaptic/physiology
  • Visual Cortex/physiology


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