Non-ionotropic NMDA receptor signaling drives activity-induced dendritic spine shrinkage

Ivar S. Stein, John Gray, Karen Zito

Research output: Contribution to journalArticlepeer-review

85 Scopus citations


The elimination of dendritic spine synapses is a critical step in the refinement of neuronal circuits during development of the cerebral cortex. Several studies have shown that activity-induced shrinkage and retraction of dendritic spines depend on activation of the NMDAtype glutamate receptor (NMDAR), which leads to influx of extracellular calcium ions and activation of calcium-dependent phosphatases that modify regulators of the spine cytoskeleton, suggesting that influx of extracellular calcium ions drives spine shrinkage. Intriguingly, a recent report revealed a novel non-ionotropic function of the NMDAR in the regulation of synaptic strength, which relies on glutamate binding but is independent of ion flux through the receptor (Nabavi et al., 2013). Here, we tested whether non-ionotropic NMDAR signaling could also play a role in driving structural plasticity of dendritic spines. Using two-photon glutamate uncaging and time-lapse imaging of rat hippocampal CA1 neurons, we show that low-frequency glutamatergic stimulation results in shrinkage of dendritic spines even in the presence of the NMDAR D-serine/glycine binding site antagonist 7-chlorokynurenic acid (7CK), which fully blocks NMDARmediated currents and Ca2+ transients. Notably, application of 7CK or MK-801 also converts spine enlargement resulting from a high-frequency uncaging stimulus into spine shrinkage, demonstrating that strong Ca2+ influx through the NMDAR normally overcomes a non-ionotropic shrinkage signal to drive spine growth. Our results support a model in which NMDAR signaling, independent of ion flux, drives structural shrinkage at spiny synapses.

Original languageEnglish (US)
Pages (from-to)12303-12308
Number of pages6
JournalJournal of Neuroscience
Issue number35
StatePublished - Sep 2 2015


  • Dendritic spine
  • Glutamate uncaging
  • Long-term depression
  • NMDA receptor
  • Structural plasticity
  • Two-photon microscopy

ASJC Scopus subject areas

  • Neuroscience(all)


Dive into the research topics of 'Non-ionotropic NMDA receptor signaling drives activity-induced dendritic spine shrinkage'. Together they form a unique fingerprint.

Cite this