Abstract
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 language | English (US) |
|---|---|
| Pages (from-to) | 12303-12308 |
| Number of pages | 6 |
| Journal | Journal of Neuroscience |
| Volume | 35 |
| Issue number | 35 |
| DOIs | |
| State | Published - Sep 2 2015 |
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Keywords
- Dendritic spine
- Glutamate uncaging
- Long-term depression
- NMDA receptor
- Structural plasticity
- Two-photon microscopy
ASJC Scopus subject areas
- Neuroscience(all)
Cite this
Non-ionotropic NMDA receptor signaling drives activity-induced dendritic spine shrinkage. / Stein, Ivar S.; Gray, John; Zito, Karen.
In: Journal of Neuroscience, Vol. 35, No. 35, 02.09.2015, p. 12303-12308.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Non-ionotropic NMDA receptor signaling drives activity-induced dendritic spine shrinkage
AU - Stein, Ivar S.
AU - Gray, John
AU - Zito, Karen
PY - 2015/9/2
Y1 - 2015/9/2
N2 - 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.
AB - 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.
KW - Dendritic spine
KW - Glutamate uncaging
KW - Long-term depression
KW - NMDA receptor
KW - Structural plasticity
KW - Two-photon microscopy
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U2 - 10.1523/JNEUROSCI.4289-14.2015
DO - 10.1523/JNEUROSCI.4289-14.2015
M3 - Article
VL - 35
SP - 12303
EP - 12308
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 35
ER -