Induction of input-specific spine shrinkage on dendrites of rodent hippocampal CA1 neurons using two-photon glutamate uncaging

Jang, Jin–Young; Anisimova, Margarita; Oh, Won Chan; Zito, Karen

doi:10.1016/j.xpro.2021.100996

Cited by 4 publications

(6 citation statements)

References 11 publications

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“…We next examined whether long-term dendritic spine shrinkage driven by ion flux-independent NMDAR signaling (Stein et al, 2015; Stein et al, 2020; Stein et al, 2021) was similarly blocked by d -serine. For these experiments, we used a low frequency uncaging protocol (LFU) designed to induce LTD and long-term spine shrinkage (Oh et al, 2013; Stein et al, 2020; Jang et al, 2021). We isolated ion flux-independent NMDAR-mediated plasticity by examining spine shrinkage with an LTD-inducing stimulus in the presence of MK801.…”

Section: Resultsmentioning

confidence: 99%

“…Physiologically, ion flux-independent NMDAR-mediated forms of plasticity and signaling are likely to be most relevant at individual synapses during Mg 2+ block of ion flow through the NMDAR, as expected at resting membrane potentials and at silent synapses, or in physiological or disease states associated with reduced d -serine levels (Park et al, 2022b; Park et al, 2022a). Because our single-spine plasticity protocols were originally developed using low or zero Mg 2+ to mimic coincident pre- and post-synaptic activity (Oh et al, 2013; Jang et al, 2021), we chose to examine next whether d -serine levels would act to modulate NMDAR-mediated structural plasticity during Mg 2+ block. For these experiments, we implemented a high frequency glutamate uncaging protocol (HFU) that typically results in long-term potentiation (LTP) and spine growth but, in the presence of MK801 or L689 to block ion flow through the NMDAR, instead leads to a robust LTD and LTD-associated spine shrinkage mediated by ion flux-independent NMDAR signaling (Stein et al, 2015; Stein et al, 2020; Stein et al, 2021).…”

Section: Resultsmentioning

confidence: 99%

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D-Serine inhibits non-ionotropic NMDA receptor signaling

Barragan,

Anisimova,

Vijayakumar

et al. 2024

Preprint

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NMDA-type glutamate receptors (NMDARs) are widely recognized as master regulators of synaptic plasticity, most notably for driving long-term changes in synapse size and strength that support learning. NMDARs are unique among neurotransmitter receptors in that they require binding of both neurotransmitter (glutamate) and co-agonist (e.g.d-serine) to open the receptor channel, which leads to the influx of calcium ions that drive synaptic plasticity. Over the past decade, evidence has accumulated that NMDARs also support synaptic plasticity via ion flux-independent (non-ionotropic) signaling upon the binding of glutamate in the absence of co-agonist, although conflicting results have led to significant controversy. Here, we hypothesized that a major source of contradictory results can be attributed to variable occupancy of the co-agonist binding site under different experimental conditions. To test this hypothesis, we manipulated co-agonist availability in acute hippocampal slices from mice of both sexes. We found that enzymatic scavenging of endogenous co-agonists enhanced the magnitude of LTD induced by non-ionotropic NMDAR signaling in the presence of the NMDAR pore blocker, MK801. Conversely, a saturating concentration ofd-serine completely inhibited both LTD and spine shrinkage induced by glutamate binding in the presence of MK801. Using a FRET-based assay in cultured neurons, we further found thatd-serine completely blocked NMDA-induced conformational movements of the GluN1 cytoplasmic domains in the presence of MK801. Our results support a model in whichd-serine inhibits ion flux-independent NMDAR signaling and plasticity, and thusd-serine availability could serve to modulate NMDAR signaling even when the NMDAR is blocked by magnesium.Significance StatementNMDARs are glutamate-gated cation channels that are key regulators of neurodevelopment and synaptic plasticity and unique in their requirement for binding of a co-agonist (e.g.d-serine) in order for the channel to open. NMDARs have been found to drive synaptic plasticity via non-ionotropic (ion flux-independent) signaling upon the binding of glutamate in the absence of co-agonist, though conflicting results have led to controversy. Here, we found thatd-serine inhibits non-ionotropic NMDAR-mediated LTD and LTD-associated spine shrinkage. Thus, a major source of the contradictory findings might be attributed to experimental variability ind-serine availability. In addition, the developmental regulation ofd-serine levels suggests a role for non-ionotropic NMDAR plasticity during critical periods of plasticity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

D-Serine inhibits non-ionotropic NMDA receptor signaling

Barragan,

Anisimova,

Vijayakumar

et al. 2024

Preprint

Self Cite

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“…Interestingly, the enlargement of spines may show a more rapid washout by whole-cell perfusion compared to LTP. 155),223),224) A similar dissociation is observed when p38 mitogen-activated protein kinase (p38 MAPK) is blocked, 225) indicating that not all instances of LTP are accompanied by LTE. The structure-function relationship (P1) suggests that when LTP does not coincide with structural changes, it may have a shorter duration, lack synapse specificity, 226) and be less distinctive than spine enlargement.…”

Section: Actin Dynamics During Early Spine Enlargementmentioning

confidence: 93%

“…Spine shrinkage, which reflects a reduction in the size of the PSD, occurs gradually with a time constant of approximately 10 minutes in the hippocampus, 109 , 225 ) and in the adult neocortex. 343 ) It appears that activated cofilin severs F-actin, eventually leading to a reduction in PSD size.…”

Section: Activity-dependent Structural Plasticity (P2: Extrinsic Dyna...mentioning

confidence: 99%

Unraveling the mysteries of dendritic spine dynamics: Five key principles shaping memory and cognition

KASAI

2023

Proc. Jpn. Acad., Ser. B

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Recent research extends our understanding of brain processes beyond just action potentials and chemical transmissions within neural circuits, emphasizing the mechanical forces generated by excitatory synapses on dendritic spines to modulate presynaptic function. From in vivo and in vitro studies, we outline five central principles of synaptic mechanics in brain function: P1: Stability – Underpinning the integral relationship between the structure and function of the spine synapses. P2: Extrinsic dynamics – Highlighting synapse-selective structural plasticity which plays a crucial role in Hebbian associative learning, distinct from pathway-selective long-term potentiation (LTP) and depression (LTD). P3: Neuromodulation – Analyzing the role of G-protein-coupled receptors, particularly dopamine receptors, in time-sensitive modulation of associative learning frameworks such as Pavlovian classical conditioning and Thorndike’s reinforcement learning (RL). P4: Instability – Addressing the intrinsic dynamics crucial to memory management during continual learning, spotlighting their role in “spine dysgenesis” associated with mental disorders. P5: Mechanics – Exploring how synaptic mechanics influence both sides of synapses to establish structural traces of short- and long-term memory, thereby aiding the integration of mental functions. We also delve into the historical background and foresee impending challenges.

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“…Indeed, full saturation of LTD-associated spine shrinkage occurs 30 min post-LTD induction by low-frequency glutamate uncaging at individual dendritic spines (figure 9 a,b ) [136]. Because LTD was induced in these experiments using a low-frequency glutamate uncaging (LFU) [136,138], the induction of LTD and associated spine shrinkage bypasses presynaptic stimulation and produces a spine-specific coordinated decrease in size and synapse strength. These findings suggest that LTD saturation originates postsynaptically and is transmitted back to the presynaptic side through retrograde messengers, bidirectional adhesive signalling or direct physical forces, as described for LTP above.…”

Section: Modelling the Saturation And Recovery Of Ltd And Its Impact ...mentioning

confidence: 99%

Synapse-specific structural plasticity that protects and refines local circuits during LTP and LTD

Harris,

Kuwajima,

Flores

et al. 2024

Phil. Trans. R. Soc. B

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Synapses form trillions of connections in the brain. Long-term potentiation (LTP) and long-term depression (LTD) are cellular mechanisms vital for learning that modify the strength and structure of synapses. Three-dimensional reconstruction from serial section electron microscopy reveals three distinct pre- to post-synaptic arrangements: strong active zones (AZs) with tightly docked vesicles, weak AZs with loose or non-docked vesicles, and nascent zones (NZs) with a postsynaptic density but no presynaptic vesicles. Importantly, LTP can be temporarily saturated preventing further increases in synaptic strength. At the onset of LTP, vesicles are recruited to NZs, converting them to AZs. During recovery of LTP from saturation (1–4 h), new NZs form, especially on spines where AZs are most enlarged by LTP. Sentinel spines contain smooth endoplasmic reticulum (SER), have the largest synapses and form clusters with smaller spines lacking SER after LTP recovers. We propose a model whereby NZ plasticity provides synapse-specific AZ expansion during LTP and loss of weak AZs that drive synapse shrinkage during LTD. Spine clusters become functionally engaged during LTP or disassembled during LTD. Saturation of LTP or LTD probably acts to protect recently formed memories from ongoing plasticity and may account for the advantage of spaced over massed learning. This article is part of a discussion meeting issue ‘Long-term potentiation: 50 years on’.

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Induction of input-specific spine shrinkage on dendrites of rodent hippocampal CA1 neurons using two-photon glutamate uncaging

Cited by 4 publications

References 11 publications

D-Serine inhibits non-ionotropic NMDA receptor signaling

D-Serine inhibits non-ionotropic NMDA receptor signaling

Unraveling the mysteries of dendritic spine dynamics: Five key principles shaping memory and cognition

Synapse-specific structural plasticity that protects and refines local circuits during LTP and LTD

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