PSD-95 promotes synaptogenesis and multiinnervated spine formation through nitric oxide signaling

Nikonenko, Irina; Boda, Bernadett; Steen, Sylvain; Knott, Graham; Welker, Egbert; Michelet, Dominique

doi:10.1083/jcb.200805132

Cited by 157 publications

(149 citation statements)

References 45 publications

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“…We analyzed PSD95 expression in hippocampal area CA1 after contextual fear conditioning and show that only under a condition that leads to LTM formation is there a pronounced training-induced PSD95 overexpression in the T286A mutants. Thus, the persistent increase in MIS in T286A mutants accompanies training-induced PSD95 overexpression in agreement with the hippocampal slice culture experiments (21). We show also that the training-induced PSD95 overexpression in T286A mutants is blocked by the mTOR inhibitor rapamycin.…”

Section: Discussionsupporting

confidence: 90%

“…The postsynaptic scaffolding protein PSD95 has been linked with synaptogenesis (20). Furthermore, in hippocampal slice cultures overexpression of PSD95 leads to MIS formation, in particular (21). This fact, together with our finding that contextual LTM in T286A mutants is linked with synaptogenesis including persistent MIS generation, suggested that PSD95 overexpression is involved in memory formation in T286A mutants.…”

Section: Resultssupporting

confidence: 63%

“…Psd95 mRNA is dendritically localized and locally translated via activation of the mTOR pathway (22,23,30,31). In hippocampal slice cultures, overexpression of PSD95 induces MIS formation (21). We analyzed PSD95 expression in hippocampal area CA1 after contextual fear conditioning and show that only under a condition that leads to LTM formation is there a pronounced training-induced PSD95 overexpression in the T286A mutants.…”

Section: Discussionmentioning

confidence: 96%

“…MIS develop by the attraction of presynaptic terminals onto existing spines (21,28). Thus, MIS formation is a specific form of synaptogenesis that seems to serve the purpose of strengthening and/or modifying existing inputs onto neurons.…”

Section: Discussionmentioning

confidence: 99%

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Mechanism for long-term memory formation when synaptic strengthening is impaired

Radwańska

Medvedev

Pereira

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Long-term memory (LTM) formation has been linked with functional strengthening of existing synapses and other processes including de novo synaptogenesis. However, it is unclear whether synaptogenesis can contribute to LTM formation. Here, using α-calcium/calmodulin kinase II autophosphorylation-deficient (T286A) mutants, we demonstrate that when functional strengthening is severely impaired, contextual LTM formation is linked with traininginduced PSD95 up-regulation followed by persistent generation of multiinnervated spines, a type of synapse that is characterized by several presynaptic terminals contacting the same postsynaptic spine. Both PSD95 up-regulation and contextual LTM formation in T286A mutants required signaling by the mammalian target of rapamycin (mTOR). Furthermore, we show that contextual LTM resists destabilization in T286A mutants, indicating that LTM is less flexible when synaptic strengthening is impaired. Taken together, we suggest that activation of mTOR signaling, followed by overexpression of PSD95 protein and synaptogenesis, contributes to formation of invariant LTM when functional strengthening is impaired.synaptic plasticity | hippocampus | immediate-early gene | reconsolidation A fundamental question in neuroscience concerns the cellular mechanisms that lead to long-term memory (LTM) formation (1-3). It has been shown that LTM formation is associated with and demands strengthening of existing synapses, socalled functional plasticity (3-5), but it may also be linked with a more overt form of structural plasticity, an increase in synapse density (6-9). It is, however, unclear whether de novo synaptogenesis is critical for LTM formation.The participation of synaptogenesis for LTM formation can be investigated when synaptic strengthening is fully blocked. It would be ideal to also block training-induced changes in neuronal excitability that have been implicated in memory formation (10). However, technically this block may not be achievable as, for example, there are distinct types of synaptic strengthening. As a proxy, here we have studied T286A missense mutant mice lacking autophosphorylation at threonine 286 of the α-isoform of calcium/calmodulindependent kinase II (αCaMKII), a major protein of glutamatergic synapses in the forebrain (11). The T286A mutants have fully blocked NMDA receptor-dependent synaptic strengthening at hippocampal CA1 synapses (11-14), and they have impaired regulation of the postburst afterhyperpolarization (AHP) in CA1 pyramidal neurons (15). Accordingly, T286A mutants are deficient in contextual fear conditioning after a single training trial (16). However, after five massed training trials, T286A mutants can form contextual LTM (16) and this type of LTM is hippocampus-dependent (14).Here, we have used T286A mutants as tools to investigate the mechanism of LTM formation when NMDA receptor-dependent synaptic strengthening is blocked. Our study provides evidence that activation of mTOR signaling in the hippocampus, followed by overexpression of PSD95 protein and...

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Section: Discussionsupporting

confidence: 90%

Section: Resultssupporting

confidence: 63%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Mechanism for long-term memory formation when synaptic strengthening is impaired

Radwańska

Medvedev

Pereira

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…NR2B‐rich NMDARs suppress prosurvival CREB‐mediated gene expression by activating PSD95/nNOS signaling (Martel et al., 2012; Soriano et al., 2008). However, PSD95‐nNOS interaction is critical for synaptic connections (Nikonenko et al., 2008), and therefore, prolonged suppression of PSD95‐nNOS interaction may lead to unknown risks.…”

Section: Introductionmentioning

confidence: 99%

nNOS–CAPON interaction mediates amyloid‐β‐induced neurotoxicity, especially in the early stages

et al. 2018

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SummaryIn neurons, increased protein–protein interactions between neuronal nitric oxide synthase (nNOS) and its carboxy‐terminal PDZ ligand (CAPON) contribute to excitotoxicity and abnormal dendritic spine development, both of which are involved in the development of Alzheimer's disease. In models of Alzheimer's disease, increased nNOS–CAPON interaction was detected after treatment with amyloid‐β in vitro, and a similar change was found in the hippocampus of APP/PS1 mice (a transgenic mouse model of Alzheimer's disease), compared with age‐matched background mice in vivo. After blocking the nNOS–CAPON interaction, memory was rescued in 4‐month‐old APP/PS1 mice, and dendritic impairments were ameliorated both in vivo and in vitro. Furthermore, we demonstrated that S‐nitrosylation of Dexras1 and inhibition of the ERK–CREB–BDNF pathway might be downstream of the nNOS–CAPON interaction.

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Gens PSD‐95 and GSK‐3β expression improved by hair follicular stem cells‐conditioned medium enhances synaptic transmission and cognitive abilities in the rat model of vascular dementia

Ghobadi,

Akbari,

Bayat

et al. 2023

Brain and Behavior

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IntroductionVascular dementia (VaD) is a common type of dementia. The aim of this study was to investigate the cellular and molecular mechanism of conditioned medium (CM) in VaD.Material and methodsThe rats were divided into four groups of control (n = 9), sham‐operation (n = 10), VaD with vehicle (n = 9), and VaD with CM (n = 12) that received CM on days 4, 14, and 24 after 2VO. Before sacrificing the rats, cognitive performance was assessed through the open‐field (OP), passive‐avoidance, and Morris‐water maze. The field‐potential recording was used to investigate basal synaptic transmission (BST) and long‐term potentiation (LTP). Subsequently, the hippocampus was dissected, and real‐time PCR was used to quantify the expression levels of β1‐catenin, insulin‐like growth factor‐1 (IGF‐1), transforming growth factor‐beta (TGF‐β), glycogen synthase kinase‐3β (GSK‐3β), postsynaptic density protein 95 (PSD‐95), and NR2B genes.ResultsThe results indicated impaired performance in behavioral tests in 2VO rats, coupled with reductions in BST and LTP induction. The expression levels of β1‐catenin, IGF‐1, PSD‐95, and TGF‐β genes decreased, whereas NR2B and GSK‐3β expression increased. Treatment with CM restores the expression of PSD‐95 and GSK‐3β as well as fear‐memory, spatial learning, and grooming number without a positive effect on memory retrieval, time spent on the periphery and center of OP. The BST recovered upon administration of CM but, the LTP induction was still impaired.ConclusionThe recovery of BST in VaD rats appears to be the most important outcome of this study which is caused by the improvement of gene expression and leads to the restoration of fear memory.

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PSD-95 promotes synaptogenesis and multiinnervated spine formation through nitric oxide signaling

Cited by 157 publications

References 45 publications

Mechanism for long-term memory formation when synaptic strengthening is impaired

Mechanism for long-term memory formation when synaptic strengthening is impaired

nNOS–CAPON interaction mediates amyloid‐β‐induced neurotoxicity, especially in the early stages

Gens PSD‐95 and GSK‐3β expression improved by hair follicular stem cells‐conditioned medium enhances synaptic transmission and cognitive abilities in the rat model of vascular dementia

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