Continual remodeling of postsynaptic density and its regulation by synaptic activity

Okabe, Susumu; Kim, Hong-Duck; Miwa, Akiko; Kuriu, Toshihiko; Okado, Haruo

doi:10.1038/12175

Cited by 231 publications

(221 citation statements)

References 41 publications

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“…1a). PSD-95-GFP clusters are a reliable marker for the postsynaptic structure [34][35][36] . Therefore, spines containing PSD-95-GFP (PSD-95-GFP-( þ ) spines) can be classified as more differentiated spines.…”

Section: Resultsmentioning

confidence: 99%

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Enhanced synapse remodelling as a common phenotype in mouse models of autism

et al. 2014

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Developmental deficits in neuronal connectivity are considered to be present in patients with autism spectrum disorders (ASDs). Here we examine this possibility by using in vivo spine imaging in the early postnatal cortex of ASD mouse models. Spines are classified by the presence of either the excitatory postsynaptic marker PSD-95 or the inhibitory postsynaptic marker gephyrin. ASD mouse models show consistent upregulation in the dynamics of PSD-95-positive spines, which may subsequently contribute to stable synaptic connectivity. In contrast, spines receiving inputs from the thalamus, detected by the presence of gephyrin clusters, are larger, highly stable and unaffected in ASD mouse models. Importantly, two distinct mouse models, human 15q11-13 duplication and neuroligin-3 R451C point mutation, show highly similar phenotypes in spine dynamics. This selective impairment in dynamics of PSD-95-positive spines receiving intracortical projections may be a core component of early pathological changes and be a potential target of early intervention.

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Section: Resultsmentioning

confidence: 99%

“…Synapse turnover is regulated by both activitydependent and -independent pathways 32,34,49 . Synapses can still be generated without activity-dependent processes, but the process of synapse stabilization may be selectively affected 50 .…”

Section: Discussionmentioning

confidence: 99%

Enhanced synapse remodelling as a common phenotype in mouse models of autism

et al. 2014

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“…A number of studies have shown that CaMKII and PSD-95 puncta are dynamic [3,4,7,17,34] but how these dynamics relate to the formation, loss and stabilization of synaptic contacts where both pre-and postsynaptic structures can be followed simultaneously has not been studied. To begin to understand how PSD-95 and CaMKII are distributed at stable and labile AD connections, we first assessed their static localization rates to presynaptic sites in fixed cultures, using either sites of AD contact (figure 1a) or the excitatory presynaptic marker VGlut1.…”

Section: Resultsmentioning

confidence: 99%

“…Presumably neurons must form and then maintain a population of stable contacts with specific synaptic partners in order to ensure proper circuit function, but the molecular mechanisms that underlie this process of synapse stabilization are still poorly understood [1,2]. Further, the ability of a synapse to remain stable is complicated by the recent demonstration that many synaptic proteins are highly dynamic and turn over in both activity-dependent and independent manners [3][4][5][6][7]. Here, we used time-lapse imaging of synapse formation in cultured neocortical neurons to examine the dynamics of association of Ca 2þ /calmodulin-dependent protein kinase II (CaMKII) and postsynaptic density-95 (PSD-95) with sites of axon-dendrite (AD) contact, in order to assess how the localization and amount of these proteins correlates with changes in contact turnover.…”

Section: Introductionmentioning

confidence: 99%

“…The scaffold protein PSD-95 is highly abundant at [15], and clusters very early at [16][17][18] excitatory synapses. Further, PSD-95 is more strongly associated with stable than transient spines [19], and is thought to accelerate synaptic maturation [3,[20][21][22] through coordinated regulation of postsynaptic AMPA-type glutamate receptors (GluARs) [23][24][25] and neuroligins [26,27]. Synaptic PSD-95 levels increase during development and with time in vitro [28,29], over a similar developmental window there is a reduction in synapse turnover [30], and knockdown of PSD-95 increases spine turnover [31].…”

Section: Introductionmentioning

confidence: 99%

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PSD-95 promotes the stabilization of young synaptic contacts

Taft

Turrigiano

2014

Phil. Trans. R. Soc. B

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Maintaining a population of stable synaptic connections is probably of critical importance for the preservation of memories and functional circuitry, but the molecular dynamics that underlie synapse stabilization is poorly understood. Here, we use simultaneous time-lapse imaging of post synaptic density-95 (PSD-95) and Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) to investigate the dynamics of protein composition at axodendritic (AD) contacts. Our data reveal that this composition is highly dynamic, with both proteins moving into and out of the same synapse independently, so that synapses cycle rapidly between states in which they are enriched for none, one or both proteins. We assessed how PSD-95 and CaMKII interact at stable and transient AD sites and found that both phospho-CaMKII and PSD-95 are present more often at stable than labile contacts. Finally, we found that synaptic contacts are more stable in older neurons, and this process can be mimicked in younger neurons by overexpression of PSD-95. Taken together, these data show that synaptic protein composition is highly variable over a time-scale of hours, and that PSD-95 is probably a key synaptic protein that promotes synapse stability.

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Synaptic Structure Quantification in Cultured Neurons

2014

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Behavioral problems (e.g. learning and memory) following developmental exposure to toxicants suggests that dysregulation of the process of synapse formation and function may occur. The ability to assess these changes is thus of value. This protocol describes a method to investigate toxicant-induced changes to synaptic structure formation in primary hippocampal neurons using immunocytochemical labeling of the pre- and post-synaptic markers synaptophysin and PSD-95, confocal imaging, and three-dimensional object analysis. Protocols for the long-term culturing of primary hippocampal neurons and of primary cortical astrocytes, as well as their co-culture are included. While the described methods focus on how astrocytes influence synapse formation and how toxicants may interfere in this process, modifications to the experimental plan can easily be implemented. This would allow for the investigation of the effects of toxicants after treating neurons alone, or both astrocytes and neurons in co-culture. With the common endpoint of synapse structure formation, differences between varying treatment paradigms can expand our understanding of the influence of particular toxicants on these diverse cell types and provide insight into potential mechanisms of effect and the contributions of each to synapse formation.

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Continual remodeling of postsynaptic density and its regulation by synaptic activity

Cited by 231 publications

References 41 publications

Enhanced synapse remodelling as a common phenotype in mouse models of autism

Enhanced synapse remodelling as a common phenotype in mouse models of autism

PSD-95 promotes the stabilization of young synaptic contacts

Synaptic Structure Quantification in Cultured Neurons

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