Wnt Signaling Through Nitric Oxide Synthase Promotes the Formation of Multi-Innervated Spines

McLeod, Faye; Boyle, Kieran A.; Marzo, Aude; Martín‐Flores, Núria; Moe, Thaw Zin; Palomer, Ernest; Gibb, Alasdair J.; Salinas, Patricia C.

doi:10.3389/fnsyn.2020.575863

Cited by 11 publications

(4 citation statements)

References 47 publications

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“…Although these changes also occur during normal aging, as reported in other aged species [26,27], in the 3xTg-AD mice, the downregulation of these Wnt components occurred earlier than in the control mice and was particularly severe. In addition to the negative effects of Dkk-1 and the decrease in the agonist Wnt7a, we found that the symptomatic stage of pathology in transgenic mice could worsen synaptic function because of its role in promoting synaptic plasticity events [36,37].…”

Section: Discussionmentioning

confidence: 99%

Age- and sex-associated Wnt signaling dysregulation is exacerbated from the early stages of neuropathology in an Alzheimer´s disease model

Colín-Martínez,

Espino-de-la-Fuente,

Arias

2024

Preprint

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Emerging studies suggest that Wnt signaling is dysregulated in the brains of AD patients, suggesting that this pathway may also contribute to disease progression. However, it remains to be determined whether alterations in the Wnt pathway are the cause or consequence of this disease and which elements of Wnt signaling mainly contribute to the appearance of AD histopathological markers early in disease compared to what occurs during normal aging. The present study aimed to describe the status of several canonical Wnt pathway components and the expression of the AD marker p-tau in the hippocampi of female and male 3xTg-AD mice during disease progression compared to those during normal aging. We analyzed the levels of the canonical Wnt components Wnt7a, Dkk-1, LRP6 and GSK3β as well as the levels of p-tau and BDNF at 3, 6, 9–12 and 18 months of age. We found a gradual increase in Dkk-1 levels during aging prior to Wnt7a and LRP5/6 depletion, which was strongly exacerbated in 3xTg-AD mice even at young ages and correlated with GSK3β activation and p-tau-S202/T205 expression. Dkk-1 upregulation, as well as the level of p-tau, was significantly greater in females than in males. Our results suggest that Dkk-1 upregulation is involved in the expression of several features of AD at the presymptomatic stage, which supports the possibility of positively modulating the canonical Wnt pathway as a therapeutic tool to delay this disease at early stages.

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Section: Discussionmentioning

confidence: 99%

Age- and sex-associated Wnt signaling dysregulation is exacerbated from the early stages of neuropathology in an Alzheimer´s disease model

Colín-Martínez,

Espino-de-la-Fuente,

Arias

2024

Preprint

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“…These results highlight another microanatomical specialization concerning the presence of single AS on spines, although its functional relevance remains unclear. In fact, the generation of multi-synaptic spines has been associated with synaptic potentiation, and has been linked to memory processes (Giese et al, 2015; McLeod et al, 2020). Furthermore, in the mouse neocortex, it has been suggested that spines receiving one AS and one SS are electrically more stable than spines establishing a single AS (Villa et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Volume Electron Microscopy Reveals Unique Laminar Synaptic Characteristics in the Human Entorhinal Cortex

Plaza-Alonso,

Cano-Astorga,

DeFelipe

et al. 2023

Preprint

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The entorhinal cortex (EC) plays a pivotal role in memory function and spatial navigation, connecting the hippocampus with the neocortex. The EC integrates a wide range of cortical and subcortical inputs, but its synaptic organization in the human brain is largely unknown. We used volume electron microscopy to perform a 3D analysis of the synapses in all layers of the medial EC (MEC) from the human brain. Using this technology, 12,974 synapses were fully 3D reconstructed at the ultrastructural level. The MEC presented a distinct set of synaptic features, differentiating this region from other human cortical areas. Furthermore, synaptic organization within the MEC was predominantly homogeneous, although layers I and VI exhibited several synaptic characteristics that were distinct from other layers. The present study constitutes an extensive description of the synaptic organization of the neuropil of all layers of the EC, a crucial step to better understand the connectivity of this cortical region, in both health and disease.Significance StatementAnalysis of the synaptic characteristics provides crucial data on cortical organization. However, synaptic organization data for the normal human brain is virtually non-existent. The present study analyzes synaptic characteristics of the human entorhinal cortex at the ultrastructural level. This brain region is essential for memory processes and spatial navigation, acting as an interface between sensory areas and the hippocampus. Moreover, the entorhinal cortex is one of the first regions affected by Alzheimer’s disease. The present results provide a large quantitative ultrastructural dataset of synapses in all layers of the entorhinal cortex using 3D electron microscopy. Our findings show remarkable uniformity in the synaptic characteristics. This may seem surprising given the cytoarchitectonic and innervation complexity of the medial entorhinal cortex.

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“…The functional significance of having single or multiple synapses on the same spine is yet to be fully understood. The formation of multi-synaptic spines has been linked to synaptic potentiation and memory processes (Giese et al, 2015; McLeod et al, 2020). In the mouse neocortex, it has been suggested that spines receiving one AS and one SS are electrically more stable than spines with a single AS (Villa et al, 2016).…”

Section: Common Synaptic Characteristicsmentioning

confidence: 99%

Volume Electron Microscopy Analysis of Synapses in Associative and Primary Regions of the Human Cerebral Cortex

Cano-Astorga,

Plaza-Alonso,

DeFelipe

et al. 2024

Preprint

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Functional and structural studies investigating macroscopic connectivity in the human cerebral cortex suggest that high-order associative regions exhibit greater connectivity compared to primary ones. However, the synaptic organization of these brain regions remains unexplored due to the difficulties involved in studying the human brain at the nanoscopic level. In the present work, we conducted volume electron microscopy to investigate the synaptic organization of the human brain obtained at autopsy. Specifically, we examined layer III of Brodmann areas 17, 3b, and 4, as representative areas of primary visual, somatosensorial, and motor cortex. Additionally, we conducted comparative analyses with our previous synaptic datasets of layer III from temporopolar and anterior cingulate associative cortical regions (Brodmann areas 24, 38, and 21). 9,690 synaptic junctions were 3D reconstructed, showing that certain synaptic characteristics appeared to be specific to particular cortical regions. The number of synapses per volume, the proportion of the postsynaptic targets, and the synaptic size may distinguish one region from another, regardless of whether they are associative or primary cortex. By contrast, other synaptic characteristics were common to all analyzed regions, such as the proportion of excitatory and inhibitory synapses, their shapes, their spatial distribution, and a higher proportion of synapses located on dendritic spines. These observations may be included within the general rules of synaptic organization of the human cerebral cortex. The present results on nanoscopic characteristics of synapses provide further insights into the structural design of the human cerebral cortex.

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Wnt Signaling Through Nitric Oxide Synthase Promotes the Formation of Multi-Innervated Spines

Cited by 11 publications

References 47 publications

Age- and sex-associated Wnt signaling dysregulation is exacerbated from the early stages of neuropathology in an Alzheimer´s disease model

Age- and sex-associated Wnt signaling dysregulation is exacerbated from the early stages of neuropathology in an Alzheimer´s disease model

Volume Electron Microscopy Reveals Unique Laminar Synaptic Characteristics in the Human Entorhinal Cortex

Volume Electron Microscopy Analysis of Synapses in Associative and Primary Regions of the Human Cerebral Cortex

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