Age-related spatial learning impairment is unrelated to spinophilin immunoreactive spine number and protein levels in rat hippocampus
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Abstract Determining the density and morphology of dendritic spines is of high biological significance given the role of spines in synaptic plasticity and in neurodegenerative and neuropsychiatric disorders. Precise quantification of spines in three dimensions (3D) is essential for understanding the structural determinants of normal and pathological neuronal function. However, this quantification has been restricted to time‐ and labor‐intensive methods such as electron microscopy and manual counting, which have limited throughput and are impractical for studies of large samples. While there have been some automated software packages that quantify spine number, they are limited in terms of their characterization of spine structure. This unit presents methods for objective dendritic spine morphometric analysis by providing image acquisition parameters needed to ensure optimal data series for proper spine detection, characterization, and quantification with Neurolucida 360. These protocols will be a valuable reference for scientists working towards quantifying and characterizing spines. © 2016 by John Wiley & Sons, Inc.
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Dendritic filopodia
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Since their first description by Ramon y Cajal at the end of the 19th century, dendritic spines have been proposed as important sites of neuronal contacts and it has been suggested that changes in the activity of neurons directly affect spine morphology. In fact, since then it has been shown that about 90% of excitatory synapses end on spines. Recent data indicate that spines are highly dynamic structures and that spine shape correlates with the strength of synaptic transmission. Furthermore, several mental disorders including Alzheimers disease (AD) are associated with spine pathology suggesting that spine alterations play a central role in mental deficits. The aim of this review is to provide an overview about the current knowledge on spine morphology and function as well as about different experimental models to analyze spine changes and dynamics. The second part concentrates on disease-relevant factors that are associated with AD and which lead to spine alterations. In particular, data that provide evidence that Aβ oligomers or fibrillar Aβ deposits influence spine morphology and function will be presented and the contribution of tau pathology will be discussed. The review ends with the discussion of potential mechanisms how disease-relevant factors influence dendritic spines and whether and how spine changes could be therapeutically suppressed or reversed.
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Dendritic spines are membranous protrusions that receive essentially all excitatory inputs in most mammalian neurons. Spines, with a bulbous head connected to the dendrite by a thin neck, have a variety of morphologies that likely impact their functional properties. Nevertheless, the question of whether spines belong to distinct morphological subtypes is still open. Addressing this quantitatively requires clear identification and measurements of spine necks. Recent advances in electron microscopy enable large-scale systematic reconstructions of spines with nanometer precision in 3D. Analyzing ultrastructural reconstructions from mouse neocortical neurons with computer vision algorithms, we demonstrate that the vast majority of spine structures can be rigorously separated into heads and necks, enabling morphological measurements of spine necks. We then used a database of spine morphological parameters to explore the potential existence of different spine classes. Without exception, our analysis revealed unimodal distributions of individual morphological parameters of spine heads and necks, without evidence for subtypes of spines. The postsynaptic density size was strongly correlated with the spine head volume. The spine neck diameter, but not the neck length, was also correlated with the head volume. Spines with larger head volumes often had a spine apparatus and pairs of spines in a post-synaptic cell contacted by the same axon had similar head volumes. Our data reveal a lack of morphological subtypes of spines and indicate that the spine neck length and head volume must be independently regulated. These results have repercussions for our understanding of the function of dendritic spines in neuronal circuits.
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Changes in neuronal structure are thought to underlie long-term behavioral modifications associated with learning and memory. In particular, considerable evidence implicates the destabilization and retraction of dendritic spines along with the loss of spine synapses as an important cellular mechanism for refining brain circuits, yet the molecular mechanisms regulating spine elimination remain ill-defined. The postsynaptic density protein, PSD-95, is highly enriched in dendritic spines and has been associated with spine stability. Because spines with low levels of PSD-95 are more dynamic, and the recruitment of PSD-95 to nascent spines has been associated with spine stabilization, we hypothesized that loss of PSD-95 enrichment would be a prerequisite for spine retraction. To test this hypothesis, we used dual-color time-lapse two-photon microscopy to monitor rat hippocampal pyramidal neurons cotransfected with PSD-95-GFP and DsRed-Express, and we analyzed the relationship between PSD-95-GFP enrichment and spine morphological changes. Consistent with our hypothesis, we found that the majority of spines that retracted were relatively unenriched for PSD-95-GFP. However, in the subset of PSD-95-GFP-enriched spines that retracted, spine shrinkage and loss of PSD-95-GFP were tightly coupled, suggesting that loss of PSD-95-GFP enrichment did not precede spine retraction. Moreover, we found that, in some instances, spine retraction resulted in a significant enrichment of PSD-95-GFP on the dendritic shaft. Our data support a model of spine retraction in which loss of PSD-95 enrichment is not required prior to the destabilization of spines.
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Spine loss represents a common hallmark of neurodegenerative diseases. However, little is known about the underlying mechanisms, especially the relationship between spine elimination and neuritic destruction. We imaged cortical dendrites throughout a neurodegenerative disease using scrapie in mice as a model. Two-photon in vivo imaging over 2 months revealed a linear decrease of spine density. Interestingly, only persistent spines (lifetime ≥8 d) disappeared, whereas the density of transient spines (lifetime ≤4 d) was unaffected. Before spine loss, dendritic varicosities emerged preferentially at sites where spines protrude from the dendrite. These results implicate that the location where the spine protrudes from the dendrite may be particularly vulnerable and that dendritic varicosities may actually cause spine loss.
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Abstract Cognitive functions decline during aging. This decline could be caused by changes in dendritic spine stability and altered spine dynamics. Previously, we have shown that a low dose chronic THC treatment improves learning abilities in old whereas impairs learning abilities in young mice. The mechanism underlying this age-dependent effect is not known. Dendritic spine stability is a key for memory formation, therefore we hypothesized that THC affects spine dynamics in an age-dependent manner. We applied longitudinal 2-photon in vivo imaging to 3- and 18-month-old mice treated with 3 mg/kg/day of THC for 28 days via an osmotic pump. We imaged the same dendritic segments before, during and after the treatment and assessed changes in spine density and stability. We now show that in old mice THC improved spine stability resulting in a long-lasting increase in spine density. In contrast, in young mice THC transiently increased spine turnover and destabilized the spines.
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