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Science Signaling Mar 2018Early-stage Alzheimer's disease is characterized by the loss of dendritic spines in the neocortex of the brain. This phenomenon precedes tau pathology, plaque formation,...
Early-stage Alzheimer's disease is characterized by the loss of dendritic spines in the neocortex of the brain. This phenomenon precedes tau pathology, plaque formation, and neurodegeneration and likely contributes to synaptic loss, memory impairment, and behavioral changes in patients. Studies suggest that dendritic spine loss is induced by soluble, multimeric amyloid-β (Aβ), which, through postsynaptic signaling, activates the protein phosphatase calcineurin. We investigated how calcineurin caused spine pathology and found that the cis-trans prolyl isomerase Pin1 was a critical downstream target of Aβ-calcineurin signaling. In dendritic spines, Pin1 interacted with and was dephosphorylated by calcineurin, which rapidly suppressed its isomerase activity. Knockout of Pin1 or exposure to Aβ induced the loss of mature dendritic spines, which was prevented by exogenous Pin1. The calcineurin inhibitor FK506 blocked dendritic spine loss in Aβ-treated wild-type cells but had no effect on -null neurons. These data implicate Pin1 in dendritic spine maintenance and synaptic loss in early Alzheimer's disease.
Topics: Amyloid beta-Peptides; Animals; Calcineurin; Calcineurin Inhibitors; Cells, Cultured; Dendritic Spines; Mice, Inbred C57BL; Mice, Knockout; NIMA-Interacting Peptidylprolyl Isomerase; Phosphorylation; Signal Transduction; Tacrolimus
PubMed: 29559586
DOI: 10.1126/scisignal.aap8734 -
Growth Hormone & IGF Research :... Feb 2020Growth hormone (GH) is widely known for its peripheral effects during growth and development. However, numerous reports also suggest that GH exert pro-cognitive,...
OBJECTIVE
Growth hormone (GH) is widely known for its peripheral effects during growth and development. However, numerous reports also suggest that GH exert pro-cognitive, restorative, and protective properties in the brain. In in vitro studies, the detection of dendritic spines, small protrusions extending from axons, can act as a marker for cognition-related function as spine formation is considered to be associated with learning and memory. Here we show that an acute 24-hour treatment of GH can increase dendritic spine density in primary hippocampal cell cultures.
DESIGN
Primary hippocampal cells were harvested from embryonic Wistar rats and cultured for 14 days. Cells were treated with supra-physiological doses of GH (10-1000 nM) and subjected to a high-throughput screening protocol. Images were acquired and analyzed using automated image analysis and the number of spines, spines per neurite length, neurite length, and mean area of spines, was reported.
RESULTS
GH treatment (1000 nM) increased the number of dendritic spines by 83% and spines per neurite length by 82% when compared to control. For comparison BDNF, a known inducer of spine densities, produced statistically non-significant increase in this setting.
CONCLUSION
The results was found significant using the highest supra-physiological dose of GH, and the present study further confirms a potential role of the hormone in the treatment of cognitive dysfunction.
Topics: Animals; Brain-Derived Neurotrophic Factor; Dendritic Spines; Growth Hormone; High-Throughput Screening Assays; Hippocampus; In Vitro Techniques; Neurites; Primary Cell Culture; Rats
PubMed: 31862540
DOI: 10.1016/j.ghir.2019.12.003 -
Molecular and Cellular Neurosciences Oct 2017Dendritic spines form typical excitatory synapses in the brain and their shapes vary depending on synaptic inputs. It has been suggested that the morphological changes... (Review)
Review
Dendritic spines form typical excitatory synapses in the brain and their shapes vary depending on synaptic inputs. It has been suggested that the morphological changes of dendritic spines play an important role in synaptic plasticity. Dendritic spines contain a high concentration of actin, which has a central role in supporting cell motility, and polymerization of actin filaments (F-actin) is most likely involved in spine shape changes. Drebrin is an actin-binding protein that forms stable F-actin and is highly accumulated within dendritic spines. Drebrin has two isoforms, embryonic-type drebrin E and adult-type drebrin A, that change during development from E to A. Inhibition of drebrin A expression results in a delay of synapse formation and inhibition of postsynaptic protein accumulation, suggesting that drebrin A has an important role in spine maturation. In mature synapses, glutamate stimulation induces rapid spine-head enlargement during long-term potentiation (LTP) formation. LTP stimulation induces Ca entry through N-methyl-d-aspartate (NMDA) receptors, which causes drebrin exodus from dendritic spines. Once drebrin exits from dendritic spine heads, the dynamic actin pool increases in spine heads to facilitate F-actin polymerization. To maintain enlarged spine heads, drebrin-decorated F-actin is thought to reform within the spine heads. Thus, drebrin plays a pivotal role in spine plasticity through regulation of F-actin.
Topics: Animals; Dendrites; Dendritic Spines; Humans; Neuronal Plasticity; Neurons; Neuropeptides; Synapses
PubMed: 28161364
DOI: 10.1016/j.mcn.2017.01.004 -
Current Protocols in Neuroscience Oct 2016Determining the density and morphology of dendritic spines is of high biological significance given the role of spines in synaptic plasticity and in neurodegenerative...
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.
Topics: Animals; Dendritic Spines; Imaging, Three-Dimensional; Microscopy, Confocal; Microscopy, Electron; Neuronal Plasticity; Neurons
PubMed: 27696360
DOI: 10.1002/cpns.16 -
Molecular and Cellular Neurosciences Jul 2022Dendritic spines are small, ratchet-like protrusions on neuronal dendrites that form synapses for receiving neuronal messages. Dendritic spine morphology is associated...
Dendritic spines are small, ratchet-like protrusions on neuronal dendrites that form synapses for receiving neuronal messages. Dendritic spine morphology is associated with synapse function. If neurons degrade or are damaged, the spine morphology of neurons changes. Given that most commercially available spine analysis software is expensive and complex, this study investigated a semi-automated spine analysis software, CTSpine, and used previously published data to verify the accuracy of the analysis results of this software. We also applied CTSpine to understand whether aging causes alterations in the hippocampal spine morphology and whether physical exercise can impede dendritic spine changes in 20 male Sprague Dawley rats. The spines of pyramidal cells in the hippocampal Cornu Ammonis 1 (CA1) region in the aging group were more enriched in filopodium type pattern than those in the control group, whereas the spines of the exercised aging group showed a similar pattern to that of the control. No significant changes were observed in neuronal dendritic spines in other hippocampal regions. However, long-term hippocampal memory was considerably decreased in the aging group, which was reversed to some extent in the exercised aging group. CTSpine, a self-developed semi-automatic spine analysis software, showed results similar to those noted in published data and can be effectively applied to the study of dendritic patterns, including neurodevelopment and disease.
Topics: Aging; Animals; Dendritic Spines; Hippocampus; Male; Memory Disorders; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Software; Swimming
PubMed: 35850447
DOI: 10.1016/j.mcn.2022.103755 -
The Journal of Neuroscience : the... May 2012Diabetic neuropathic pain imposes a huge burden on individuals and society, and represents a major public health problem. Despite aggressive efforts, diabetic...
Diabetic neuropathic pain imposes a huge burden on individuals and society, and represents a major public health problem. Despite aggressive efforts, diabetic neuropathic pain is generally refractory to available clinical treatments. A structure-function link between maladaptive dendritic spine plasticity and pain has been demonstrated previously in CNS and PNS injury models of neuropathic pain. Here, we reasoned that if dendritic spine remodeling contributes to diabetic neuropathic pain, then (1) the presence of malformed spines should coincide with the development of pain, and (2) disrupting maladaptive spine structure should reduce chronic pain. To determine whether dendritic spine remodeling contributes to neuropathic pain in streptozotocin (STZ)-induced diabetic rats, we analyzed dendritic spine morphology and electrophysiological and behavioral signs of neuropathic pain. Our results show changes in dendritic spine shape, distribution, and shape on wide-dynamic-range (WDR) neurons within lamina IV-V of the dorsal horn in diabetes. These diabetes-induced changes were accompanied by WDR neuron hyperexcitability and decreased pain thresholds at 4 weeks. Treatment with NSC23766 (N(6)-[2-[[4-(diethylamino)-1-methylbutyl]amino]-6-methyl-4-pyrimidinyl]-2-methyl-4,6-quinolinediamine trihydrochloride), a Rac1-specific inhibitor known to interfere with spine plasticity, decreased the presence of malformed spines in diabetes, attenuated neuronal hyperresponsiveness to peripheral stimuli, reduced spontaneous firing activity from WDR neurons, and improved nociceptive mechanical pain thresholds. At 1 week after STZ injection, animals with hyperglycemia with no evidence of pain had few or no changes in spine morphology. These results demonstrate that diabetes-induced maladaptive dendritic spine remodeling has a mechanistic role in neuropathic pain. Molecular pathways that control spine morphogenesis and plasticity may be promising future targets for treatment.
Topics: Action Potentials; Aminoquinolines; Animals; Dendritic Spines; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Injections, Spinal; Male; Neuronal Plasticity; Pain Threshold; Posterior Horn Cells; Pyrimidines; Rats; Rats, Sprague-Dawley; rac1 GTP-Binding Protein
PubMed: 22593049
DOI: 10.1523/JNEUROSCI.1017-12.2012 -
Current Alzheimer Research 2020Studies have suggested that cognitive impairment in Alzheimer's disease (AD) is associated with dendritic spine loss, especially in the hippocampus. Fluoxetine (FLX) has...
BACKGROUND
Studies have suggested that cognitive impairment in Alzheimer's disease (AD) is associated with dendritic spine loss, especially in the hippocampus. Fluoxetine (FLX) has been shown to improve cognition in the early stage of AD and to be associated with diminishing synapse degeneration in the hippocampus. However, little is known about whether FLX affects the pathogenesis of AD in the middle-tolate stage and whether its effects are correlated with the amelioration of hippocampal dendritic dysfunction. Previously, it has been observed that FLX improves the spatial learning ability of middleaged APP/PS1 mice.
OBJECTIVE
In the present study, we further characterized the impact of FLX on dendritic spines in the hippocampus of middle-aged APP/PS1 mice.
RESULTS
It has been found that the numbers of dendritic spines in dentate gyrus (DG), CA1 and CA2/3 of hippocampus were significantly increased by FLX. Meanwhile, FLX effectively attenuated hyperphosphorylation of tau at Ser396 and elevated protein levels of postsynaptic density 95 (PSD-95) and synapsin-1 (SYN-1) in the hippocampus.
CONCLUSION
These results indicated that the enhanced learning ability observed in FLX-treated middle-aged APP/PS1 mice might be associated with remarkable mitigation of hippocampal dendritic spine pathology by FLX and suggested that FLX might be explored as a new strategy for therapy of AD in the middle-to-late stage.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Dendritic Spines; Disease Models, Animal; Fluoxetine; Hippocampus; Maze Learning; Mice; Mice, Transgenic; Neurons; Phosphorylation; Presenilin-1; Selective Serotonin Reuptake Inhibitors; Spatial Learning; tau Proteins
PubMed: 32053075
DOI: 10.2174/1567205017666200213095419 -
The Neuroscientist : a Review Journal... Oct 2021Cognitive resilience is often defined as the ability to remain cognitively normal in the face of insults to the brain. These insults can include disease pathology, such... (Review)
Review
Cognitive resilience is often defined as the ability to remain cognitively normal in the face of insults to the brain. These insults can include disease pathology, such as plaques and tangles associated with Alzheimer's disease, stroke, traumatic brain injury, or other lesions. Factors such as physical or mental activity and genetics may contribute to cognitive resilience, but the neurobiological underpinnings remain ill-defined. Emerging evidence suggests that dendritic spine structural plasticity is one plausible mechanism. In this review, we highlight the basic structure and function of dendritic spines and discuss how spine density and morphology change in aging and Alzheimer's disease. We note evidence that spine plasticity mediates resilience to stress, and we tackle dendritic spines in the context of cognitive resilience to Alzheimer's disease. Finally, we examine how lifestyle and genetic factors may influence dendritic spine plasticity to promote cognitive resilience before discussing evidence for actin regulatory kinases as therapeutic targets for Alzheimer's disease.
Topics: Aging; Alzheimer Disease; Brain; Cognition; Dendritic Spines; Humans
PubMed: 32812494
DOI: 10.1177/1073858420945964 -
Brain Research Sep 2011Fyn is a Src-family tyrosine kinase that affects long term potentiation (LTP), synapse formation, and learning and memory. Fyn is also implicated in dendritic spine...
Fyn is a Src-family tyrosine kinase that affects long term potentiation (LTP), synapse formation, and learning and memory. Fyn is also implicated in dendritic spine formation both in vitro and in vivo. However, whether Fyn's regulation of dendritic spine formation is brain-region specific and age-dependent is unknown. In the present study, we systematically examined whether Fyn altered dendritic spine density and morphology in the cortex and hippocampus and if these effects were age-dependent. We found that Fyn knockout mice trended toward a decrease in dendritic spine density in cortical layers II/III, but not in the hippocampus, at 1 month of age. Additionally, Fyn knockout mice had significantly decreased dendritic spine density in both the cortex and hippocampus at 3 months and 1 year, and Fyn's effect on dendritic spine density was age-dependent in the hippocampus. Moreover, Fyn knockout mice had wider spines at the three time points (1 month, 3 months, 1 year) in the cortex. These findings suggest that Fyn regulates dendritic spine number and morphology over time and provide further support for Fyn's role in maintaining proper synaptic function in vivo.
Topics: Age Factors; Animals; Cerebral Cortex; Dendrites; Dendritic Spines; Hippocampus; Mice; Mice, Knockout; Neurons; Proto-Oncogene Proteins c-fyn
PubMed: 21872217
DOI: 10.1016/j.brainres.2011.07.059 -
Journal of Neurophysiology Jun 2016Neuropathic pain is a significant complication following spinal cord injury (SCI) with few effective treatments. Drug development for neuropathic pain often fails...
Neuropathic pain is a significant complication following spinal cord injury (SCI) with few effective treatments. Drug development for neuropathic pain often fails because preclinical studies do not always translate well to clinical conditions. Identification of biological characteristics predictive of disease state or drug responsiveness could facilitate more effective clinical translation. Emerging evidence indicates a strong correlation between dendritic spine dysgenesis and neuropathic pain. Because dendritic spines are located on dorsal horn neurons within the spinal cord nociceptive system, dendritic spine remodeling provides a unique opportunity to understand sensory dysfunction after SCI. In this study, we provide support for the postulate that dendritic spine profiles can serve as biomarkers for neuropathic pain. We show that dendritic spine profiles after SCI change to a dysgenic state that is characteristic of neuropathic pain in a Rac1-dependent manner. Suppression of the dysgenic state through inhibition of Rac1 activity is accompanied by attenuation of neuropathic pain. Both dendritic spine dysgenesis and neuropathic pain return when inhibition of Rac1 activity is lifted. These findings suggest the utility of dendritic spines as structural biomarkers for neuropathic pain.
Topics: Animals; Catheters, Indwelling; Dendritic Spines; Male; Microelectrodes; Neuralgia; Neuronal Plasticity; Posterior Horn Cells; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries; Time Factors; Touch; rac1 GTP-Binding Protein
PubMed: 26936986
DOI: 10.1152/jn.01057.2015