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Sunghoe Chang - One of the best experts on this subject based on the ideXlab platform.
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adp ribosylation factor 6 arf6 bidirectionally regulates Dendritic Spine formation depending on neuronal maturation and activity
Journal of Biological Chemistry, 2015Co-Authors: Yoonju Kim, Sang Eun Lee, Joo Hyun Park, Minhyung Kim, Boyoon Lee, Daehee Hwang, Sunghoe ChangAbstract:Abstract Recent studies reported conflicting results regarding the role of ARF6 in Dendritic Spine development but no clear answer for the controversy has been suggested. We found that ARF6 either positively or negatively regulates Dendritic Spine formation depending on neuronal maturation and activity. ARF6 activation increases the Spine formation in developing neurons while it decreasing Spine density in mature neurons. Genome-wide microarray analysis revealed that ARF6 activation in each stage leads to opposite expression patterns of a subset of genes that are involved in neuronal morphology. ARF6-mediated Rac1 activation via phospholipase D pathway is the coincident factor in both stages but antagonistic RhoA pathway becomes involved in the mature stage. Furthermore, blocking neuronal activity in developing neurons using TTX or enhancing the activity in mature neurons using PTX or chemical-LTP reverses the effect of ARF6 on each stage. Thus, activity-dependent dynamic changes in ARF6-mediated Spine structures may play a role in structural plasticity of mature neurons.
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adp ribosylation factor 6 arf6 bidirectionally regulates Dendritic Spine formation depending on neuronal maturation and activity
Journal of Biological Chemistry, 2015Co-Authors: Yoonju Kim, Sang Eun Lee, Joo Hyun Park, Minhyung Kim, Boyoon Lee, Daehee Hwang, Sunghoe ChangAbstract:Recent studies have reported conflicting results regarding the role of ARF6 in Dendritic Spine development, but no clear answer for the controversy has been suggested. We found that ADP-ribosylation factor 6 (ARF6) either positively or negatively regulates Dendritic Spine formation depending on neuronal maturation and activity. ARF6 activation increased the Spine formation in developing neurons, whereas it decreased Spine density in mature neurons. Genome-wide microarray analysis revealed that ARF6 activation in each stage leads to opposite patterns of expression of a subset of genes that are involved in neuronal morphology. ARF6-mediated Rac1 activation via the phospholipase D pathway is the coincident factor in both stages, but the antagonistic RhoA pathway becomes involved in the mature stage. Furthermore, blocking neuronal activity in developing neurons using tetrodotoxin or enhancing the activity in mature neurons using picrotoxin or chemical long term potentiation reversed the effect of ARF6 on each stage. Thus, activity-dependent dynamic changes in ARF6-mediated Spine structures may play a role in structural plasticity of mature neurons.
Daehee Hwang - One of the best experts on this subject based on the ideXlab platform.
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adp ribosylation factor 6 arf6 bidirectionally regulates Dendritic Spine formation depending on neuronal maturation and activity
Journal of Biological Chemistry, 2015Co-Authors: Yoonju Kim, Sang Eun Lee, Joo Hyun Park, Minhyung Kim, Boyoon Lee, Daehee Hwang, Sunghoe ChangAbstract:Abstract Recent studies reported conflicting results regarding the role of ARF6 in Dendritic Spine development but no clear answer for the controversy has been suggested. We found that ARF6 either positively or negatively regulates Dendritic Spine formation depending on neuronal maturation and activity. ARF6 activation increases the Spine formation in developing neurons while it decreasing Spine density in mature neurons. Genome-wide microarray analysis revealed that ARF6 activation in each stage leads to opposite expression patterns of a subset of genes that are involved in neuronal morphology. ARF6-mediated Rac1 activation via phospholipase D pathway is the coincident factor in both stages but antagonistic RhoA pathway becomes involved in the mature stage. Furthermore, blocking neuronal activity in developing neurons using TTX or enhancing the activity in mature neurons using PTX or chemical-LTP reverses the effect of ARF6 on each stage. Thus, activity-dependent dynamic changes in ARF6-mediated Spine structures may play a role in structural plasticity of mature neurons.
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adp ribosylation factor 6 arf6 bidirectionally regulates Dendritic Spine formation depending on neuronal maturation and activity
Journal of Biological Chemistry, 2015Co-Authors: Yoonju Kim, Sang Eun Lee, Joo Hyun Park, Minhyung Kim, Boyoon Lee, Daehee Hwang, Sunghoe ChangAbstract:Recent studies have reported conflicting results regarding the role of ARF6 in Dendritic Spine development, but no clear answer for the controversy has been suggested. We found that ADP-ribosylation factor 6 (ARF6) either positively or negatively regulates Dendritic Spine formation depending on neuronal maturation and activity. ARF6 activation increased the Spine formation in developing neurons, whereas it decreased Spine density in mature neurons. Genome-wide microarray analysis revealed that ARF6 activation in each stage leads to opposite patterns of expression of a subset of genes that are involved in neuronal morphology. ARF6-mediated Rac1 activation via the phospholipase D pathway is the coincident factor in both stages, but the antagonistic RhoA pathway becomes involved in the mature stage. Furthermore, blocking neuronal activity in developing neurons using tetrodotoxin or enhancing the activity in mature neurons using picrotoxin or chemical long term potentiation reversed the effect of ARF6 on each stage. Thus, activity-dependent dynamic changes in ARF6-mediated Spine structures may play a role in structural plasticity of mature neurons.
Peter Penzes - One of the best experts on this subject based on the ideXlab platform.
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Kalirin-7 prevents Dendritic Spine dysgenesis induced by amyloid beta-derived oligomers.
The European journal of neuroscience, 2019Co-Authors: Zhong Xie, Michael E Cahill, Lauren P. Shapiro, Theron A. Russell, Pascale N. Lacor, William L. Klein, Peter PenzesAbstract:Synapse degeneration and Dendritic Spine dysgenesis are believed to be crucial early steps in Alzheimer's disease (AD), and correlate with cognitive deficits in AD patients. Soluble amyloid beta (Aβ)-derived oligomers, also termed Aβ-derived diffusible ligands (ADDLs), accumulate in the brain of AD patients and play a crucial role in AD pathogenesis. ADDLs bind to mature hippocampal neurons, induce structural changes in Dendritic Spines and contribute to neuronal death. However, mechanisms underlying structural and toxic effects are not fully understood. Here, we report that ADDLs bind to cultured mature cortical pyramidal neurons and induce Spine dysgenesis. ADDL treatment induced the rapid depletion of kalirin-7, a brain-specific guanine-nucleotide exchange factor for the small GTPase Rac1, from Spines. Kalirin-7 is a key regulator of Dendritic Spine morphogenesis and maintenance in forebrain pyramidal neurons and here we show that overexpression of kalirin-7 prevents ADDL-induced Spine degeneration. Taken together, our results suggest that kalirin-7 may play a role in the early events leading to synapse degeneration, and its pharmacological activation may prevent or delay synapse pathology in AD.
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Loss of Microtubule-Associated Protein 2 Immunoreactivity Linked to Dendritic Spine Loss in Schizophrenia
Biological psychiatry, 2015Co-Authors: Micah A. Shelton, Jason T. Newman, Allan R. Sampson, Kenneth N. Fish, Matthew L. Macdonald, Caitlin E. Moyer, James V. Dibitetto, Karl Anton Dorph-petersen, Peter PenzesAbstract:Abstract Background Microtubule-associated protein 2 (MAP2) is a neuronal protein that plays a role in maintaining Dendritic structure through its interaction with microtubules. In schizophrenia (Sz), numerous studies have revealed that the typically robust immunoreactivity (IR) of MAP2 is significantly reduced across several cortical regions. The relationship between MAP2-IR reduction and lower Dendritic Spine density, which is frequently reported in Sz, has not been explored in previous studies, and MAP2-IR loss has not been investigated in the primary auditory cortex (Brodmann area 41), a site of conserved pathology in Sz. Methods Using quantitative spinning disk confocal microscopy in two cohorts of subjects with Sz and matched control subjects (Sz subjects, n = 20; control subjects, n = 20), we measured MAP2-IR and Dendritic Spine density and Spine number in deep layer 3 of BA41. Results Subjects with Sz exhibited a significant reduction in MAP2-IR. The reductions in MAP2-IR were not associated with neuron loss, loss of MAP2 protein, clinical confounders, or technical factors. Dendritic Spine density and number also were reduced in Sz and correlated with MAP2-IR. In 12 (60%) subjects with Sz, MAP2-IR values were lower than the lowest values in control subjects; only in this group were Spine density and number significantly reduced. Conclusions These findings demonstrate that MAP2-IR loss is closely linked to Dendritic Spine pathology in Sz. Because MAP2 shares substantial sequence, regulatory, and functional homology with MAP tau, the wealth of knowledge regarding tau biology and the rapidly expanding field of tau therapeutics provide resources for identifying how MAP2 is altered in Sz and possible leads to novel therapeutics.
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Neuregulin1 signaling promotes Dendritic Spine growth through kalirin.
Journal of neurochemistry, 2013Co-Authors: Michael E Cahill, Zhong Xie, Robert A. Sweet, Kelly A. Jones, Christine L. Remmers, Peter PenzesAbstract:The biological functions of the NRG1 (Neuregulin-1) and ERBB4 genes have received much recent attention due to several studies showing associations between these genes and schizophrenia. Moreover, reduced forebrain Dendritic Spine density is a consistent feature of schizophrenia. It is thus important to understand the mechanisms whereby NRG1 and erbB4 modulate Spine morphogenesis. Here we show that long-term incubation with NRG1 increases both Spine size and density in cortical pyramidal neurons. NRG1 also enhances the content of AMPA receptors in Spines. Knockdown of ERBB4 expression prevented the effects of NRG1 on Spine size, but not on Spine density. The effects of NRG1 and erbB4 on Spines were mediated by the RacGEF kalirin, a well-characterized regulator of Dendritic Spines. Finally, we show that environmental enrichment, known to promote Spine growth, robustly enhances the levels of erbB4 protein in the forebrain. These findings provide a mechanistic link between NRG1 signaling and Spine morphogenesis.
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Analysis of Dendritic Spine morphology in cultured CNS neurons.
Journal of visualized experiments : JoVE, 2011Co-Authors: Deepak Srivastava, Kevin M. Woolfrey, Peter PenzesAbstract:Dendritic Spines are the sites of the majority of excitatory connections within the brain, and form the post-synaptic compartment of synapses. These structures are rich in actin and have been shown to be highly dynamic. In response to classical Hebbian plasticity as well as neuromodulatory signals, Dendritic Spines can change shape and number, which is thought to be critical for the refinement of neural circuits and the processing and storage of information within the brain. Within Dendritic Spines, a complex network of proteins link extracellular signals with the actin cyctoskeleton allowing for control of Dendritic Spine morphology and number. Neuropathological studies have demonstrated that a number of disease states, ranging from schizophrenia to autism spectrum disorders, display abnormal Dendritic Spine morphology or numbers. Moreover, recent genetic studies have identified mutations in numerous genes that encode synaptic proteins, leading to suggestions that these proteins may contribute to aberrant Spine plasticity that, in part, underlie the pathophysiology of these disorders. In order to study the potential role of these proteins in controlling Dendritic Spine morphologies/number, the use of cultured cortical neurons offers several advantages. Firstly, this system allows for high-resolution imaging of Dendritic Spines in fixed cells as well as time-lapse imaging of live cells. Secondly, this in vitro system allows for easy manipulation of protein function by expression of mutant proteins, knockdown by shRNA constructs, or pharmacological treatments. These techniques allow researchers to begin to dissect the role of disease-associated proteins and to predict how mutations of these proteins may function in vivo.
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Epac2-mediated Dendritic Spine remodeling: Implications for disease
Molecular and cellular neurosciences, 2010Co-Authors: Peter Penzes, Kevin M. Woolfrey, Deepak SrivastavaAbstract:In the mammalian forebrain, most glutamatergic excitatory synapses occur on small Dendritic protrusions called Dendritic Spines. Dendritic Spines are highly plastic and can rapidly change morphology in response to numerous stimuli. This dynamic remodeling of Dendritic Spines is thought to be critical for information processing, memory and cognition. Conversely, multiple studies have revealed that neuropathologies such as autism spectrum disorders (ASDs) are linked with alterations in Dendritic Spine morphologies and miswiring of neural circuitry. One compelling hypothesis is that abnormal Dendritic Spine remodeling is a key contributing factor for this miswiring. Ongoing research has identified a number of mechanisms that are critical for the control of Dendritic Spine remodeling. Among these mechanisms, regulation of small GTPase signaling by guanine-nucleotide exchange factors (GEFs) is emerging as a critical mechanism for integrating physiological signals in the control of Dendritic Spine remodeling. Furthermore, multiple proteins associated with regulation of Dendritic Spine remodeling have also been implicated with multiple neuropathologies, including ASDs. Epac2, a GEF for the small GTPase Rap, has recently been described as a novel cAMP (yet PKA-independent) target localized to Dendritic Spines. Signaling via this protein in response to pharmacological stimulation or cAMP accumulation, via the dopamine D1/5 receptor, results in Rap activation, promotes structural destabilization, in the form of Dendritic Spine shrinkage, and functional depression due to removal of GluR2/3-containing AMPA receptors. In addition, Epac2 forms macromolecular complexes with ASD-associated proteins, which are sufficient to regulate Epac2 localization and function. Furthermore, rare non-synonymous variants of the EPAC2 gene associated with the ASD phenotype alter protein function, synaptic protein distribution, and Spine morphology. We review here the role of Epac2 in the remodeling of Dendritic Spines under normal conditions, the mechanisms that underlie these effects, and the implications these disease-associated variants have on our understanding of the pathophysiology of ASD.
Ye Xiong - One of the best experts on this subject based on the ideXlab platform.
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A Small Molecule Spinogenic Compound Enhances Functional Outcome and Dendritic Spine Plasticity in a Rat Model of Traumatic Brain Injury.
Henry Ford Health System Scholarly Commons, 2019Co-Authors: Zhang Yanlu, Simmon Vincent F, Chopp Michael, Rex, Christopher S, Sarraf, Stella T, Zhang Zhenggang, Mahmood Asim, Ye XiongAbstract:The tetra (ethylene glycol) derivative of benzothiazole aniline (SPG101) has been shown to improve Dendritic Spine density and cognitive memory in the triple transgenic mouse model of Alzheimer disease (AD) when administered intraperitoneally. The present study was designed to investigate the therapeutic effects of SPG101 on Dendritic Spine density and morphology and sensorimotor and cognitive functional recovery in a rat model of traumatic brain injury (TBI) induced by controlled cortical impact (CCI). Young adult male Wistar rats with CCI were randomly divided into the following two groups (n = 7/group): (1) Vehicle, and (2) SPG101. SPG101 (30 mg/kg) dissolved in vehicle (1% dimethyl sulfoxide in phosphate buffered saline) or Vehicle were intraperitoneally administered starting at 1 h post-injury and once daily for the next 34 days. Sensorimotor deficits were assessed using a modified neurological severity score and adhesive removal and foot fault tests. Cognitive function was measured by Morris water maze, novel object recognition (NOR), and three-chamber social recognition tests. The animals were sacrificed 35 days after injury, and their brains were processed for measurement of Dendritic Spine density and morphology using ballistic dye labeling. Compared with the vehicle treatment, SPG101 treatment initiated 1 h post-injury significantly improved sensorimotor functional recovery (days 7-35, p \u3c 0.0001), spatial learning (days 32-35, p \u3c 0.0001), NOR (days 14 and 35, p \u3c 0.0001), social recognition (days 14 and 35, p \u3c 0.0001). Further, treatment significantly increased Dendritic Spine density in the injured cortex (p \u3c 0.05), decreased heterogeneous distribution of Spine lengths in the injured cortex and hippocampus (p \u3c 0.0001), modifications that are associated with the promotion of Spine maturation in these brain regions. In summary, treatment with SPG101 initiated 1 h post-injury and continued for an additional 34 days improves both sensorimotor and cognitive functional recovery, indicating that SPG101 acts as a spinogenic agent and may have potential as a novel treatment of TBI
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A Small Molecule Spinogenic Compound Enhances Functional Outcome and Dendritic Spine Plasticity in a Rat Model of Traumatic Brain Injury
Journal of neurotrauma, 2018Co-Authors: Yanlu Zhang, Michael Chopp, Christopher S. Rex, Simmon Vincent F, Stella T. Sarraf, Zheng Gang Zhang, Asim Mahmood, Ye XiongAbstract:Abstract The tetra (ethylene glycol) derivative of benzothiazole aniline (SPG101) has been shown to improve Dendritic Spine density and cognitive memory in the triple transgenic mouse model of Alzh...
Yoonju Kim - One of the best experts on this subject based on the ideXlab platform.
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adp ribosylation factor 6 arf6 bidirectionally regulates Dendritic Spine formation depending on neuronal maturation and activity
Journal of Biological Chemistry, 2015Co-Authors: Yoonju Kim, Sang Eun Lee, Joo Hyun Park, Minhyung Kim, Boyoon Lee, Daehee Hwang, Sunghoe ChangAbstract:Abstract Recent studies reported conflicting results regarding the role of ARF6 in Dendritic Spine development but no clear answer for the controversy has been suggested. We found that ARF6 either positively or negatively regulates Dendritic Spine formation depending on neuronal maturation and activity. ARF6 activation increases the Spine formation in developing neurons while it decreasing Spine density in mature neurons. Genome-wide microarray analysis revealed that ARF6 activation in each stage leads to opposite expression patterns of a subset of genes that are involved in neuronal morphology. ARF6-mediated Rac1 activation via phospholipase D pathway is the coincident factor in both stages but antagonistic RhoA pathway becomes involved in the mature stage. Furthermore, blocking neuronal activity in developing neurons using TTX or enhancing the activity in mature neurons using PTX or chemical-LTP reverses the effect of ARF6 on each stage. Thus, activity-dependent dynamic changes in ARF6-mediated Spine structures may play a role in structural plasticity of mature neurons.
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adp ribosylation factor 6 arf6 bidirectionally regulates Dendritic Spine formation depending on neuronal maturation and activity
Journal of Biological Chemistry, 2015Co-Authors: Yoonju Kim, Sang Eun Lee, Joo Hyun Park, Minhyung Kim, Boyoon Lee, Daehee Hwang, Sunghoe ChangAbstract:Recent studies have reported conflicting results regarding the role of ARF6 in Dendritic Spine development, but no clear answer for the controversy has been suggested. We found that ADP-ribosylation factor 6 (ARF6) either positively or negatively regulates Dendritic Spine formation depending on neuronal maturation and activity. ARF6 activation increased the Spine formation in developing neurons, whereas it decreased Spine density in mature neurons. Genome-wide microarray analysis revealed that ARF6 activation in each stage leads to opposite patterns of expression of a subset of genes that are involved in neuronal morphology. ARF6-mediated Rac1 activation via the phospholipase D pathway is the coincident factor in both stages, but the antagonistic RhoA pathway becomes involved in the mature stage. Furthermore, blocking neuronal activity in developing neurons using tetrodotoxin or enhancing the activity in mature neurons using picrotoxin or chemical long term potentiation reversed the effect of ARF6 on each stage. Thus, activity-dependent dynamic changes in ARF6-mediated Spine structures may play a role in structural plasticity of mature neurons.