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The Journal of Neuroscience : the... Nov 2016Actin polymerization governs activity-dependent modulation of excitatory synapses, including their morphology and functionality. It is clear from human genetics that... (Review)
Review
Actin polymerization governs activity-dependent modulation of excitatory synapses, including their morphology and functionality. It is clear from human genetics that neuropsychiatric and neurodevelopmental disturbances are multigenetic in nature, highlighting the need to better understand the critical neural pathways associated with these disorders and how they are altered by genetic risk alleles. One such signaling pathway that is heavily implicated by candidate genes for psychiatric and neurodevelopmental disorders are regulators of signaling to the actin cytoskeleton, suggesting that its disruption and the ensuring abnormalities of spine structures and postsynaptic complexes is a commonly affected pathway in brain disorders. This review will discuss recent experimental findings that strongly support genetic evidence linking the synaptic cytoskeleton to mental disorders, such as schizophrenia and autism spectrum disorders.
Topics: Actin Cytoskeleton; Actins; Animals; Brain; Dendritic Spines; Humans; Mental Disorders; Synapses; Synaptic Transmission
PubMed: 27911743
DOI: 10.1523/JNEUROSCI.2360-16.2016 -
ENeuro 2019Dendritic spines are the postsynaptic targets of excitatory synaptic inputs that undergo extensive proliferation and maturation during the first postnatal month in mice....
Dendritic spines are the postsynaptic targets of excitatory synaptic inputs that undergo extensive proliferation and maturation during the first postnatal month in mice. However, our understanding of the molecular mechanisms that regulate spines during this critical period is limited. Previous work has shown that pannexin 1 (Panx1) regulates neurite growth and synaptic plasticity. We therefore investigated the impact of global Panx1 KO on spontaneous cortical neuron activity using Ca imaging and network analysis. Panx1 KO increased both the number and size of spontaneous co-active cortical neuron network ensembles. To understand the basis for these findings, we investigated Panx1 expression in postnatal synaptosome preparations from early postnatal mouse cortex. Between 2 and 4 postnatal weeks, we observed a precipitous drop in cortical synaptosome protein levels of Panx1, suggesting it regulates synapse proliferation and/or maturation. At the same time points, we observed significant enrichment of the excitatory postsynaptic density proteins PSD-95, GluA1, and GluN2a in cortical synaptosomes from global Panx1 knock-out mice. analysis of pyramidal neuron structure in somatosensory cortex revealed a consistent increase in dendritic spine densities in both male and female Panx1 KO mice. Similar findings were observed in an excitatory neuron-specific Panx1 KO line (Emx1-Cre driven; Panx1 cKO) and in primary Panx1 KO cortical neurons cultured Altogether, our study suggests that Panx1 negatively regulates cortical dendritic spine development.
Topics: Animals; Calcium Signaling; Cerebral Cortex; Connexins; Dendritic Spines; Disks Large Homolog 4 Protein; Female; Male; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Neural Pathways; Optical Imaging; Synaptosomes
PubMed: 31118206
DOI: 10.1523/ENEURO.0503-18.2019 -
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 -
The Journal of Neuroscience : the... Sep 2020Accumulating evidence has established a firm role for synaptic plasticity in the pathogenesis of neuropathic pain. Recent advances have highlighted the importance of... (Review)
Review
Accumulating evidence has established a firm role for synaptic plasticity in the pathogenesis of neuropathic pain. Recent advances have highlighted the importance of dendritic spine remodeling in driving synaptic plasticity within the CNS. Identifying the molecular players underlying neuropathic pain induced structural and functional maladaptation is therefore critical to understanding its pathophysiology. This process of dynamic reorganization happens in unique phases that have diverse pathologic underpinnings in the initiation and maintenance of neuropathic pain. Recent evidence suggests that pharmacological targeting of specific proteins during distinct phases of neuropathic pain development produces enhanced antinociception. These findings outline a potential new paradigm for targeted treatment and the development of novel therapies for neuropathic pain. We present a concise review of the role of dendritic spines in neuropathic pain and outline the potential for modulation of spine dynamics by targeting two proteins, srGAP3 and Rac1, critically involved in the regulation of the actin cytoskeleton.
Topics: Animals; Dendritic Spines; Humans; Neuralgia; Neuronal Plasticity; Nociception
PubMed: 32998955
DOI: 10.1523/JNEUROSCI.1664-20.2020 -
Neurobiology of Aging Jan 2019Subtle alterations in dendritic spine morphology can induce marked effects on connectivity patterns of neuronal circuits and subsequent cognitive behavior. Past studies...
Subtle alterations in dendritic spine morphology can induce marked effects on connectivity patterns of neuronal circuits and subsequent cognitive behavior. Past studies of rodent and nonhuman primate aging revealed reductions in spine density with concomitant alterations in spine morphology among pyramidal neurons in the prefrontal cortex. In this report, we visualized and digitally reconstructed the three-dimensional morphology of dendritic spines from the dorsolateral prefrontal cortex in cognitively normal individuals aged 40-94 years. Linear models defined relationships between spines and age, Mini-Mental State Examination, apolipoprotein E (APOE) ε4 allele status, and Alzheimer's disease (AD) pathology. Similar to findings in other mammals, spine density correlated negatively with human aging. Reduced spine head diameter associated with higher Mini-Mental State Examination scores. Individuals harboring an APOE ε4 allele displayed greater numbers of dendritic filopodia and structural alterations in thin spines. The presence of AD pathology correlated with increased spine length, reduced thin spine head diameter, and increased filopodia density. Our study reveals how spine morphology in the prefrontal cortex changes in human aging and highlights key structural alterations in selective spine populations that may promote cognitively normal function despite harboring the APOE ε4 allele or AD pathology.
Topics: Adult; Aged; Aging; Alzheimer Disease; Apolipoprotein E4; Cognition; Cognitive Aging; Dendritic Spines; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Neuronal Plasticity; Prefrontal Cortex
PubMed: 30339964
DOI: 10.1016/j.neurobiolaging.2018.09.003 -
Neurobiology of Disease Feb 2020Pten, a gene associated with autism spectrum disorder, is an upstream regulator of receptor tyrosine kinase intracellular signaling pathways that mediate extracellular...
Pten, a gene associated with autism spectrum disorder, is an upstream regulator of receptor tyrosine kinase intracellular signaling pathways that mediate extracellular cues to inform cellular development and activity-dependent plasticity. We therefore hypothesized that Pten loss would interfere with activity dependent dendritic growth. We investigated the effects of this interaction on the maturation of retrovirally labeled postnatally generated wild-type and Pten knockout granule neurons in male and female mouse dentate gyrus while using chemogenetics to manipulate the activity of the perforant path afferents. We find that enhancing network activity accelerates the dendritic outgrowth of wild-type, but not Pten knockout, neurons. This was specific to immature neurons during an early developmental window. We also examined synaptic connectivity and physiological measures of neuron maturation. The input resistance, membrane capacitance, dendritic spine morphology, and frequency of spontaneous synaptic events were not differentially altered by activity in wild-type versus Pten knockout neurons. Therefore, Pten and its downstream signaling pathways regulate the activity-dependent sculpting of the dendritic arbor during neuronal maturation.
Topics: Action Potentials; Animals; Dendritic Spines; Dentate Gyrus; Female; Male; Mice, Transgenic; PTEN Phosphohydrolase; Synapses
PubMed: 31838155
DOI: 10.1016/j.nbd.2019.104703 -
Cell and Tissue Research Oct 2020Dendritic spines are tiny membrane specialization forming the postsynaptic part of most excitatory synapses. They have been suggested to play a crucial role in... (Review)
Review
Dendritic spines are tiny membrane specialization forming the postsynaptic part of most excitatory synapses. They have been suggested to play a crucial role in regulating synaptic transmission during development and in adult learning processes. Changes in their number, size, and shape are correlated with processes of structural synaptic plasticity and learning and memory and also with neurodegenerative diseases, when spines are lost. Thus, their alterations can correlate with neuronal homeostasis, but also with dysfunction in several neurological disorders characterized by cognitive impairment. Therefore, it is important to understand how different stages in the life of a dendritic spine, including formation, maturation, and plasticity, are strictly regulated. In this context, brain-derived neurotrophic factor (BDNF), belonging to the NGF-neurotrophin family, is among the most intensively investigated molecule. This review would like to report the current knowledge regarding the role of BDNF in regulating dendritic spine number, structure, and plasticity concentrating especially on its signaling via its two often functionally antagonistic receptors, TrkB and p75. In addition, we point out a series of open points in which, while the role of BDNF signaling is extremely likely conclusive, evidence is still missing.
Topics: Animals; Brain-Derived Neurotrophic Factor; Dendritic Spines; Humans; Neurons; Signal Transduction
PubMed: 32537724
DOI: 10.1007/s00441-020-03226-5 -
Schizophrenia Bulletin Aug 2018Contrary to the notion that neurology but not psychiatry is the domain of disorders evincing structural brain alterations, it is now clear that there are subtle but... (Review)
Review
Contrary to the notion that neurology but not psychiatry is the domain of disorders evincing structural brain alterations, it is now clear that there are subtle but consistent neuropathological changes in schizophrenia. These range from increases in ventricular size to dystrophic changes in dendritic spines. A decrease in dendritic spine density in the prefrontal cortex (PFC) is among the most replicated of postmortem structural findings in schizophrenia. Examination of the mechanisms that account for the loss of dendritic spines has in large part focused on genes and molecules that regulate neuronal structure. But the simple question of what is the effector of spine loss, ie, where do the lost spines go, is unanswered. Recent data on glial cells suggest that microglia (MG), and perhaps astrocytes, play an important physiological role in synaptic remodeling of neurons during development. Synapses are added to the dendrites of pyramidal cells during the maturation of these neurons; excess synapses are subsequently phagocytosed by MG. In the PFC, this occurs during adolescence, when certain symptoms of schizophrenia emerge. This brief review discusses recent advances in our understanding of MG function and how these non-neuronal cells lead to structural changes in neurons in schizophrenia.
Topics: Dendritic Spines; Humans; Microglia; Prefrontal Cortex; Pyramidal Cells; Schizophrenia
PubMed: 30124942
DOI: 10.1093/schbul/sby088 -
ELife Sep 2023Interactions between an enzyme kinase, an ion channel and cytoskeletal proteins maintain the structure of synapses involved in memory formation.
Interactions between an enzyme kinase, an ion channel and cytoskeletal proteins maintain the structure of synapses involved in memory formation.
Topics: Dendritic Spines; Cytoskeletal Proteins
PubMed: 37676261
DOI: 10.7554/eLife.91566 -
CNS Neuroscience & Therapeutics Aug 2023Functional recovery is associated with the preservation of dendritic spines in the penumbra area after stroke. Previous studies found that polymerized microtubules (MTs)...
BACKGROUND AND AIM
Functional recovery is associated with the preservation of dendritic spines in the penumbra area after stroke. Previous studies found that polymerized microtubules (MTs) serve a crucial role in regulating dendritic spine formation and plasticity. However, the mechanisms that are involved are poorly understood. This study is designed to understand whether the upregulation of acetylated α-tubulin (α-Ac-Tub, a marker for stable, and polymerized MTs) could alleviate injury to the dendritic spines in the penumbra area and motor dysfunction after ischemic stroke.
METHODS
Ischemic stroke was mimicked both in an in vivo and in vitro setup using middle cerebral artery occlusion and oxygen-glucose deprivation models. Thy1-YFP mice were utilized to observe the morphology of the dendritic spines in the penumbra area. MEC17 is the specific acetyltransferase of α-tubulin. Thy1 Cre and MEC17 mice were mated to produce mice with decreased expression of α-Ac-Tub in dendritic spines of pyramidal neurons in the cerebral cortex. Moreover, AAV-PHP.B-DIO-MEC17 virus and tubastatin A (TBA) were injected into Thy1 Cre and Thy1-YFP mice to increase α-Ac-Tub expression. Single-pellet retrieval, irregular ladder walking, rotarod, and cylinder tests were performed to test the motor function after the ischemic stroke.
RESULTS
α-Ac-Tub was colocalized with postsynaptic density 95. Although knockout of MEC17 in the pyramidal neurons did not affect the density of the dendritic spines, it significantly aggravated the injury to them in the penumbra area and motor dysfunction after stroke. However, MEC17 upregulation in the pyramidal neurons and TBA treatment could maintain mature dendritic spine density and alleviate motor dysfunction after stroke.
CONCLUSION
Our study demonstrated that α-Ac-Tub plays a crucial role in the maintenance of the structure and functions of mature dendritic spines. Moreover, α-Ac-Tub protected the dendritic spines in the penumbra area and alleviated motor dysfunction after stroke.
Topics: Mice; Animals; Dendritic Spines; Tubulin; Ischemic Stroke; Pyramidal Cells; Stroke
PubMed: 36965035
DOI: 10.1111/cns.14184