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Acta Neuropathologica Jul 2015Synaptic failure is an immediate cause of cognitive decline and memory dysfunction in Alzheimer's disease. Dendritic spines are specialized structures on neuronal... (Review)
Review
Synaptic failure is an immediate cause of cognitive decline and memory dysfunction in Alzheimer's disease. Dendritic spines are specialized structures on neuronal processes, on which excitatory synaptic contacts take place and the loss of dendritic spines directly correlates with the loss of synaptic function. Dendritic spines are readily accessible for both in vitro and in vivo experiments and have, therefore, been studied in great detail in Alzheimer's disease mouse models. To date, a large number of different mechanisms have been proposed to cause dendritic spine dysfunction and loss in Alzheimer's disease. For instance, amyloid beta fibrils, diffusible oligomers or the intracellular accumulation of amyloid beta have been found to alter the function and structure of dendritic spines by distinct mechanisms. Furthermore, tau hyperphosphorylation and microglia activation, which are thought to be consequences of amyloidosis in Alzheimer's disease, may also contribute to spine loss. Lastly, genetic and therapeutic interventions employed to model the disease and elucidate its pathogenetic mechanisms in experimental animals may cause alterations of dendritic spines on their own. However, to date none of these mechanisms have been translated into successful therapeutic approaches for the human disease. Here, we critically review the most intensely studied mechanisms of spine loss in Alzheimer's disease as well as the possible pitfalls inherent in the animal models of such a complex neurodegenerative disorder.
Topics: Alzheimer Disease; Amyloid; Animals; Brain; Dendritic Spines; Humans
PubMed: 26063233
DOI: 10.1007/s00401-015-1449-5 -
Seminars in Cell & Developmental Biology May 2022Synapses are specialized sites where neurons connect and communicate with each other. Activity-dependent modification of synaptic structure and function provides a... (Review)
Review
Synapses are specialized sites where neurons connect and communicate with each other. Activity-dependent modification of synaptic structure and function provides a mechanism for learning and memory. The advent of high-resolution time-lapse imaging in conjunction with fluorescent biosensors and actuators enables researchers to monitor and manipulate the structure and function of synapses both in vitro and in vivo. This review focuses on recent imaging studies on the synaptic modification underlying learning and memory.
Topics: Dendritic Spines; Learning; Neurons; Synapses
PubMed: 34020876
DOI: 10.1016/j.semcdb.2021.05.015 -
Cells Sep 2021Dendritic spines are small, bulbous protrusions along neuronal dendrites where most of the excitatory synapses are located. Dendritic spine density in normal human brain... (Review)
Review
Dendritic spines are small, bulbous protrusions along neuronal dendrites where most of the excitatory synapses are located. Dendritic spine density in normal human brain increases rapidly before and after birth achieving the highest density around 2-8 years. Density decreases during adolescence, reaching a stable level in adulthood. The changes in dendritic spines are considered structural correlates for synaptic plasticity as well as the basis of experience-dependent remodeling of neuronal circuits. Alterations in spine density correspond to aberrant brain function observed in various neurodevelopmental and neuropsychiatric disorders. Dendritic spine initiation affects spine density. In this review, we discuss the importance of spine initiation in brain development, learning, and potential complications resulting from altered spine initiation in neurological diseases. Current literature shows that two Bin Amphiphysin Rvs (BAR) domain-containing proteins, MIM/Mtss1 and SrGAP3, are involved in spine initiation. We review existing literature and open databases to discuss whether other BAR-domain proteins could also take part in spine initiation. Finally, we discuss the potential molecular mechanisms on how BAR-domain proteins could regulate spine initiation.
Topics: Adaptor Proteins, Signal Transducing; Brain; Brain Diseases; Dendritic Spines; Humans; Learning; Nuclear Proteins; Protein Domains; Tumor Suppressor Proteins
PubMed: 34572042
DOI: 10.3390/cells10092392 -
Cells Feb 2020The protein kinase JNK1 exhibits high activity in the developing brain, where it regulates dendrite morphology through the phosphorylation of cytoskeletal regulatory...
The protein kinase JNK1 exhibits high activity in the developing brain, where it regulates dendrite morphology through the phosphorylation of cytoskeletal regulatory proteins. JNK1 also phosphorylates dendritic spine proteins, and mice display a long-term depression deficit. Whether JNK1 or other JNKs regulate spine morphology is thus of interest. Here, we characterize dendritic spine morphology in hippocampus of mice lacking using Lucifer yellow labelling. We find that mushroom spines decrease and thin spines increase in apical dendrites of CA3 pyramidal neurons with no spine changes in basal dendrites or in CA1. Consistent with this spine deficit, mice display impaired acquisition learning in the Morris water maze. In hippocampal cultures, we show that cytosolic but not nuclear JNK, regulates spine morphology and expression of phosphomimicry variants of JNK substrates doublecortin (DCX) or myristoylated alanine-rich C kinase substrate-like protein-1 (MARCKSL1), rescue mushroom, thin, and stubby spines differentially. These data suggest that physiologically active JNK controls the equilibrium between mushroom, thin, and stubby spines via phosphorylation of distinct substrates.
Topics: Animals; Dendritic Spines; Doublecortin Protein; Humans; MAP Kinase Kinase 4; MAP Kinase Signaling System; Mice; Morris Water Maze Test; Transfection
PubMed: 32074971
DOI: 10.3390/cells9020440 -
Neural Plasticity 2016Structural plasticity of excitatory synapses is a vital component of neuronal development, synaptic plasticity, and behaviour. Abnormal development or regulation of... (Review)
Review
Structural plasticity of excitatory synapses is a vital component of neuronal development, synaptic plasticity, and behaviour. Abnormal development or regulation of excitatory synapses has also been strongly implicated in many neurodevelopmental, psychiatric, and neurodegenerative disorders. In the mammalian forebrain, the majority of excitatory synapses are located on dendritic spines, specialized dendritic protrusions that are enriched in actin. Research over recent years has begun to unravel the complexities involved in the regulation of dendritic spine structure. The small GTPase family of proteins have emerged as key regulators of structural plasticity, linking extracellular signals with the modulation of dendritic spines, which potentially underlies their ability to influence cognition. Here we review a number of studies that examine how small GTPases are activated and regulated in neurons and furthermore how they can impact actin dynamics, and thus dendritic spine morphology. Elucidating this signalling process is critical for furthering our understanding of the basic mechanisms by which information is encoded in neural circuits but may also provide insight into novel targets for the development of effective therapies to treat cognitive dysfunction seen in a range of neurological disorders.
Topics: Animals; Brain; Dendritic Spines; Humans; Microfilament Proteins; Monomeric GTP-Binding Proteins; Neuronal Plasticity; Neurons; Signal Transduction
PubMed: 26989514
DOI: 10.1155/2016/3025948 -
Cells Jul 2021Neurogenesis and functional brain activity require complex associations of inherently programmed secretory elements that are regulated precisely and temporally. Family...
Neurogenesis and functional brain activity require complex associations of inherently programmed secretory elements that are regulated precisely and temporally. Family with sequence similarity 19 A1 (FAM19A1) is a secreted protein primarily expressed in subsets of terminally differentiated neuronal precursor cells and fully mature neurons in specific brain substructures. Several recent studies have demonstrated the importance of FAM19A1 in brain physiology; however, additional information is needed to support its role in neuronal maturation and function. In this study, dendritic spine morphology in -ablated mice and neurite development during in vitro neurogenesis were examined to understand the putative role of FAM19A1 in neural integrity. Adult -deficient mice showed low dendritic spine density and maturity with reduced dendrite complexity compared to wild-type (WT) littermates. To further explore the effect of FAM19A1 on neuronal maturation, the neurite outgrowth pattern in primary neurons was analyzed in vitro with and without FAM19A1. In response to FAM19A1, WT primary neurons showed reduced neurite complexity, whereas -decifient primary neurons exhibited increased neurite arborization, which was reversed by supplementation with recombinant FAM19A1. Together, these findings suggest that FAM19A1 participates in dendritic spine development and neurite arborization.
Topics: Age Factors; Animals; Brain; Cells, Cultured; Chemokines; Dendritic Spines; Female; Gestational Age; Male; Mice, Inbred C57BL; Mice, Knockout; Neurites; Neuronal Outgrowth; Pregnancy; Signal Transduction; Mice
PubMed: 34440636
DOI: 10.3390/cells10081868 -
Neuropharmacology Jan 2016IRSp53 (also known as BAIAP2) is a multi-domain scaffolding and adaptor protein that has been implicated in the regulation of membrane and actin dynamics at subcellular... (Review)
Review
IRSp53 (also known as BAIAP2) is a multi-domain scaffolding and adaptor protein that has been implicated in the regulation of membrane and actin dynamics at subcellular structures, including filopodia and lamellipodia. Accumulating evidence indicates that IRSp53 is an abundant component of the postsynaptic density at excitatory synapses and an important regulator of actin-rich dendritic spines. In addition, IRSp53 has been implicated in diverse psychiatric disorders, including autism spectrum disorders, schizophrenia, and attention deficit/hyperactivity disorder. Mice lacking IRSp53 display enhanced NMDA (N-methyl-d-aspartate) receptor function accompanied by social and cognitive deficits, which are reversed by pharmacological suppression of NMDA receptor function. These results suggest the hypothesis that defective actin/membrane modulation in IRSp53-deficient dendritic spines may lead to social and cognitive deficits through NMDA receptor dysfunction. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.
Topics: Actin Cytoskeleton; Animals; Brain; Cell Membrane; Dendritic Spines; Humans; Mental Disorders; Mice; Nerve Tissue Proteins; Phenotype; Post-Synaptic Density; Protein Interaction Domains and Motifs; RNA, Messenger; Receptors, N-Methyl-D-Aspartate
PubMed: 26275848
DOI: 10.1016/j.neuropharm.2015.06.019 -
Current Opinion in Neurobiology Aug 2016Synapses are the basic unit of neuronal communication and their disruption is associated with many neurological disorders. Significant progress has been made towards... (Review)
Review
Synapses are the basic unit of neuronal communication and their disruption is associated with many neurological disorders. Significant progress has been made towards understanding the molecular and genetic regulation of synapse formation, modulation, and dysfunction, but the underlying cellular mechanisms remain incomplete. The actin cytoskeleton not only provides the structural foundation for synapses, but also regulates a diverse array of cellular activities underlying synaptic function. Here we will discuss the regulation of the actin cytoskeleton in dendritic spines, the postsynaptic compartment of excitatory synapses. We will focus on a select number of actin regulatory processes, highlighting recent advances, the complexity of crosstalk between different pathways, and the challenges of understanding their precise impact on the structure and function of synapses.
Topics: Actin Cytoskeleton; Dendritic Spines; Humans; Neurogenesis; Neuronal Plasticity; Synapses
PubMed: 27138585
DOI: 10.1016/j.conb.2016.04.010 -
Organization and dynamics of the actin cytoskeleton during dendritic spine morphological remodeling.Cellular and Molecular Life Sciences :... Aug 2016In the central nervous system, most excitatory post-synapses are small subcellular structures called dendritic spines. Their structure and morphological remodeling are... (Review)
Review
In the central nervous system, most excitatory post-synapses are small subcellular structures called dendritic spines. Their structure and morphological remodeling are tightly coupled to changes in synaptic transmission. The F-actin cytoskeleton is the main driving force of dendritic spine remodeling and sustains synaptic plasticity. It is therefore essential to understand how changes in synaptic transmission can regulate the organization and dynamics of actin binding proteins (ABPs). In this review, we will provide a detailed description of the organization and dynamics of F-actin and ABPs in dendritic spines and will discuss the current models explaining how the actin cytoskeleton sustains both structural and functional synaptic plasticity.
Topics: Actin Cytoskeleton; Actins; Animals; Dendritic Spines; Humans; Microfilament Proteins; Neuronal Plasticity; Signal Transduction; Synapses
PubMed: 27105623
DOI: 10.1007/s00018-016-2214-1 -
Human Vaccines & Immunotherapeutics Nov 2022Bacillus Calmette - Guerin (BCG) is an immune regulator that can enhance hippocampal synaptic plasticity in rats; however, it is unclear whether it can improve synaptic...
Bacillus Calmette - Guerin (BCG) is an immune regulator that can enhance hippocampal synaptic plasticity in rats; however, it is unclear whether it can improve synaptic function in a mouse model with Alzheimer's disease (AD). We hypothesized that BCG plays a protective role in AD mice and investigated its effect on dendritic morphology. The results obtained show that BCG immunization significantly increases dendritic complexity, as indicated by the increased number of dendritic intersections and branch points, as well as the increase in the fractal dimension. Furthermore, the number of primary neurites and dendritic length also increased following BCG immunization, which increased the number of spines and promoted maturation. IFN-γ and IL-4 levels increased, while TNF-α levels decreased following BCG immunization; expression levels of -JAK2, P-STAT3, SYN, and PSD-95 also increased. Therefore, this study demonstrates that BCG immunization in APP/PS1 mice mitigated hippocampal dendritic spine pathology, especially after the third round of immunization. This effect could possibly be attributed to; changes in dendritic arborization and spine morphology or increases in SYN and PSD-95 expression levels. It could also be related to mechanisms of BCG-induced increases in IFN-γ or IL-4/JAK2/STAT3 levels.
Topics: Animals; Mice; Alzheimer Disease; Dendritic Spines; Disease Models, Animal; Hippocampus; Interleukin-4; Mice, Transgenic; BCG Vaccine; Dendrites; Tumor Necrosis Factor-alpha
PubMed: 36113067
DOI: 10.1080/21645515.2022.2121568