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Molecular Brain Nov 2023Protein kinases are responsible for protein phosphorylation and are involved in important intracellular signal transduction pathways in various cells, including neurons;...
Protein kinases are responsible for protein phosphorylation and are involved in important intracellular signal transduction pathways in various cells, including neurons; however, a considerable number of poorly characterized kinases may be involved in neuronal development. Here, we considered mitogen-activated protein kinase kinase kinase kinases (MAP4Ks), related to as candidate regulators of neurite outgrowth and synaptogenesis, by examining the effects of a selective MAP4K inhibitor PF06260933. PF06260933 treatments of the cultured neurons reduced neurite lengths, not the number of synapses, and phosphorylation of GAP43 and JNK, relative to the control. These results suggest that MAP4Ks are physiologically involved in normal neuronal development and that the resultant impaired neurite outgrowth by diminished MAP4Ks' activity, is related to psychiatric disorders.
Topics: Humans; Neurons; Neurites; Signal Transduction; Phosphorylation; Neuronal Outgrowth
PubMed: 37980537
DOI: 10.1186/s13041-023-01066-2 -
Molecular Biology of the Cell Oct 2023Nervous systems exhibit dramatic diversity in cell morphology and size. How neurons regulate their biosynthetic and secretory machinery to support such diversity is not...
Nervous systems exhibit dramatic diversity in cell morphology and size. How neurons regulate their biosynthetic and secretory machinery to support such diversity is not well understood. Endoplasmic reticulum exit sites (ERESs) are essential for maintaining secretory flux, and are required for normal dendrite development, but how neurons of different size regulate secretory capacity remains unknown. In , we find that the ERES number is strongly correlated with the size of a neuron's dendritic arbor. The elaborately branched sensory neuron, PVD, has especially high ERES numbers. Asymmetric cell division provides PVD with a large initial cell size critical for rapid establishment of PVD's high ERES number before neurite outgrowth, and these ERESs are maintained throughout development. Maintenance of ERES number requires the cell fate transcription factor MEC-3, TOR (), and nutrient availability, with and mutant PVDs both displaying reductions in ERES number, soma size, and dendrite size. Notably, mutant animals exhibit reduced expression of a reporter in PVD, and starvation reduces ERES number and somato-dendritic size in a manner genetically redundant with perturbation. Our data suggest that both asymmetric cell division and nutrient sensing pathways regulate secretory capacities to support elaborate dendritic arbors.
Topics: Animals; Caenorhabditis elegans; Sensory Receptor Cells; Caenorhabditis elegans Proteins; Biological Transport; Endoplasmic Reticulum; Dendrites
PubMed: 37556208
DOI: 10.1091/mbc.E23-03-0090 -
Neural Regeneration Research Sep 2024Aging is the leading risk factor for Alzheimer's disease and other neurodegenerative diseases. We now understand that a breakdown in the neuronal cytoskeleton, mainly...
Aging is the leading risk factor for Alzheimer's disease and other neurodegenerative diseases. We now understand that a breakdown in the neuronal cytoskeleton, mainly underpinned by protein modifications leading to the destabilization of microtubules, is central to the pathogenesis of Alzheimer's disease. This is accompanied by morphological defects across the somatodendritic compartment, axon, and synapse. However, knowledge of what occurs to the microtubule cytoskeleton and morphology of the neuron during physiological aging is comparatively poor. Several recent studies have suggested that there is an age-related increase in the phosphorylation of the key microtubule stabilizing protein tau, a modification, which is known to destabilize the cytoskeleton in Alzheimer's disease. This indicates that the cytoskeleton and potentially other neuronal structures reliant on the cytoskeleton become functionally compromised during normal physiological aging. The current literature shows age-related reductions in synaptic spine density and shifts in synaptic spine conformation which might explain age-related synaptic functional deficits. However, knowledge of what occurs to the microtubular and actin cytoskeleton, with increasing age is extremely limited. When considering the somatodendritic compartment, a regression in dendrites and loss of dendritic length and volume is reported whilst a reduction in soma volume/size is often seen. However, research into cytoskeletal change is limited to a handful of studies demonstrating reductions in and mislocalizations of microtubule-associated proteins with just one study directly exploring the integrity of the microtubules. In the axon, an increase in axonal diameter and age-related appearance of swellings is reported but like the dendrites, just one study investigates the microtubules directly with others reporting loss or mislocalization of microtubule-associated proteins. Though these are the general trends reported, there are clear disparities between model organisms and brain regions that are worthy of further investigation. Additionally, longitudinal studies of neuronal/cytoskeletal aging should also investigate whether these age-related changes contribute not just to vulnerability to disease but also to the decline in nervous system function and behavioral output that all organisms experience. This will highlight the utility, if any, of cytoskeletal fortification for the promotion of healthy neuronal aging and potential protection against age-related neurodegenerative disease. This review seeks to summarize what is currently known about the physiological aging of the neuron and microtubular cytoskeleton in the hope of uncovering mechanisms underpinning age-related risk to disease.
PubMed: 38227514
DOI: 10.4103/1673-5374.390974 -
Membranes Jul 2023The protection of zinc anodes in zinc-air batteries (ZABs) is an efficient way to reduce corrosion and Zn dendrite formation and improve cyclability and battery...
The protection of zinc anodes in zinc-air batteries (ZABs) is an efficient way to reduce corrosion and Zn dendrite formation and improve cyclability and battery efficiency. Anion-conducting poly(N-vinylbenzyl N,N,N-trimethylammonium)chloride (PVBTMA) thin films were electrodeposited directly on zinc metal using cyclic voltammetry. This deposition process presents a combination of advantages, including selective anion transport in PVBTMA reducing zinc crossover, high interface quality by electrodeposition improving the corrosion protection of zinc and high ionomer stiffness opposing zinc dendrite perforation. The PVBTMA layer was observed by optical and electron microscopy, and the wettability of the ionomer-coated surface was investigated by contact angle measurements. ZABs with PVBTMA-coated Zn showed an appreciable and stable open-circuit voltage both in alkaline electrolyte (1.55 V with a Pt cathode) and in miniaturized batteries (1.31 V with a carbon paper cathode). Cycling tests at 0.5 mA/cm within voltage limits of 2.1 and 0.8 V gave a stable discharge capacity for nearly 100 cycles with a liquid electrolyte and more than 20 cycles in miniaturized batteries. The faster degradation of the latter ZAB was attributed to the clogging of the carbon air cathode and drying or carbonation of the electrolyte sorbed in a Whatman paper.
PubMed: 37505046
DOI: 10.3390/membranes13070680 -
Nature Communications Mar 2024Axonal growth cones mediate axonal guidance and growth regulation. We show that migrating neurons in mice possess a growth cone at the tip of their leading process,...
Axonal growth cones mediate axonal guidance and growth regulation. We show that migrating neurons in mice possess a growth cone at the tip of their leading process, similar to that of axons, in terms of the cytoskeletal dynamics and functional responsivity through protein tyrosine phosphatase receptor type sigma (PTPσ). Migrating-neuron growth cones respond to chondroitin sulfate (CS) through PTPσ and collapse, which leads to inhibition of neuronal migration. In the presence of CS, the growth cones can revert to their extended morphology when their leading filopodia interact with heparan sulfate (HS), thus re-enabling neuronal migration. Implantation of an HS-containing biomaterial in the CS-rich injured cortex promotes the extension of the growth cone and improve the migration and regeneration of neurons, thereby enabling functional recovery. Thus, the growth cone of migrating neurons is responsive to extracellular environments and acts as a primary regulator of neuronal migration.
Topics: Mice; Animals; Growth Cones; Receptor-Like Protein Tyrosine Phosphatases, Class 2; Neurogenesis; Axons; Chondroitin Sulfates; Brain; Cells, Cultured
PubMed: 38461182
DOI: 10.1038/s41467-024-45825-8 -
Human Brain Mapping Nov 2023The hippocampus is classically divided into mesoscopic subfields which contain varying microstructure that contribute to their unique functional roles. It has been...
The hippocampus is classically divided into mesoscopic subfields which contain varying microstructure that contribute to their unique functional roles. It has been challenging to characterize this microstructure with current magnetic resonance based neuroimaging techniques. In this work, we used diffusion magnetic resonance imaging (dMRI) and a novel surface-based approach in the hippocampus which revealed distinct microstructural distributions of neurite density and dispersion, T1w/T2w ratio as a proxy for myelin content, fractional anisotropy, and mean diffusivity. We used the neurite orientation dispersion and density imaging (NODDI) model optimized for grey matter diffusivity to characterize neurite density and dispersion. We found that neurite dispersion was highest in the cornu ammonis (CA) 1 and subiculum subfields which likely captures the large heterogeneity of tangential and radial fibres, such as the Schaffer collaterals, perforant path, and pyramidal neurons. Neurite density and T1w/T2w were highest in the subiculum and CA3 and lowest in CA1, which may reflect known myeloarchitectonic differences between these subfields. Using a simple logistic regression model, we showed that neurite density, dispersion, and T1w/T2w measures were separable across the subfields, suggesting that they may be sensitive to the known variability in subfield cyto- and myeloarchitecture. We report macrostructural measures of gyrification, thickness, and curvature that were in line with ex vivo descriptions of hippocampal anatomy. We employed a multivariate orthogonal projective non-negative matrix factorization (OPNNMF) approach to capture co-varying regions of macro- and microstructure across the hippocampus. The clusters were highly variable along the medial-lateral (proximal-distal) direction, likely reflecting known differences in morphology, cytoarchitectonic profiles, and connectivity. Finally, we show that by examining the main direction of diffusion relative to canonical hippocampal axes, we could identify regions with stereotyped microstructural orientations that may map onto specific fibre pathways, such as the Schaffer collaterals, perforant path, fimbria, and alveus. These results highlight the value of combining in vivo dMRI with computational approaches for capturing hippocampal microstructure, which may provide useful features for understanding cognition and for diagnosis of disease states.
Topics: Humans; Diffusion Tensor Imaging; Diffusion Magnetic Resonance Imaging; Neuroimaging; Hippocampus; Gray Matter; Neurites; White Matter
PubMed: 37615057
DOI: 10.1002/hbm.26461 -
Scientific Reports Aug 2023Here we use phase field to model and simulate "hopper" crystals, so named because of their underlying cubic structure but with a hopper-like depression on each of the...
Here we use phase field to model and simulate "hopper" crystals, so named because of their underlying cubic structure but with a hopper-like depression on each of the six faces. Over the past three decades simulations of single phase solidification have successfully explored dendritic structures, in two and three dimensions, formed under high undercooling from a slight perturbation in anisotropy. More recently we see the modelling of faceted structures at near equilibrium, and also, under high undercooling, the formation of dendritic-like structures in two dimensions which retain some faceting in the dendrite arms. A cubic hopper crystal appears to be a hybrid structure, somewhere between a perfect cube and a dendrite, and, to date, has not appeared in the modelling literature. In this paper we describe a model for faceted cubic growth and explore results, necessarily in three dimensions, that include perfect cube, hopper and dendritic. We also touch briefly on one other morphology-octahedral.
PubMed: 37537188
DOI: 10.1038/s41598-023-38741-2 -
ELife Jul 2023Ca/calmodulin-dependent protein kinase II (CaMKII) is essential for long-term potentiation (LTP) of excitatory synapses that is linked to learning and memory. In this...
Ca/calmodulin-dependent protein kinase II (CaMKII) is essential for long-term potentiation (LTP) of excitatory synapses that is linked to learning and memory. In this study, we focused on understanding how interactions between CaMKIIα and the actin-crosslinking protein α-actinin-2 underlie long-lasting changes in dendritic spine architecture. We found that association of the two proteins was unexpectedly elevated within 2 minutes of NMDA receptor stimulation that triggers structural LTP in primary hippocampal neurons. Furthermore, disruption of interactions between the two proteins prevented the accumulation of enlarged mushroom-type dendritic spines following NMDA receptor activation. α-Actinin-2 binds to the regulatory segment of CaMKII. Calorimetry experiments, and a crystal structure of α-actinin-2 EF hands 3 and 4 in complex with the CaMKII regulatory segment, indicate that the regulatory segment of autoinhibited CaMKII is not fully accessible to α-actinin-2. Pull-down experiments show that occupation of the CaMKII substrate-binding groove by GluN2B markedly increases α-actinin-2 access to the CaMKII regulatory segment. Furthermore, in situ labelling experiments are consistent with the notion that recruitment of CaMKII to NMDA receptors contributes to elevated interactions between the kinase and α-actinin-2 during structural LTP. Overall, our study provides new mechanistic insight into the molecular basis of structural LTP and reveals an added layer of sophistication to the function of CaMKII.
Topics: Calcium-Calmodulin-Dependent Protein Kinase Type 2; Actinin; Receptors, N-Methyl-D-Aspartate; Dendritic Spines; Synapses; Long-Term Potentiation
PubMed: 37489746
DOI: 10.7554/eLife.85008 -
Neural Development Oct 2023Neocortex development has been extensively studied in altricial rodents such as mouse and rat. Identification of alternative animal models along the...
BACKGROUND
Neocortex development has been extensively studied in altricial rodents such as mouse and rat. Identification of alternative animal models along the "altricial-precocial" spectrum in order to better model and understand neocortex development is warranted. The Greater cane rat (GCR, Thyronomys swinderianus) is an indigenous precocial African rodent. Although basic aspects of brain development in the GCR have been documented, detailed information on neocortex development including the occurrence and abundance of the distinct types of neural progenitor cells (NPCs) in the GCR are lacking.
METHODS
GCR embryos and fetuses were obtained from timed pregnant dams between gestation days 50-140 and their neocortex was analyzed by immunofluorescence staining using characteristic marker proteins for NPCs, neurons and glia cells. Data were compared with existing data on closely related precocial and altricial species, i.e. guinea pig and dwarf rabbit.
RESULTS
The primary sequence of neuro- and gliogenesis, and neuronal maturation is preserved in the prenatal GCR neocortex. We show that the GCR exhibits a relatively long period of cortical neurogenesis of 70 days. The subventricular zone becomes the major NPC pool during mid-end stages of neurogenesis with Pax6 + NPCs constituting the major basal progenitor subtype in the GCR neocortex. Whereas dendrite formation in the GCR cortical plate appears to initiate immediately after the onset of neurogenesis, major aspects of axon formation and maturation, and astrogenesis do not begin until mid-neurogenesis. Similar to the guinea pig, the GCR neocortex exhibits a high maturation status, containing neurons with well-developed dendrites and myelinated axons and astrocytes at birth, thus providing further evidence for the notion that a great proportion of neocortex growth and maturation in precocial mammals occurs before birth.
CONCLUSIONS
Together, this work has deepened our understanding of neocortex development of the GCR, of the timing and the cellular differences that regulate brain growth and development within the altricial-precocial spectrum and its suitability as a research model for neurodevelopmental studies. The timelines of brain development provided by this study may serve as empirical reference data and foundation in future studies in order to model and better understand neurodevelopment and associated alterations.
Topics: Animals; Female; Pregnancy; Rats; Neocortex; Neural Stem Cells; Neurogenesis; Neurons; Rodentia
PubMed: 37833718
DOI: 10.1186/s13064-023-00175-x -
Neuroscience Dec 2023Fragile X syndrome (FXS) is the most common single gene disorder contributing to autism spectrum disorder (ASD). Although significant sex differences are observed in...
Fragile X syndrome (FXS) is the most common single gene disorder contributing to autism spectrum disorder (ASD). Although significant sex differences are observed in FXS, few studies have focused on the phenotypic characteristics as well as the differences in brain pathological changes and gene expression in FXS by sex. Therefore, we analyzed sex differences in autism-like behavior and dendritic spine development in two-month-old male and female Fmr1 KO and C57 mice and evaluated the mechanisms at transcriptome level. Results suggest that Fmr1 KO mice display sex differences in autism-like behavior and dendritic spine density. Compared to females, male had more severe effects on anxiety, repetitive stereotype-like behaviors, and socializing, with higher dendritic spine density. Furthermore, two male-biased and five female-biased expressed genes were screened based on KEGG pathway enrichment and protein-protein interaction (PPI) analyses. In conclusion, our findings show mutations in the Fmr1 gene lead to aberrant expression of related genes and affect the sex-differentiated behavioral phenotypes of Fmr1 KO mice by affecting brain development and functional architecture, and suggest future studies should focus on including female subjects to comprehensively reflect the differentiation of FXS in both sexes and develop more precise and effective therapeutic strategies.
Topics: Humans; Animals; Female; Male; Mice; Infant; Fragile X Mental Retardation Protein; Dendritic Spines; Transcriptome; Autistic Disorder; Sex Characteristics; Autism Spectrum Disorder; Mice, Knockout; Mutation; Fragile X Syndrome; Disease Models, Animal
PubMed: 37852411
DOI: 10.1016/j.neuroscience.2023.10.001