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Cell Reports Dec 2023Huntington's disease (HD) usually causes cognitive disorders, including learning difficulties, that emerge before motor symptoms. Mutations related to lysosomal...
Huntington's disease (HD) usually causes cognitive disorders, including learning difficulties, that emerge before motor symptoms. Mutations related to lysosomal trafficking are linked to the pathogenesis of neurological diseases, whereas the cellular mechanisms remain elusive. Here, we discover a reduction in the dendritic density of lysosomes in the hippocampus that correlates with deficits in synaptic plasticity and spatial learning in early CAG-140 HD model mice. We directly manipulate intraneuronal lysosomal positioning with light-induced CRY2:CIB1 dimerization and demonstrate that lysosomal abundance in dendrites positively modulates long-term potentiation of glutamatergic synapses onto the neuron. This modulation depends on lysosomal Ca release, which further promotes endoplasmic reticulum (ER) entry into spines. Importantly, optogenetically restoring lysosomal density in dendrites rescues the synaptic plasticity deficit in hippocampal slices of CAG-140 mice. Our data reveal dendritic lysosomal density as a modulator of synaptic plasticity and suggest a role of lysosomal mispositioning in cognitive decline in HD.
Topics: Mice; Animals; Huntington Disease; Neuronal Plasticity; Neurons; Hippocampus; Synapses; Lysosomes; Dendrites; Dendritic Spines
PubMed: 38096054
DOI: 10.1016/j.celrep.2023.113573 -
Materials (Basel, Switzerland) Nov 2023Severe erosion wear is found on valve spools, which threatens the safety and reliability of these units. The use of the plasma beam spraying surfacing method can...
The Preparation, Microstructure, and Wet Wear Properties of an Fe55-Based Welding Layer with the Co-Addition of 0.01 wt% CeO and 1.5 wt% SiC Particles Using the Plasma Beam Spraying Method.
Severe erosion wear is found on valve spools, which threatens the safety and reliability of these units. The use of the plasma beam spraying surfacing method can significantly improve the corrosion resistance and sealing performance of hydraulic valve spools, reduce material waste, and reduce maintenance costs. The effects of the co-addition of CeO and SiC particles on the morphology, surface cracks, microstructure, precipitated phases, and wear property of plasma-beam-sprayed Fe55-based coatings on 1025 steel were investigated using OM, EDS, ultra-deep field microscopy, and a wet sand rubber wheel friction tester, respectively. The dendrite exhibited a directional growth pattern perpendicular to the substrate and the transitional states of the microstructure with the co-addition of CeO and SiC particles. CeO or SiC reduced the liquid phase diffusion coefficient D of Cr and C and resulted in a decrease in the G/R ratio. The dendrites changed into equiaxed grains. The main phase composition of the Fe55 welding layer was CrC, γ-Fe. The martensite in the surfacing layer and the carbides formed CrC, which can improve the hardness of the surfacing layer. The grain boundaries consisted mainly of a reticular eutectic structure. The uniform distribution of the CrC hard phase in the Fe55+1.5 wt% SiC+0.01 wt% CeO resulted in a uniformly worn surface. The sub-wear mechanisms during the friction process were micro-ploughing and micro-cutting. The hardness and toughness of Fe55+1.5 wt% SiC+0.01 wt% CeO were well-matched, avoiding excessive micro-cutting and microplastic deformation. A low content of CeO could lead to the formation of equiaxed grain and effectively improve the uniformity of the microstructure. The wear-resistant layer of Fe55+1.5 wt% SiC+0.01 wt% CeO can effectively improve the service life and long-term sealing performance of the valve spools.
PubMed: 38068183
DOI: 10.3390/ma16237439 -
Nature Communications Jan 2024Synapses are pivotal sites of plasticity and memory formation. Consequently, synapses are energy consumption hotspots susceptible to dysfunction when their energy...
Synapses are pivotal sites of plasticity and memory formation. Consequently, synapses are energy consumption hotspots susceptible to dysfunction when their energy supplies are perturbed. Mitochondria are stabilized near synapses via the cytoskeleton and provide the local energy required for synaptic plasticity. However, the mechanisms that tether and stabilize mitochondria to support synaptic plasticity are unknown. We identified proteins exclusively tethering mitochondria to actin near postsynaptic spines. We find that VAP, the vesicle-associated membrane protein-associated protein implicated in amyotrophic lateral sclerosis, stabilizes mitochondria via actin near the spines. To test if the VAP-dependent stable mitochondrial compartments can locally support synaptic plasticity, we used two-photon glutamate uncaging for spine plasticity induction and investigated the induced and adjacent uninduced spines. We find VAP functions as a spatial stabilizer of mitochondrial compartments for up to ~60 min and as a spatial ruler determining the ~30 μm dendritic segment supported during synaptic plasticity.
Topics: Actins; Dendritic Spines; Neuronal Plasticity; Synapses; Mitochondria
PubMed: 38177103
DOI: 10.1038/s41467-023-44233-8 -
Frontiers in Immunology 2024Efferocytosis, the process of engulfing and removing apoptotic cells, plays an essential role in preserving tissue health and averting undue inflammation. While... (Review)
Review
Efferocytosis, the process of engulfing and removing apoptotic cells, plays an essential role in preserving tissue health and averting undue inflammation. While macrophages are primarily known for this task, dendritic cells (DCs) also play a significant role. This review delves into the unique contributions of various DC subsets to efferocytosis, highlighting the distinctions in how DCs and macrophages recognize and handle apoptotic cells. It further explores how efferocytosis influences DC maturation, thereby affecting immune tolerance. This underscores the pivotal role of DCs in orchestrating immune responses and sustaining immune equilibrium, providing new insights into their function in immune regulation.
Topics: Dendritic Cells; Humans; Phagocytosis; Animals; Macrophages; Apoptosis; Immune Tolerance; Efferocytosis
PubMed: 38835772
DOI: 10.3389/fimmu.2024.1415573 -
Cell Reports Nov 2023Deletion of the obsessive-compulsive disorder (OCD)-associated gene SAP90/PSD-95-associated protein 3 (Sapap3), which encodes a postsynaptic anchoring protein at...
Deletion of the obsessive-compulsive disorder (OCD)-associated gene SAP90/PSD-95-associated protein 3 (Sapap3), which encodes a postsynaptic anchoring protein at corticostriatal synapses, causes OCD-like motor behaviors in mice. While corticostriatal synaptic dysfunction is central to this phenotype, the striatum efficiently adapts to pathological changes, often in ways that expand upon the original circuit impairment. Here, we show that SAPAP3 deletion causes non-synaptic and pathway-specific alterations in dorsolateral striatum circuit function. While somatic excitability was elevated in striatal projection neurons (SPNs), dendritic excitability was exclusively enhanced in direct pathway SPNs. Layered on top of this, cholinergic modulation was altered in opposing ways: striatal cholinergic interneuron density and evoked acetylcholine release were elevated, while basal muscarinic modulation of SPNs was reduced. These data describe how SAPAP3 deletion alters the striatal landscape upon which impaired corticostriatal inputs will act, offering a basis for how pathological synaptic integration and unbalanced striatal output underlying OCD-like behaviors may be shaped.
Topics: Mice; Animals; Nerve Tissue Proteins; Corpus Striatum; Neostriatum; Obsessive-Compulsive Disorder; Cholinergic Agents
PubMed: 37934666
DOI: 10.1016/j.celrep.2023.113384 -
The Journal of Biological Chemistry Feb 2024Sterile alpha and toll/interleukin receptor motif-containing 1 (SARM1) is a critical regulator of axon degeneration that acts through hydrolysis of NAD following injury....
Sterile alpha and toll/interleukin receptor motif-containing 1 (SARM1) is a critical regulator of axon degeneration that acts through hydrolysis of NAD following injury. Recent work has defined the mechanisms underlying SARM1's catalytic activity and advanced our understanding of SARM1 function in axons, yet the role of SARM1 signaling in other compartments of neurons is still not well understood. Here, we show in cultured hippocampal neurons that endogenous SARM1 is present in axons, dendrites, and cell bodies and that direct activation of SARM1 by the neurotoxin Vacor causes not just axon degeneration, but degeneration of all neuronal compartments. In contrast to the axon degeneration pathway defined in dorsal root ganglia, SARM1-dependent hippocampal axon degeneration in vitro is not sensitive to inhibition of calpain proteases. Dendrite degeneration downstream of SARM1 in hippocampal neurons is dependent on calpain 2, a calpain protease isotype enriched in dendrites in this cell type. In summary, these data indicate SARM1 plays a critical role in neurodegeneration outside of axons and elucidates divergent pathways leading to degeneration in hippocampal axons and dendrites.
Topics: Animals; Mice; Armadillo Domain Proteins; Axons; Calpain; Cytoskeletal Proteins; Dendrites; Neurons; Signal Transduction
PubMed: 38199568
DOI: 10.1016/j.jbc.2024.105630 -
Scientific Reports Jul 2023In vitro model networks could provide cellular models of physiological relevance to reproduce and investigate the basic function of neural circuits on a chip in the...
In vitro model networks could provide cellular models of physiological relevance to reproduce and investigate the basic function of neural circuits on a chip in the laboratory. Several tools and methods have been developed since the past decade to build neural networks on a chip; among them, microfluidic circuits appear to be a highly promising approach. One of the numerous advantages of this approach is that it preserves stable somatic and axonal compartments over time due to physical barriers that prevent the soma from exploring undesired areas and guide neurites along defined pathways. As a result, neuron compartments can be identified and isolated, and their interconnectivity can be modulated to build a topological neural network (NN). Here, we have assessed the extent to which the confinement imposed by the microfluidic environment can impact cell development and shape NN activity. Toward that aim, microelectrode arrays have enabled the monitoring of the short- and mid-term evolution of neuron activation over the culture period at specific locations in organized (microfluidic) and random (control) networks. In particular, we have assessed the spike and burst rate, as well as the correlations between the extracted spike trains over the first stages of maturation. This study enabled us to observe intense neurite communications that would have been weaker and more delayed within random networks; the spiking rate, burst and correlations being reinforced over time in terms of number and amplitude, exceeding the electrophysiological features of standard cultures. Beyond the enhanced detection efficiency that was expected from the microfluidic channels, the confinement of cells seems to reinforce neural communications and cell development throughout the network.
Topics: Microfluidics; Neurons; Neurites; Axons; Cardiac Electrophysiology
PubMed: 37516789
DOI: 10.1038/s41598-023-39477-9 -
PLoS Computational Biology Jun 2024A fundamental function of cortical circuits is the integration of information from different sources to form a reliable basis for behavior. While animals behave as if...
A fundamental function of cortical circuits is the integration of information from different sources to form a reliable basis for behavior. While animals behave as if they optimally integrate information according to Bayesian probability theory, the implementation of the required computations in the biological substrate remains unclear. We propose a novel, Bayesian view on the dynamics of conductance-based neurons and synapses which suggests that they are naturally equipped to optimally perform information integration. In our approach apical dendrites represent prior expectations over somatic potentials, while basal dendrites represent likelihoods of somatic potentials. These are parametrized by local quantities, the effective reversal potentials and membrane conductances. We formally demonstrate that under these assumptions the somatic compartment naturally computes the corresponding posterior. We derive a gradient-based plasticity rule, allowing neurons to learn desired target distributions and weight synaptic inputs by their relative reliabilities. Our theory explains various experimental findings on the system and single-cell level related to multi-sensory integration, which we illustrate with simulations. Furthermore, we make experimentally testable predictions on Bayesian dendritic integration and synaptic plasticity.
Topics: Bayes Theorem; Dendrites; Models, Neurological; Animals; Neuronal Plasticity; Synapses; Computer Simulation; Cues; Computational Biology; Neurons; Action Potentials
PubMed: 38865345
DOI: 10.1371/journal.pcbi.1012047 -
Genes To Cells : Devoted To Molecular &... Aug 2023Methotrexate (MTX) is an anti-metabolite that has been used for the treatment of patients of acute lymphocytic leukemia or non-Hodgikin lymphoma for decades. In some...
Methotrexate (MTX) is an anti-metabolite that has been used for the treatment of patients of acute lymphocytic leukemia or non-Hodgikin lymphoma for decades. In some cases, MTX-treated patients suffer from neurological side effects, including seizures and cognitive dysfunctions. While most patients are at developmental stages, information of the mechanisms of the side effects of MTX treatment on the developing neurons has been limited. Neurons develop in five steps in the human brain: neurogenesis, polarity formation, dendrite and axon development, synapse formation, and neuronal death. Except for neurogenesis, these processes can be recapitulated in the primary culture system of cortical neurons. Using primary cultured cortical neurons, we studied the impact of MTX treatment on dendrite development, synapse formation, and neuronal death in the present report. MTX treatment impaired neuronal survival, dendrite development, and synapse formation. Interestingly, half maximal effective concentrations (EC s) of MTX for all three processes are at the similar range and lower than the MTX concentration in the cerebrospinal fluid in treated patients. Our results provide possible mechanisms of neurological side effects in treated patients.
Topics: Humans; Methotrexate; Neurons; Neurogenesis; Dendrites; Synapses
PubMed: 37170756
DOI: 10.1111/gtc.13035 -
Molecular Autism Jan 2024SHANK3 gene is a highly replicated causative gene for autism spectrum disorder and has been well characterized in multiple Shank3 mutant rodent models. When compared to...
BACKGROUND
SHANK3 gene is a highly replicated causative gene for autism spectrum disorder and has been well characterized in multiple Shank3 mutant rodent models. When compared to rodents, domestic dogs are excellent animal models in which to study social cognition as they closely interact with humans and exhibit similar social behaviors. Using CRISPR/Cas9 editing, we recently generated a dog model carrying Shank3 mutations, which displayed a spectrum of autism-like behaviors, such as social impairment and heightened anxiety. However, the neural mechanism underlying these abnormal behaviors remains to be identified.
METHODS
We used Shank3 mutant dog models to examine possible relationships between Shank3 mutations and neuronal dysfunction. We studied electrophysiological properties and the synaptic transmission of pyramidal neurons from acute brain slices of the prefrontal cortex (PFC). We also examined dendrite elaboration and dendritic spine morphology in the PFC using biocytin staining and Golgi staining. We analyzed the postsynaptic density using electron microscopy.
RESULTS
We established a protocol for the electrophysiological recording of canine brain slices and revealed that excitatory synaptic transmission onto PFC layer 2/3 pyramidal neurons in Shank3 heterozygote dogs was impaired, and this was accompanied by reduced dendrite complexity and spine density when compared to wild-type dogs. Postsynaptic density structures were also impaired in Shank3 mutants; however, pyramidal neurons exhibited hyperexcitability.
LIMITATIONS
Causal links between impaired PFC pyramidal neuron function and behavioral alterations remain unclear. Further experiments such as manipulating PFC neuronal activity or restoring synaptic transmission in Shank3 mutant dogs are required to assess PFC roles in altered social behaviors.
CONCLUSIONS
Our study demonstrated the feasibility of using canine brain slices as a model system to study neuronal circuitry and disease. Shank3 haploinsufficiency causes morphological and functional abnormalities in PFC pyramidal neurons, supporting the notion that Shank3 mutant dogs are new and valid animal models for autism research.
Topics: Humans; Dogs; Animals; Autistic Disorder; Autism Spectrum Disorder; Nerve Tissue Proteins; Pyramidal Cells; Synaptic Transmission; Prefrontal Cortex; Anxiety; Disease Models, Animal
PubMed: 38297387
DOI: 10.1186/s13229-024-00587-4