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Ecotoxicology and Environmental Safety Oct 2023Lead (Pb), cadmium (Cd), and mercury (Hg) are environmentally toxic heavy metals that can be simultaneously detected at low levels in the blood of the general...
Lead (Pb), cadmium (Cd), and mercury (Hg) are environmentally toxic heavy metals that can be simultaneously detected at low levels in the blood of the general population. Although our previous studies have demonstrated neurodevelopmental toxicity upon co-exposure to these heavy metals at these low levels, the precise mechanisms remain largely unknown. Dendritic spines are the structural foundation of memory and undergo significant dynamic changes during development. This study focused on the dynamics of dendritic spines during brain development following Pb, Cd, and Hg co-exposure-induced memory impairment. First, the dynamic characteristics of dendritic spines in the prefrontal cortex were observed throughout the life cycle of normal rats. We observed that dendritic spines increased rapidly from birth to their peak value at weaning, followed by significant pruning and a decrease during adolescence. Dendritic spines tended to be stable until their loss in old age. Subsequently, a rat model of low-dose Pb, Cd, and Hg co-exposure from embryo to adolescence was established. The results showed that exposure to low doses of heavy metals equivalent to those detected in the blood of the general population impaired spatial memory and altered the dynamics of dendritic spine pruning from weaning to adolescence. Proteomic analysis of brain and blood samples suggested that differentially expressed proteins upon heavy metal exposure were enriched in dendritic spine-related cytoskeletal regulation and axon guidance signaling pathways and that cofilin was enriched in both of these pathways. Further experiments confirmed that heavy metal exposure altered actin cytoskeleton dynamics and disturbed the dendritic spine pruning-related LIM domain kinase 1-cofilin pathway in the rat prefrontal cortex. Our findings demonstrate that low-dose Pb, Cd, and Hg co-exposure may promote memory impairment by perturbing dendritic spine dynamics through dendritic spine pruning-related signaling pathways.
Topics: Humans; Adolescent; Animals; Rats; Cadmium; Mercury; Dendritic Spines; Lead; Proteomics; Actin Depolymerizing Factors; Brain; Memory Disorders
PubMed: 37660527
DOI: 10.1016/j.ecoenv.2023.115425 -
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 -
Science (New York, N.Y.) Jan 2022Dendritic spines mediate most excitatory neurotransmission in the nervous system, so their function must be critical for the brain. Spines are biochemical compartments...
Dendritic spines mediate most excitatory neurotransmission in the nervous system, so their function must be critical for the brain. Spines are biochemical compartments but might also electrically modify synaptic potentials. Using two-photon microscopy and a genetically encoded voltage indicator, we measured membrane potentials in spines and dendrites from pyramidal neurons in the somatosensory cortex of mice during spontaneous activity and sensory stimulation. Spines and dendrites were depolarized together during action potentials, but, during subthreshold and resting potentials, spines often experienced different voltages than parent dendrites, even activating independently. Spine voltages remained compartmentalized after two-photon optogenetic activation of individual spine heads. We conclude that spines are elementary voltage compartments. The regulation of voltage compartmentalization could be important for synaptic function and plasticity, dendritic integration, and disease states.
Topics: Action Potentials; Animals; Dendritic Spines; Membrane Potentials; Mice; Optogenetics; Patch-Clamp Techniques; Pyramidal Cells; Somatosensory Cortex; Synapses; Synaptic Potentials
PubMed: 34762487
DOI: 10.1126/science.abg0501 -
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 -
Journal of Alzheimer's Disease : JAD 2021To deeply understand late onset Alzheimer's disease (LOAD), it may be necessary to change the concept that it is a disease exclusively driven by aging processes. The... (Review)
Review
To deeply understand late onset Alzheimer's disease (LOAD), it may be necessary to change the concept that it is a disease exclusively driven by aging processes. The onset of LOAD could be associated with a previous peripheral stress at the level of the gut (changes in the gut microbiota), obesity (metabolic stress), and infections, among other systemic/environmental stressors. The onset of LOAD, then, may result from the generation of mild peripheral inflammatory processes involving cytokine production associated with peripheral stressors that in a second step enter the brain and spread out the process causing a neuroinflammatory brain disease. This hypothesis could explain the potential efficacy of Sodium Oligomannate (GV-971), a mixture of acidic linear oligosaccharides that have shown to remodel gut microbiota and slowdown LOAD. However, regardless of the origin of the disease, the end goal of LOAD-related preventative or disease modifying therapies is to preserve dendritic spines and synaptic plasticity that underlay and support healthy cognition. Here we discuss how systemic/environmental stressors impact pathways associated with the regulation of spine morphogenesis and synaptic maintenance, including insulin receptor and the brain derived neurotrophic factor signaling. Spine structure remodeling is a plausible mechanism to maintain synapses and provide cognitive resilience in LOAD patients. Importantly, we also propose a combination of drugs targeting such stressors that may be able to modify the course of LOAD by acting on preventing dendritic spines and synapsis loss.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Dendritic Spines; Diet, Healthy; Exercise; Gastrointestinal Microbiome; Humans; Mannose; Oligosaccharides; Synapses
PubMed: 33325386
DOI: 10.3233/JAD-201106 -
ENeuro 2021ADAP1/Centaurin-α1 (CentA1) functions as an Arf6 GTPase-activating protein highly enriched in the brain. Previous studies demonstrated the involvement of CentA1 in...
ADAP1/Centaurin-α1 (CentA1) functions as an Arf6 GTPase-activating protein highly enriched in the brain. Previous studies demonstrated the involvement of CentA1 in brain function as a regulator of dendritic differentiation and a potential mediator of Alzheimer's disease (AD) pathogenesis. To better understand the neurobiological functions of CentA1 signaling in the brain, we developed knock-out (KO) mice. The KO animals showed neither brain development nor synaptic ultrastructure deficits in the hippocampus. However, they exhibited significantly higher density and enhanced structural plasticity of dendritic spines in the CA1 region of the hippocampus compared with non-transgenic (NTG) littermates. Moreover, the deletion of improved performance in the object-in-place (OIP) spatial memory task. These results suggest that CentA1 functions as a negative regulator of spine density and plasticity, and of hippocampus-dependent memory formation. Thus, CentA1 and its downstream signaling may serve as a potential therapeutic target to prevent memory decline associated with aging and brain disorders.
Topics: Adaptor Proteins, Signal Transducing; Alzheimer Disease; Animals; Dendritic Spines; GTPase-Activating Proteins; Hippocampus; Memory; Mice; Nerve Tissue Proteins
PubMed: 33139322
DOI: 10.1523/ENEURO.0111-20.2020 -
Neuroendocrinology 2020Synaptic plasticity is the neuronal capacity to modify the function and structure of dendritic spines (DS) in response to neuromodulators. Sex steroids, particularly...
BACKGROUND
Synaptic plasticity is the neuronal capacity to modify the function and structure of dendritic spines (DS) in response to neuromodulators. Sex steroids, particularly 17β-estradiol (E2) and progesterone (P4), are key regulators in the control of DS formation through multiprotein complexes including WAVE1 protein, and are thus fundamental for the development of learning and memory.
OBJECTIVES
The aim of this work was to evaluate the molecular switch Cdk5 kinase/protein phosphatase 2A (PP2A) in the control of WAVE1 protein (phosphorylation/dephosphorylation) and the regulation of WAVE1 and cortactin to the Arp2/3 complex, in response to rapid treatments with E2 and P4 in cortical neuronal cells.
RESULTS
Rapid treatment with E2 and P4 modified neuronal morphology and significantly increased the number of DS. This effect was reduced by the use of a Cdk5 inhibitor (Roscovitine). In contrast, inhibition of PP2A with PP2A dominant negative construct significantly increased DS formation, evidencing the participation of kinase/phosphatase in the regulation of WAVE1 in DS formation induced by E2 and P4. Cortactin regulates DS formation via Src and PAK1 kinase induced by E2 and P4. Both cortactin and WAVE1 signal to Arp2/3 complex to synergistically promote actin nucleation.
CONCLUSION
These results suggest that E2 and P4 dynamically regulate neuron morphology through nongenomic signaling via cortactin/WAVE1-Arp2/3 complex. The control of these proteins is tightly orchestrated by phosphorylation, where kinases and phosphatases are essential for actin nucleation and, finally, DS formation. This work provides a deeper understanding of the biological actions of sex steroids in the regulation of DS turnover and neuronal plasticity processes.
Topics: Actin-Related Protein 2-3 Complex; Animals; Cerebral Cortex; Cortactin; Cyclin-Dependent Kinase 5; Dendritic Spines; Embryo, Mammalian; Estradiol; Progesterone; Protein Kinase Inhibitors; Protein Phosphatase 2; Rats; Roscovitine; Signal Transduction; Wiskott-Aldrich Syndrome Protein Family
PubMed: 31509830
DOI: 10.1159/000503310 -
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 -
Molecular Autism May 2020Autism spectrum disorder (ASD) is a brain disorder that involves changes in neuronal connections. Abnormal morphology of dendritic spines on postsynaptic neurons has... (Review)
Review
Autism spectrum disorder (ASD) is a brain disorder that involves changes in neuronal connections. Abnormal morphology of dendritic spines on postsynaptic neurons has been observed in ASD patients and transgenic mice that model different monogenetic causes of ASD. A number of ASD-associated genetic variants are known to disrupt dendritic local protein synthesis, which is essential for spine morphogenesis, synaptic transmission, and plasticity. Most of our understanding on the molecular mechanism underlying ASD depends on studies using rodents. However, recent advance in human pluripotent stem cells and their neural differentiation provides a powerful alternative tool to understand the cellular aspects of human neurological disorders. In this review, we summarize recent progress on studying mRNA targeting and local protein synthesis in stem cell-derived neurons, and discuss how perturbation of these processes may impact synapse development and functions that are relevant to cognitive deficits in ASD.
Topics: Animals; Autism Spectrum Disorder; Biomarkers; Cell Differentiation; Dendritic Spines; Disease Susceptibility; Gene Expression Regulation; Humans; Morphogenesis; Mutation; Neurons; Pluripotent Stem Cells; Protein Biosynthesis; RNA, Messenger
PubMed: 32460854
DOI: 10.1186/s13229-020-00349-y -
Brain, Behavior, and Immunity Oct 2021Autoantibodies targeting the GluA3 subunit of AMPA receptors (AMPARs) have been found in patients with Rasmussen's encephalitis and different types of epilepsy and were...
Autoantibodies targeting the GluA3 subunit of AMPA receptors (AMPARs) have been found in patients with Rasmussen's encephalitis and different types of epilepsy and were associated with the presence of learning and attention deficits. Our group recently identified the presence of anti-GluA3 immunoglobulin G (IgG) in about 25% of patients with frontotemporal dementia (FTD), thus suggesting a novel pathogenetic role also in chronic neurodegenerative diseases. However, the in vivo behavioral, molecular and morphological effects induced these antibodies are still unexplored. We injected anti-GluA3 IgG purified from the serum of FTD patients, or control IgG, in mice by intracerebroventricular infusion. Biochemical analyses showed a reduction of synaptic levels of GluA3-containing AMPARs in the prefrontal cortex (PFC), and not in the hippocampus. Accordingly, animals injected with anti-GluA3 IgG showed significant changes in recognition memory and impairments in social behavior and in social cognitive functions. As visualized by confocal imaging, functional outcomes were paralleled by profound alterations of dendritic spine morphology in the PFC. All observed behavioral, molecular and morphological alterations were transient and not detected 10-14 days from anti-GluA3 IgG injection. Overall, our in vivo preclinical data provide novel insights into autoimmune encephalitis associated with anti-GluA3 IgG and indicate an additional pathological mechanism affecting the excitatory synapses in FTD patients carrying anti-GluA3 IgG that could contribute to clinical symptoms.
Topics: Animals; Autoantibodies; Dendritic Spines; Hippocampus; Humans; Mice; Receptors, AMPA; Synapses
PubMed: 34246733
DOI: 10.1016/j.bbi.2021.07.001