Journal articles on the topic 'Hippocampal neurons, synaptogenesis, Oligodendrocytes maturation'
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1
Ferreira, A. "Abnormal synapse formation in agrin-depleted hippocampal neurons." Journal of Cell Science 112, no. 24 (December 15, 1999): 4729–38. http://dx.doi.org/10.1242/jcs.112.24.4729.
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Agrin, a 200 kDa extracellular matrix protein, participates in the maturation of the postsynaptic target at the neuromuscular junction. Although agrin has also been detected in central neurons, little is known about its role in the formation of their synapses. In the present study, the pattern of expression, localization and function of agrin in developing hippocampal neurons were analyzed. The results indicate that an increase in agrin protein levels precedes synaptogenesis in cultured hippocampal neurons. This increase in agrin expression is accompanied by its extracellular deposition along the distal third of the axon. To investigate whether agrin plays a role during synapse formation, its expression in cultured hippocampal neurons was suppressed by means of antisense oligonucleotide treatment. The suppression of agrin expression results in the impairment of dendritic development and the formation of fewer synapses than in non-treated or sense-treated neurons. Moreover, this decreased synaptic density is accompanied by a selective inhibition of the clustering of GABA receptors. These results lead to the conclusion that agrin may be an important regulator of the maturation of dendrites and synaptogenesis in central neurons.
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Tsai, Yi-Wei, Yea-Ru Yang, Synthia H. Sun, Keng-Chen Liang, and Ray-Yau Wang. "Post Ischemia Intermittent Hypoxia Induces Hippocampal Neurogenesis and Synaptic Alterations and Alleviates Long-Term Memory Impairment." Journal of Cerebral Blood Flow & Metabolism 33, no. 5 (February 27, 2013): 764–73. http://dx.doi.org/10.1038/jcbfm.2013.15.
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Adult hippocampal neurogenesis is important for learning and memory, especially after a brain injury such as ischemia. Newborn hippocampal neurons contribute to memory performance by establishing functional synapses with target cells. This study demonstrated that the maturation of hippocampal neurons is enhanced by postischemia intermittent hypoxia (IH) intervention. The effects of IH intervention in cultured neurons were mediated by increased synaptogenesis, which was primarily regulated by brain-derived neurotrophic factor (BDNF)/PI3K/AKT. Hippocampal neo-neurons expressed BDNF and exhibited enhanced presynaptic function as indicated by increases in the pSynapsin expression, synaptophysin intensity, and postsynapse density following IH intervention after ischemia. Postischemia IH-induced hippocampal neo-neurons were affected by presynaptic activity, which reflected the dynamic plasticity of the glutamatergic receptors. These alterations were also associated with the alleviation of ischemia-induced long-term memory impairment. Our results suggest that postischemia IH intervention rescued ischemia-induced spatial learning and memory impairment by inducing hippocampal neurogenesis and functional synaptogenesis via BDNF expression.
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Schmitt, Andrea, Laura Tatsch, Alisa Vollhardt, Thomas Schneider-Axmann, Florian J. Raabe, Lukas Roell, Helmut Heinsen, Patrick R. Hof, Peter Falkai, and Christoph Schmitz. "Decreased Oligodendrocyte Number in Hippocampal Subfield CA4 in Schizophrenia: A Replication Study." Cells 11, no. 20 (October 15, 2022): 3242. http://dx.doi.org/10.3390/cells11203242.
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Hippocampus-related cognitive deficits in working and verbal memory are frequent in schizophrenia, and hippocampal volume loss, particularly in the cornu ammonis (CA) subregions, was shown by magnetic resonance imaging studies. However, the underlying cellular alterations remain elusive. By using unbiased design-based stereology, we reported a reduction in oligodendrocyte number in CA4 in schizophrenia and of granular neurons in the dentate gyrus (DG). Here, we aimed to replicate these findings in an independent sample. We used a stereological approach to investigate the numbers and densities of neurons, oligodendrocytes, and astrocytes in CA4 and of granular neurons in the DG of left and right hemispheres in 11 brains from men with schizophrenia and 11 brains from age- and sex-matched healthy controls. In schizophrenia, a decreased number and density of oligodendrocytes was detected in the left and right CA4, whereas mean volumes of CA4 and the DG and the numbers and density of neurons, astrocytes, and granular neurons were not different in patients and controls, even after adjustment of variables because of positive correlations with postmortem interval and age. Our results replicate the previously described decrease in oligodendrocytes bilaterally in CA4 in schizophrenia and point to a deficit in oligodendrocyte maturation or a loss of mature oligodendrocytes. These changes result in impaired myelination and neuronal decoupling, both of which are linked to altered functional connectivity and subsequent cognitive dysfunction in schizophrenia.
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Maqueshudul Haque Bhuiyan, Mohammad, Md Mohibbullah, Md Abdul Hannan, Yong-Ki Hong, Jae-Suk Choi, In Soon Choi, and Il Soo Moon. "Undaria pinnatifida Promotes Spinogenesis and Synaptogenesis and Potentiates Functional Presynaptic Plasticity in Hippocampal Neurons." American Journal of Chinese Medicine 43, no. 03 (January 2015): 529–42. http://dx.doi.org/10.1142/s0192415x15500330.
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Reductions in neurotrophic factors are implicated in synaptic dysfunction in the central nervous system, but exogenous neurotrophic factors with potential effects on neuritic regeneration and synaptic reconstruction could offer therapeutic and preventive strategies for treating memory-related neurological disorders. In an earlier effort to identify natural neurotrophic agents, we found that the ethanol extract of the edible marine alga Undaria pinnatifida (UPE) had promising effects on the neuritogenesis of cultured hippocampal neurons. Here, we further investigated the ability of UPE to promote spinogenesis and synaptogenesis in primary cultures of hippocampal neurons. It was found that UPE triggered significant increase in numbers of dendritic filopodia and spines, promoted the formation of excitatory and inhibitory synapses, and potentiated synaptic transmission by increasing the sizes of reserve vesicle pools at presynaptic terminals. These findings indicate a substantial role for UPE in the morphological and functional maturation of neurons and suggest that UPE is a possible therapeutic preventative measure and treatment for neurodegenerative diseases, such as those involving cognitive disorders and memory impairments.
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Varoqueaux, Frédérique, Michèle S. Sons, Jaap J. Plomp, and Nils Brose. "Aberrant Morphology and Residual Transmitter Release at the Munc13-Deficient Mouse Neuromuscular Synapse." Molecular and Cellular Biology 25, no. 14 (July 2005): 5973–84. http://dx.doi.org/10.1128/mcb.25.14.5973-5984.2005.
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ABSTRACT In cultured hippocampal neurons, synaptogenesis is largely independent of synaptic transmission, while several accounts in the literature indicate that synaptogenesis at cholinergic neuromuscular junctions in mammals appears to partially depend on synaptic activity. To systematically examine the role of synaptic activity in synaptogenesis at the neuromuscular junction, we investigated neuromuscular synaptogenesis and neurotransmitter release of mice lacking all synaptic vesicle priming proteins of the Munc13 family. Munc13-deficient mice are completely paralyzed at birth and die immediately, but form specialized neuromuscular endplates that display typical synaptic features. However, the distribution, number, size, and shape of these synapses, as well as the number of motor neurons they originate from and the maturation state of muscle cells, are profoundly altered. Surprisingly, Munc13-deficient synapses exhibit significantly increased spontaneous quantal acetylcholine release, although fewer fusion-competent synaptic vesicles are present and nerve stimulation-evoked secretion is hardly elicitable and strongly reduced in magnitude. We conclude that the residual transmitter release in Munc13-deficient mice is not sufficient to sustain normal synaptogenesis at the neuromuscular junction, essentially causing morphological aberrations that are also seen upon total blockade of neuromuscular transmission in other genetic models. Our data confirm the importance of Munc13 proteins in synaptic vesicle priming at the neuromuscular junction but indicate also that priming at this synapse may differ from priming at glutamatergic and γ-aminobutyric acid-ergic synapses and is partly Munc13 independent. Thus, non-Munc13 priming proteins exist at this synapse or vesicle priming occurs in part spontaneously: i.e., without dedicated priming proteins in the release machinery.
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Ma, Dongliang, Su-In Yoon, Chih-Hao Yang, Guillaume Marcy, Na Zhao, Wan-Ying Leong, Vinu Ganapathy, et al. "Rescue of Methyl-CpG Binding Protein 2 Dysfunction-induced Defects in Newborn Neurons by Pentobarbital." Neurotherapeutics 12, no. 2 (March 10, 2015): 477–90. http://dx.doi.org/10.1007/s13311-015-0343-0.
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Abstract Rett syndrome is a neurodevelopmental disorder that usually arises from mutations or deletions in methyl-CpG binding protein 2 (MeCP2), a transcriptional regulator that affects neuronal development and maturation without causing cell loss. Here, we show that silencing of MeCP2 decreased neurite arborization and synaptogenesis in cultured hippocampal neurons from rat fetal brains. These structural defects were associated with alterations in synaptic transmission and neural network activity. Similar retardation of dendritic growth was also observed in MeCP2-deficient newborn granule cells in the dentate gyrus of adult mouse brains in vivo, demonstrating direct and cell-autonomous effects on individual neurons. These defects, caused by MeCP2 deficiency, were reversed by treatment with the US Food and Drug Administration-approved drug, pentobarbital, in vitro and in vivo, possibly caused by modulation of γ-aminobutyric acid signaling. The results indicate that drugs modulating γ-aminobutyric acid signaling are potential therapeutics for Rett syndrome.
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Kuczynska, Zuzanna, Erkan Metin, Michal Liput, and Leonora Buzanska. "Covering the Role of PGC-1α in the Nervous System." Cells 11, no. 1 (December 30, 2021): 111. http://dx.doi.org/10.3390/cells11010111.
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The peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a well-known transcriptional coactivator involved in mitochondrial biogenesis. PGC-1α is implicated in the pathophysiology of many neurodegenerative disorders; therefore, a deep understanding of its functioning in the nervous system may lead to the development of new therapeutic strategies. The central nervous system (CNS)-specific isoforms of PGC-1α have been recently identified, and many functions of PGC-1α are assigned to the particular cell types of the central nervous system. In the mice CNS, deficiency of PGC-1α disturbed viability and functioning of interneurons and dopaminergic neurons, followed by alterations in inhibitory signaling and behavioral dysfunction. Furthermore, in the ALS rodent model, PGC-1α protects upper motoneurons from neurodegeneration. PGC-1α is engaged in the generation of neuromuscular junctions by lower motoneurons, protection of photoreceptors, and reduction in oxidative stress in sensory neurons. Furthermore, in the glial cells, PGC-1α is essential for the maturation and proliferation of astrocytes, myelination by oligodendrocytes, and mitophagy and autophagy of microglia. PGC-1α is also necessary for synaptogenesis in the developing brain and the generation and maintenance of synapses in postnatal life. This review provides an outlook of recent studies on the role of PGC-1α in various cells in the central nervous system.
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Mahdipour, Ramin, Vahid Ebrahimi, Mahmoud Hosseini, Mohammad Soukhtanloo, Seyed HamidReza Rastegar-moghaddam, Amir Mohammad Malvandi, and Abbas Mohammadipour. "Maternal exposure to silicon dioxide nanoparticles reduces hippocampal neurogenesis and synaptogenesis and induces neurodegeneration in rat offspring hippocampus." Toxicology and Industrial Health 38, no. 1 (January 2022): 41–52. http://dx.doi.org/10.1177/07482337211058671.
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Silicon dioxide nanoparticles (SiO2-NPs) are among the most widely used nanoparticles because of their chemical-physical properties. Since most brain maturation occurs in the neonatal period in humans and many mammals, it is important to understand how NPs may affect this process. This study tested the hypothesis that SiO2-NPs from treated dams could affect the hippocampus of neonatal rats during lactation. Twenty-four pregnant rats, after delivery, were divided into three groups of control, SiO2-NPs (25 mg/kg) and SiO2-NPs (100 mg/kg). The rats were treated from 2nd to 21st days post-delivery by gavage and the effects of these NPs were evaluated in the offspring’s hippocampi to reveal the effects of maternal exposure to SiO2-NPs during lactation on the offspring’s hippocampi. The offspring in the SiO2-NPs groups had higher malondialdehyde concentration and lower antioxidant activity in the hippocampi than the non-treated control group. The mean number of doublecortin positive (DCX+) cells and synaptophysin expression in the hippocampi of the SiO2-NPs groups were significantly lower than the control group, whereas the mean number of dark neurons was significantly higher. Also, animals in the SiO2-NPs groups had a weak cognitive performance in adulthood. In conclusion, maternal exposure to SiO2-NPs via breastfeeding could affect offspring’s hippocampal neurogenesis and synaptogenesis, leading to impaired cognitive performance.
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Yuan, Yun, Chunyun Wu, and Eng-Ang Ling. "Heterogeneity of Microglia Phenotypes: Developmental, Functional and Some Therapeutic Considerations." Current Pharmaceutical Design 25, no. 21 (September 26, 2019): 2375–93. http://dx.doi.org/10.2174/1381612825666190722114248.
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Background: Microglia play a pivotal role in maintaining homeostasis in complex brain environment. They first exist as amoeboid microglial cells (AMCs) in the developing brain, but with brain maturation, they transform into ramified microglial cells (RMCs). In pathological conditions, microglia are activated and have been classified into M1 and M2 phenotypes. The roles of AMCs, RMCs and M1/M2 microglia phenotypes especially in pathological conditions have been the focus of many recent studies. Methods: Here, we review the early development of the AMCs and RMCs and discuss their specific functions with reference to their anatomic locations, immunochemical coding etc. M1 and M2 microglia phenotypes in different neuropathological conditions are also reviewed. Results: Activated microglia are engaged in phagocytosis, production of proinflammatory mediators, trophic factors and synaptogenesis etc. Prolonged microglia activation, however, can cause damage to neurons and oligodendrocytes. The M1 and M2 phenotypes featured prominently in pathological conditions are discussed in depth. Experimental evidence suggests that microglia phenotype is being modulated by multiple factors including external and internal stimuli, local demands, epigenetic regulation, and herbal compounds. Conclusion: Prevailing views converge that M2 polarization is neuroprotective. Thus, proper therapeutic designs including the use of anti-inflammatory drugs, herbal agents may be beneficial in suppression of microglial activation, especially M1 phenotype, for amelioration of neuroinflammation in different neuropathological conditions. Finally, recent development of radioligands targeting 18 kDa translocator protein (TSPO) in activated microglia may hold great promises clinically for early detection of brain lesion with the positron emission tomography.
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Korotchenko, Svetlana, Lorenzo A. Cingolani, Tatiana Kuznetsova, Luca Leonardo Bologna, Michela Chiappalone, and Alexander Dityatev. "Modulation of network activity and induction of homeostatic synaptic plasticity by enzymatic removal of heparan sulfates." Philosophical Transactions of the Royal Society B: Biological Sciences 369, no. 1654 (October 19, 2014): 20140134. http://dx.doi.org/10.1098/rstb.2014.0134.
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Heparan sulfates (HSs) are complex and highly active molecules that are required for synaptogenesis and long-term potentiation. A deficit in HSs leads to autistic phenotype in mice. Here, we investigated the long-term effect of heparinase I, which digests highly sulfated HSs, on the spontaneous bioelectrical activity of neuronal networks in developing primary hippocampal cultures. We found that chronic heparinase treatment led to a significant reduction of the mean firing rate of neurons, particularly during the period of maximal neuronal activity. Furthermore, firing pattern in heparinase-treated cultures often appeared as epileptiform bursts, with long periods of inactivity between them. These changes in network activity were accompanied by an increase in the frequency and amplitude of miniature postsynaptic excitatory currents, which could be described by a linear up-scaling of current amplitudes. Biochemically, we observed an upregulation in the expression of the glutamate receptor subunit GluA1, but not GluA2, and a strong increase in autophosphorylation of α and β Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), without changes in the levels of kinase expression. These data suggest that a deficit in HSs triggers homeostatic synaptic plasticity and drastically affects functional maturation of neural network.
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Cornelissen, Frans, Peter Verstraelen, Tobias Verbeke, Isabel Pintelon, Jean-Pierre Timmermans, Rony Nuydens, and Theo Meert. "Quantitation of Chronic and Acute Treatment Effects on Neuronal Network Activity Using Image and Signal Analysis." Journal of Biomolecular Screening 18, no. 7 (April 19, 2013): 807–19. http://dx.doi.org/10.1177/1087057113486518.
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Upon maturation, primary neuronal cultures form an interconnected network based on neurite outgrowth and synaptogenesis in which spontaneous electrical activity arises. Measurement of network activity allows quantification of neuronal health and maturation. A fluorescent indicator was used to monitor secondary calcium influxes after the occurrence of action potentials, allowing us to examine activity of hippocampal cultures via confocal live cell imaging. Subsequently, nuclear staining with DAPI allows accurate cell segmentation. To analyze the calcium recording in a robust, observer-independent manner, we implemented an automated image- and signal-processing algorithm and validated it against a visual, interactive procedure. Both methods yielded similar results on the emergence of synchronized activity and allowed robust quantitative measurement of acute and chronic modulation of drugs on network activity. Both the number of days in vitro (DIV) and neutralization of nerve growth factor (NGF) have a significant effect on synchronous burst frequency and correlation. Acute effects are demonstrated using 5-HT (serotonin) and ethylene glycol tetra-acetic acid. Automated analysis allowed measuring additional features, such as peak decay times and bursting frequency of individual neurons. Based on neuronal cell cultures in 96-well plates and accurate calcium recordings, the analysis method allows development of an integrated high-content screening assay. Because molecular biological techniques can be applied to assess the influence of genes on network activity, it is applicable for neurotoxicity or neurotrophics screening as well as development of in vitro disease models via, for example, pharmacologic manipulation or RNAi.
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Dauth, Stephanie, Maike M. Schmidt, Maren Rehders, Frank Dietz, Sørge Kelm, Ralf Dringen, and Klaudia Brix. "Characterisation and metabolism of astroglia-rich primary cultures from cathepsin K-deficient mice." Biological Chemistry 393, no. 9 (September 1, 2012): 959–70. http://dx.doi.org/10.1515/hsz-2012-0145.
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Abstract Cathepsin K is important for the brain, because its deficiency in mice is associated with a marked decrease in differentiated astrocytes and changes in neuronal patterning in the hippocampus as well as with learning and memory deficits. As cathepsin K activity is most prominent in hippocampal regions of wild type animals, we hypothesised alterations in astrocyte-mediated support of neurons as a potential mechanism underlying the impaired brain functions in cathepsin K-deficient mice. To address this hypothesis, we have generated and characterised astroglia-rich primary cell cultures from cathepsin K-deficient and wild type mice and compared these cultures for possible changes in metabolic support functions and cell composition. Interestingly, cells expressing the oligodendrocytic markers myelin-associated glycoprotein and myelin basic protein were more frequent in astroglia-rich cultures from cathepsin K-deficient mice. However, cell cultures from both genotypes were morphologically comparable and similar with respect to glucose metabolism. In addition, specific glutathione content, glutathione export and γ-glutamyl-transpeptidase activity remained unchanged, whereas the specific activities of glutathione reductase and glutathione-S-transferase were increased by around 50% in cathepsin K-deficient cultures. Thus, lack of cathepsin K in astroglia-rich cultures appears not to affect metabolic supply functions of astrocytes but to facilitate the maturation of oligodendrocytes.
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Choubey, Lisha, Jantzen C. Collette, and Karen Müller Smith. "Quantitative assessment of fibroblast growth factor receptor 1 expression in neurons and glia." PeerJ 5 (April 18, 2017): e3173. http://dx.doi.org/10.7717/peerj.3173.
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BackgroundFibroblast growth factors (FGFs) and their receptors (FGFRs) have numerous functions in the developing and adult central nervous system (CNS). For example, the FGFR1 receptor is important for proliferation and fate specification of radial glial cells in the cortex and hippocampus, oligodendrocyte proliferation and regeneration, midline glia morphology and soma translocation, Bergmann glia morphology, and cerebellar morphogenesis. In addition, FGFR1 signaling in astrocytes is required for postnatal maturation of interneurons expressing parvalbumin (PV). FGFR1 is implicated in synapse formation in the hippocampus, and alterations in the expression ofFgfr1and its ligand,Fgf2accompany major depression. Understanding which cell types expressFgfr1during development may elucidate its roles in normal development of the brain as well as illuminate possible causes of certain neuropsychiatric disorders.MethodsHere, we used a BAC transgenic reporter line to traceFgfr1expression in the developing postnatal murine CNS. The specific transgenic line employed was created by the GENSAT project,tgFGFR1-EGFPGP338Gsat, and includes a gene encoding enhanced green fluorescent protein (EGFP) under the regulation of theFgfr1promoter, to traceFgfr1expression in the developing CNS. Unbiased stereological counts were performed for several cell types in the cortex and hippocampus.ResultsThis model reveals thatFgfr1is primarily expressed in glial cells, in both astrocytes and oligodendrocytes, along with some neurons. Dual labeling experiments indicate that the proportion of GFP+ (Fgfr1+) cells that are also GFAP+ increases from postnatal day 7 (P7) to 1 month, illuminating dynamic changes inFgfr1expression during postnatal development of the cortex. In postnatal neurogenic areas, GFP expression was also observed in SOX2, doublecortin (DCX), and brain lipid-binding protein (BLBP) expressing cells.Fgfr1is also highly expressed in DCX positive cells of the dentate gyrus (DG), but not in the rostral migratory stream.Fgfr1driven GFP was also observed in tanycytes and GFAP+ cells of the hypothalamus, as well as in Bergmann glia and astrocytes of the cerebellum.ConclusionsThetgFGFR1-EGFPGP338Gsatmouse model expresses GFP that is congruent with known functions of FGFR1, including hippocampal development, glial cell development, and stem cell proliferation. Understanding which cell types expressFgfr1may elucidate its role in neuropsychiatric disorders and brain development.
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Clarke, Laura E., Shane A. Liddelow, Chandrani Chakraborty, Alexandra E. Münch, Myriam Heiman, and Ben A. Barres. "Normal aging induces A1-like astrocyte reactivity." Proceedings of the National Academy of Sciences 115, no. 8 (February 7, 2018): E1896—E1905. http://dx.doi.org/10.1073/pnas.1800165115.
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The decline of cognitive function occurs with aging, but the mechanisms responsible are unknown. Astrocytes instruct the formation, maturation, and elimination of synapses, and impairment of these functions has been implicated in many diseases. These findings raise the question of whether astrocyte dysfunction could contribute to cognitive decline in aging. We used the Bac-Trap method to perform RNA sequencing of astrocytes from different brain regions across the lifespan of the mouse. We found that astrocytes have region-specific transcriptional identities that change with age in a region-dependent manner. We validated our findings using fluorescence in situ hybridization and quantitative PCR. Detailed analysis of the differentially expressed genes in aging revealed that aged astrocytes take on a reactive phenotype of neuroinflammatory A1-like reactive astrocytes. Hippocampal and striatal astrocytes up-regulated a greater number of reactive astrocyte genes compared with cortical astrocytes. Moreover, aged brains formed many more A1 reactive astrocytes in response to the neuroinflammation inducer lipopolysaccharide. We found that the aging-induced up-regulation of reactive astrocyte genes was significantly reduced in mice lacking the microglial-secreted cytokines (IL-1α, TNF, and C1q) known to induce A1 reactive astrocyte formation, indicating that microglia promote astrocyte activation in aging. Since A1 reactive astrocytes lose the ability to carry out their normal functions, produce complement components, and release a toxic factor which kills neurons and oligodendrocytes, the aging-induced up-regulation of reactive genes by astrocytes could contribute to the cognitive decline in vulnerable brain regions in normal aging and contribute to the greater vulnerability of the aged brain to injury.
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Romeo, Ramona, Kristin Glotzbach, Anja Scheller, and Andreas Faissner. "Deletion of LRP1 From Astrocytes Modifies Neuronal Network Activity in an in vitro Model of the Tripartite Synapse." Frontiers in Cellular Neuroscience 14 (January 14, 2021). http://dx.doi.org/10.3389/fncel.2020.567253.
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The low-density lipoprotein receptor-related protein 1 (LRP1) is a transmembrane receptor that binds over 40 potential ligands and is involved in processes such as cell differentiation, proliferation, and survival. LRP1 is ubiquitously expressed in the organism and enriched among others in blood vessels, liver, and the central nervous system (CNS). There, it is strongly expressed by neurons, microglia, immature oligodendrocytes, and astrocytes. The constitutive LRP1 knockout leads to embryonic lethality. Therefore, previous studies focused on conditional LRP1-knockout strategies and revealed that the deletion of LRP1 causes an increased differentiation of neural stem and precursor cells into astrocytes. Furthermore, astrocytic LRP1 is necessary for the degradation of Aβ and the reduced accumulation of amyloid plaques in Alzheimer’s disease. Although the role of LRP1 in neurons has intensely been investigated, the function of LRP1 with regard to the differentiation and maturation of astrocytes and their functionality is still unknown. To address this question, we generated an inducible conditional transgenic mouse model, where LRP1 is specifically deleted from GLAST-positive astrocyte precursor cells. The recombination with resulting knockout events was visualized by the simultaneous expression of the fluorescent reporter tdTomato. We observed a significantly increased number of GLT-1 expressing astrocytes in LRP1-depleted astrocytic cultures in comparison to control astrocytes. Furthermore, we investigated the influence of astrocytic LRP1 on neuronal activity and synaptogenesis using the co-culture of hippocampal neurons with control or LRP1-depleted astrocytes. These analyses revealed that the LRP1-deficient astrocytes caused a decreased number of single action potentials as well as a negatively influenced neuronal network activity. Moreover, the proportion of pre- and postsynaptic structures was significantly altered in neurons co-cultured with LPR1-depleted astrocytes. However, the number of structural synapses was not affected. Additionally, the supernatant of hippocampal neurons co-cultured with LRP1-deficient astrocytes showed an altered set of cytokines in comparison to the control condition, which potentially contributed to the altered neuronal transmission and synaptogenesis. Our results suggest astrocytic LRP1 as a modulator of synaptic transmission and synaptogenesis by altering the expression of the glutamate transporter on the cell surface on astrocytes and the release of cytokines in vitro.
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Saglam-Metiner, Pelin, Utku Devamoglu, Yagmur Filiz, Soheil Akbari, Goze Beceren, Bakiye Goker, Burcu Yaldiz, et al. "Spatio-temporal dynamics enhance cellular diversity, neuronal function and further maturation of human cerebral organoids." Communications Biology 6, no. 1 (February 14, 2023). http://dx.doi.org/10.1038/s42003-023-04547-1.
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AbstractThe bioengineerined and whole matured human brain organoids stand as highly valuable three-dimensional in vitro brain-mimetic models to recapitulate in vivo brain development, neurodevelopmental and neurodegenerative diseases. Various instructive signals affecting multiple biological processes including morphogenesis, developmental stages, cell fate transitions, cell migration, stem cell function and immune responses have been employed for generation of physiologically functional cerebral organoids. However, the current approaches for maturation require improvement for highly harvestable and functional cerebral organoids with reduced batch-to-batch variabilities. Here, we demonstrate two different engineering approaches, the rotating cell culture system (RCCS) microgravity bioreactor and a newly designed microfluidic platform (µ-platform) to improve harvestability, reproducibility and the survival of high-quality cerebral organoids and compare with those of traditional spinner and shaker systems. RCCS and µ-platform organoids have reached ideal sizes, approximately 95% harvestability, prolonged culture time with Ki-67 + /CD31 + /β-catenin+ proliferative, adhesive and endothelial-like cells and exhibited enriched cellular diversity (abundant neural/glial/ endothelial cell population), structural brain morphogenesis, further functional neuronal identities (glutamate secreting glutamatergic, GABAergic and hippocampal neurons) and synaptogenesis (presynaptic-postsynaptic interaction) during whole human brain development. Both organoids expressed CD11b + /IBA1 + microglia and MBP + /OLIG2 + oligodendrocytes at high levels as of day 60. RCCS and µ-platform organoids showing high levels of physiological fidelity a high level of physiological fidelity can serve as functional preclinical models to test new therapeutic regimens for neurological diseases and benefit from multiplexing.
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Benoit, Marc, Mabintou Darboe, Brati Das, Yingying Ge, John Zhou, Annie Yao, Wanxia He, Riqiang Yan, and Xiangyou Hu. "Postnatal neuronal Bace1 deletion impairs neuroblast and oligodendrocyte maturation." Human Molecular Genetics, November 12, 2022. http://dx.doi.org/10.1093/hmg/ddac282.
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Abstract BACE1 is largely expressed by neurons and is the sole β-secretase for initiating the production of neuronal β-amyloid peptides (Aβ). To fully understand the physiological functions of neuronal BACE1, we used mouse genetic approach coupled with unbiased single nucleus RNA sequencing (snRNAseq) to investigate how targeted deletion of Bace1 in neurons, driven by Thy-1-Cre recombinase, would affect functions in the nervous system. Our transcriptome results revealed that BACE1 is essential for maturation of neural precursor cells and oligodendrocytes in mice. RNA velocity analysis confirmed deficit in the trajectory of neuroblasts in reaching the immature granule neuron state in young Bace1fl/fl; Thy1-cre mice. Further analysis of differential gene expression indicated changes in genes important for SNARE signaling, tight junction signaling, synaptogenesis and insulin secretion pathways. Morphological studies revealed a hypomyelination in Bace1fl/fl;Thy1-cre sciatic nerves, but no detectable myelination changes in the corpus callosum, even though clear reduction in myelination proteins in the brain. Functional study showed reduction in long term potential, defects in synaptogenesis, and learning behavioral. Together, our results show that neuronal BACE1 is critical for optimal development of central and peripheral nervous system, and inhibition of neuronal BACE1 will result in deficits in synaptic functions and cognitive behaviors.
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Savino, Elisa, Romina Inès Cervigni, Miriana Povolo, Alessandra Stefanetti, Daniele Ferrante, Pierluigi Valente, Anna Corradi, Fabio Benfenati, Fabrizia Claudia Guarnieri, and Flavia Valtorta. "Proline-rich transmembrane protein 2 (PRRT2) regulates the actin cytoskeleton during synaptogenesis." Cell Death & Disease 11, no. 10 (October 2020). http://dx.doi.org/10.1038/s41419-020-03073-w.
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Abstract Mutations in proline-rich transmembrane protein 2 (PRRT2) have been recently identified as the leading cause of a clinically heterogeneous group of neurological disorders sharing a paroxysmal nature, including paroxysmal kinesigenic dyskinesia and benign familial infantile seizures. To date, studies aimed at understanding its physiological functions in neurons have mainly focused on its ability to regulate neurotransmitter release and neuronal excitability. Here, we show that PRRT2 expression in non-neuronal cell lines inhibits cell motility and focal adhesion turnover, increases cell aggregation propensity, and promotes the protrusion of filopodia, all processes impinging on the actin cytoskeleton. In primary hippocampal neurons, PRRT2 silencing affects the synaptic content of filamentous actin and perturbs actin dynamics. This is accompanied by defects in the density and maturation of dendritic spines. We identified cofilin, an actin-binding protein abundantly expressed at the synaptic level, as the ultimate effector of PRRT2. Indeed, PRRT2 silencing unbalances cofilin activity leading to the formation of cofilin-actin rods along neurites. The expression of a cofilin phospho-mimetic mutant (cof-S3E) is able to rescue PRRT2-dependent defects in synapse density, spine number and morphology, but not the alterations observed in neurotransmitter release. Our data support a novel function of PRRT2 in the regulation of the synaptic actin cytoskeleton and in the formation of synaptic contacts.
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Traetta, Marianela Evelyn, Martín Gabriel Codagnone, Nonthué Alejandra Uccelli, Alberto Javier Ramos, Sandra Zárate, and Analía Reinés. "Hippocampal neurons isolated from rats subjected to the valproic acid model mimic in vivo synaptic pattern: evidence of neuronal priming during early development in autism spectrum disorders." Molecular Autism 12, no. 1 (March 6, 2021). http://dx.doi.org/10.1186/s13229-021-00428-8.
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Abstract Background Autism spectrum disorders (ASD) are synaptopathies characterized by area-specific synaptic alterations and neuroinflammation. Structural and adhesive features of hippocampal synapses have been described in the valproic acid (VPA) model. However, neuronal and microglial contribution to hippocampal synaptic pattern and its time-course of appearance is still unknown. Methods Male pups born from pregnant rats injected at embryonic day 10.5 with VPA (450 mg/kg, i.p.) or saline (control) were used. Maturation, exploratory activity and social interaction were assessed as autistic-like traits. Synaptic, cell adhesion and microglial markers were evaluated in the CA3 hippocampal region at postnatal day (PND) 3 and 35. Primary cultures of hippocampal neurons from control and VPA animals were used to study synaptic features and glutamate-induced structural remodeling. Basal and stimuli-mediated reactivity was assessed on microglia primary cultures isolated from control and VPA animals. Results At PND3, before VPA behavioral deficits were evident, synaptophysin immunoreactivity and the balance between the neuronal cell adhesion molecule (NCAM) and its polysialylated form (PSA-NCAM) were preserved in the hippocampus of VPA animals along with the absence of microgliosis. At PND35, concomitantly with the establishment of behavioral deficits, the hippocampus of VPA rats showed fewer excitatory synapses and increased NCAM/PSA-NCAM balance without microgliosis. Hippocampal neurons from VPA animals in culture exhibited a preserved synaptic puncta number at the beginning of the synaptogenic period in vitro but showed fewer excitatory synapses as well as increased NCAM/PSA-NCAM balance and resistance to glutamate-induced structural synaptic remodeling after active synaptogenesis. Microglial cells isolated from VPA animals and cultured in the absence of neurons showed similar basal and stimuli-induced reactivity to the control group. Results indicate that in the absence of glia, hippocampal neurons from VPA animals mirrored the in vivo synaptic pattern and suggest that while neurons are primed during the prenatal period, hippocampal microglia are not intrinsically altered. Conclusions Our study suggests microglial role is not determinant for developing neuronal alterations or counteracting neuronal outcome in the hippocampus and highlights the crucial role of hippocampal neurons and structural plasticity in the establishment of the synaptic alterations in the VPA rat model.