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Allosteric potentiation of GABAA receptor promotes survival and maturation of oligodendroglial cells in vitro via Ca2+/CaMK/AKT signaling pathway.

Oligodendrocytes (OLs) and their precursor cells (OPCs) express specific receptors to GABA; however, the direct functional consequences of t … the myelination process in several experimental models, both in vitro and in vivo.NEW & NOTEWORTHY Oligodendrocyte precursor cells express GABAARs and release GABA into the extracellular milieu; however, direct consequences of receptor activation remain unclear. In this work, we demonstrate that positive allosteric modulation of the GABAAR increases cell survival in vitro and p …

Agenesis and Hypomyelination of Corpus Callosum in Mice Lacking Nsun5, an RNA Methyltransferase.

Williams-Beuren syndrome (WBS) is caused by microdeletions of 28 genes and is characterized by cognitive disorder and hypotrophic corpus callosum (CC). Nsun5 gene, which encodes cytosine-5 RNA methyltransferase, is located in the deletion loci of WBS. We have reported that single-gene knockout of Nsun5 (Nsun5-KO) in mice impairs spatial cognition. Herein, we report that postnatal day (PND) 60 Nsun5-KO mice showed the volumetric reduction of CC with a decline in the number of myelinated axons and loose myelin sheath. Nsun5 was highly expressed in callosal oligodendrocyte precursor cells (OPCs) …

Development of myelin mosaicism in the optic nerve of heterozygotes of the X-linked myelin-deficient (md) rat mutant.

The oligodendrocyte population of the optic nerve has been suggested to arise either from a radial migration of neuroepithelial cells of the optic stalk or from the longitudinal migration of progenitor cells into the optic nerve from the brain, via the optic chiasm. Female heterozygotes of the X-linked myelin deficient (md) rat trait show a marked mosaic pattern of myelination of the optic nerves. This degree of mosaicism is not observed in other parts of the central nervous system. A total of 235 optic nerves from female rats of from 3 weeks to 24 months of age were examined by light microsco

Microenvironmental Regulation of Central Nervous System Myelination and Remyelination.

Both myelination and remyelination in the central nervous system (CNS) rely on the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs). However, the microenvironment and underlying mechanisms of these two processes are significantly different. Myelination is driven by intrinsic developmental programs, whereas remyelination is triggered as a response to demyelinating injury. These distinct origins shape unique microenvironmental conditions that critically influence the respective processes. The microenvironment comprises, the extracellular matrix (ECM) a…

Spatial characterisation of TREM2 expression in actively demyelinating multiple sclerosis lesions supports its key roles in lipid metabolic pathways.

Reactive macrophages and microglia are predominant myeloid cell types in demyelinating multiple sclerosis (MS) lesions in the central nervous system (CNS). Triggering receptor expressed on myeloid cells-2 (TREM2) promotes clearance of myelin debris, supporting remyelination in preclinical models. However, the relevance of TREM2 in people with MS is less understood. We evaluated TREM2 expression and function in autopsy CNS tissues from individuals with and without MS. Spatial transcriptomics and gene co-expression network analysis revealed TREM2 expression in chronic active MS lesioned white ma

Robust Myelination of Regenerated Axons Induced by Combined Manipulations of GPR17 and Microglia.

Myelination facilitates rapid axonal conduction, enabling efficient communication across different parts of the nervous system. Here we examined mechanisms controlling myelination after injury and during axon regeneration in the central nervous system (CNS). Previously, we discovered multiple molecular pathways and strategies that could promote robust axon regrowth after optic nerve injury. However, regenerated axons remain unmyelinated, and the underlying mechanisms are elusive. In this study, we found that, in injured optic nerves, oligodendrocyte precursor cells (OPCs) undergo transient pro…

Single-Cell Approaches Define the Murine Leptomeninges: Cortical Brain Interface as a Distinct Cellular Neighborhood Composed of Neural and Non-neural Cell Types.

The interface barrier between the brain surface and the adjacent meninges is important for regulating exchanges of fluid, protein, and immun … relatively cell-sparse cortical layer 1 containing interneurons, microglia, parenchymal astrocytes, oligodendrocyte precursor cells, and oligodendrocytes. Except for the border astrocytes, layer 1 cells are not closely associated with the interface, suggesting that secreted ligands may be the major way the brain interface communicates with the underlying cortical parenchyma. Thu …

Early pathological changes in progressive multifocal leukoencephalopathy: a report of two asymptomatic cases occurring prior to the AIDS epidemic.

Serial sections of formalin-fixed, paraffin-embedded blocks from two asymptomatic, non-AIDS cases of progressive multifocal leukoencephalopathy (PML) were stained with a double-label immunocytochemical method for detection of glial fibrillary acidic protein and JC virus (JCV) capsid proteins and with luxol fast blue/hematoxylin-eosin. In case 1 small, rounded lesions of about 1-mm diameter were seen within a restricted area in the posterior part of the superior frontal gyrus of both cerebral hemispheres, suggesting an early manifestation of the disease. Fully developed demyelinated lesions of

Gsx2 regulates oligodendrocyte precursor formation in the zebrafish spinal cord.

Nervous system development relies on sequential and coordinated formation of diverse neurons and glia from neural progenitor cells (NPCs). In the spinal cord, NPCs of the pMN domain produce neurons early in development followed by oligodendrocyte precursor cells (OPCs), which subsequently differentiate as oligodendrocytes (OLs), the myelinating glia of the central nervous system. The mechanisms that specify neural progenitor cells to the OL lineage are not yet well understood. Using zebrafish as an experimental model system, we generated single-cell RNA sequencing and single-nuclei ATAC sequen…

Gsx2 Regulates Oligodendrocyte Precursor Formation in the Zebrafish Spinal Cord.

Nervous system development relies on sequential and coordinated formation of diverse neurons and glia from neural progenitor cells (NPCs). In the spinal cord, NPCs of the pMN domain produce neurons early in development followed by oligodendrocyte precursor cells (OPCs), which subsequently differentiate as oligodendrocytes (OLs), the myelinating glia of the central nervous system, later in development. The mechanisms that specify neural progenitor cells to the OL lineage are not yet well understood. Using zebrafish as an experimental model system, we generated single-cell RNA sequencing and sin…

Astrocytes promote TNF-mediated toxicity to oligodendrocyte precursors.

Neuroinflammation and increased production of tumor necrosis factor (TNF) in the CNS have been implicated in many neurological diseases including white matter disorders periventricular leukomalacia and multiple sclerosis. However, the exact role of TNF in these diseases and how it mediates oligodendrocyte injury remain unclear. Previously, we demonstrated that lipopolysaccharide (LPS) selectively kills oligodendrocyte precursors (preOLs) in a non-cell autonomous fashion through the induction of TNF in mixed glial cultures. Here, we report that activation of oligodendroglial, but not astroglial

Reversible inhibitory effects of interferon-gamma and tumour necrosis factor-alpha on oligodendroglial lineage cell proliferation and differentiation in vitro.

We have investigated the effects of the two prominent inflammatory cytokines, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), on oligodendroglial lineage cell development and survival. Purified oligodendrocytes and oligodendrocyte precursors obtained from neonatal rat brain primary cultures were subcultured in a defined, serum-free medium and exposed to IFN-gamma (1-100 U/ml, TNF-alpha (25-100 ng/ml) or both (100 U/ml and 50 ng/ml respectively) from day 1 to day 3 or from day 3 to day 6. While cell survival was not affected in any of the conditions tested, IFN-gamma

Arylsulfatase A Overexpressing Human iPSC-derived Neural Cells Reduce CNS Sulfatide Storage in a Mouse Model of Metachromatic Leukodystrophy.

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder resulting from a functional deficiency of arylsulfatase A (ARSA), an enzyme that catalyzes desulfation of 3-O-sulfogalactosylceramide (sulfatide). Lack of active ARSA leads to the accumulation of sulfatide in oligodendrocytes, Schwann cells and some neurons and triggers progressive demyelination, the neuropathological hallmark of MLD. Several therapeutic approaches have been explored, including enzyme replacement, autologous hematopoietic stem cell-based gene therapy, intracerebral gene therapy or cell-based gene del

Systems-Level Transcriptomic and Cellular Architecture of the Human Striatum in Schizophrenia and Bipolar Psychosis.

Psychosis involves striatal circuit dysfunction, but the regional molecular and cellular changes remain unclear. We re-analyzed 215 postmort … hrenia showed a consistently lower oligodendrocyte-lineage reference weight, whereas attribution to oligodendrocyte precursor cells specifically was method-dependent. Exploratory directional signatures (dopamine-adenosine, glutamate-calcium, Activin-SMAD, APP processing) remained supported in the caudate and putamen after direction-selection permutation conditional on fixed gene …

Гастродин поощряет миелиогенез CNS и смягчает демиелионирующее повреждение путем активации сигнала PI3K/AKT/mTOR.

Демиелинция является общей особенностью многочисленных неврологических расстройств, включая множественный склероз и лейкодистрофию. Хотя миелин может быть регенерирован самопроизвольно после травмы, этот процесс зачастую является неадекватным, что может привести к нейродегенерации и обострению неврологической дисфункции. Ряд наркотиков, направленных на содействие дифференциации клеток-прекурсоров олигодендроцитов (ОПК), привели к неудовлетворительным клиническим последствиям. В одном из недавних исследований стратегия дифференциации в пользу ОПС была переориентирована на укрепление миелиногене

Совпадение в аннотации оригинала
Demyelination is a common feature of numerous neurological disorders including multiple sclerosis and leukodystrophies. Although myelin can … and exacerbating neurological dysfunction. Several drugs aimed at promoting the differentiation of oligodendrocyte precursor cells (OPCs) have yielded unsatisfactory clinical effects. A recent study has shifted the strategy of pro-OPC differentiation towards enhancing myelinogenesis. In this study we identified the pro-myelinating drug using a zebrafish model. Five traditional …

Intermittent theta-burst stimulation alleviates hypoxia-ischemia-caused myelin damage and neurologic disability.

Neonatal hypoxia-ischemia (HI) results in behavioral deficits, characterized by neuronal injury and retarded myelin formation. To date, limi … sulting in oligodendrocyte (OL) dysfunction, including reduced proliferation and differentiation of oligodendrocyte precursor cells (OPCs), decreased OL survival, and compromised myelin in the corpus callosum (CC) and hippocampal dentate gyrus (DG). These alterations were concomitant with cognitive dysfunction and depression-like behaviors. Crucially, early iTBS treatment (15 G, …

Conditional Deletion of Foxg1 Delayed Myelination during Early Postnatal Brain Development.

FOXG1 (forkhead box G1) syndrome is a neurodevelopmental disorder caused by variants in the Foxg1 gene that affect brain structure and funct … platelet-derived growth factor receptor alpha (PDGFRα) signaling and reduced the cell cycle exit of oligodendrocyte precursor cells (OPCs), leading to their excessive proliferation and delayed maturation. Additionally, Foxg1 deletion increased the expression of Hes5, a myelin formation inhibitor, as well as Olig2 and Sox10, two promoters of OPC differentiation. Our results revea …

Progressive myelination of the retinal nerve fibre layer associated with a lamina cribrosa cleft.

Myelination of the retinal nerve fibre layer (MNFL) is generally an incidental asymptomatic finding on fundus exam. While MNFL is thought to … cup and optic stalk. This case offers support for the concept that defects in lamina cribrosa allow oligodendrocyte precursor cells to enter the retina, where they may later proliferate and differentiate to form MNFL.

Multipotential neural precursors transplanted into the metachromatic leukodystrophy brain fail to generate oligodendrocytes but contribute to limit brain dysfunction.

Neural stem cells appear to be best suited for regenerative therapy in neurological diseases. However, the effects of high levels of potentially toxic substances such as sulfatides--which accumulate in metachromatic leukodystrophy (MLD)--on this regenerative ability are still largely unclear. To start addressing this question, in vitro and in vivo experiments were used to examine the behavior of multipotential neural precursors exposed to abnormally high levels of sulfatides. Following transplantation of dissociated neurospheres into the brain of presymptomatic MLD pups, the majority of donor-

Oxycodone induces HMGB1-mediated neuroimmune crosstalk between oligodendrocytes and microglia.

Emerging evidence implicates opioid exposure in glial dysfunction and neuroimmune signaling. However, the role of oligodendrocytes in opioid-induced neuroinflammation remains poorly understood. Here, we demonstrate that oxycodone exposure upregulated high mobility group box 1 (HMGB1), a danger-associated molecular pattern (DAMP), in mature oligodendrocytes (OLs) but not oligodendrocyte precursor cells (OPCs). Oxycodone treatment significantly increased cytoplasmic translocation and extracellular release of HMGB1, which was blocked by opioid receptor antagonist naloxone. These effects occurred …