Remyelination-oriented clemastine treatment attenuates neuropathies of optic nerve and retina in glaucoma.

As one of the top causes of blindness worldwide, glaucoma leads to diverse optic neuropathies such as degeneration of retinal ganglion cells (RGCs). It is widely accepted that the level of intraocular pressure (IOP) is a major risk factor in human glaucoma, and reduction of IOP level is the principally most well-known method to prevent cell death of RGCs. However, clinical studies show that lowering IOP fails to prevent RGC degeneration in the progression of glaucoma.

Replenishing the Aged Brains: Targeting Oligodendrocytes and Myelination?

Aging affects almost all the aspects of brain functions, but the mechanisms remain largely undefined. Increasing number of literatures have manifested the important role of glial cells in regulating the aging process. Oligodendroglial lineage cell is a major type of glia in central nervous system (CNS), composed of mature oligodendrocytes (OLs), and oligodendroglia precursor cells (OPCs).

DNA Hypermethylation Induced by L-Methionine Leads to Oligodendroglial and Myelin Deficits and Schizophrenia-Like Behaviors in Adolescent Mice.

Increasing evidence has demonstrated that in addition to dysfunction of neuronal circuitry, oligodendroglial dysfunction and/or disruption of white matter integrity are found in the brains of patients with schizophrenia. DNA methylation, a well-established risk factor for schizophrenia, has been demonstrated to cause neuronal dysfunction; however, whether dysregulation of DNA methylation contributes to oligodendroglial/myelin deficits in the pathogenesis of schizophrenia remains unclear. In the present study, by using L-methionine-treated mice, we confirmed that mice with DNA hypermethylation exhibited an anxious phenotype, impaired sociability, and sensorimotor gating deficits.

Myelin Deficits Caused by Olig2 Deficiency Lead to Cognitive Dysfunction and Increase Vulnerability to Social Withdrawal in Adult Mice.

Oligodendrocyte (OL) and myelin development are crucial for network integration and are associated with higher brain functions. Accumulating evidence has demonstrated structural and functional impairment of OLs and myelin in serious mental illnesses. However, whether these deficits contribute to the brain dysfunction or pathogenesis of such diseases still lacks direct evidence.

Aberrant oligodendroglial-vascular interactions disrupt the blood-brain barrier, triggering CNS inflammation.

Disruption of the blood-brain barrier (BBB) is critical to initiation and perpetuation of disease in multiple sclerosis (MS). We report an interaction between oligodendroglia and vasculature in MS that distinguishes human white matter injury from normal rodent demyelinating injury. We find perivascular clustering of oligodendrocyte precursor cells (OPCs) in certain active MS lesions, representing an inability to properly detach from vessels following perivascular migration.

Adenosine Actions on Oligodendroglia and Myelination in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is the most commonly diagnosed neurodevelopmental disorder. Independent of neuronal dysfunction, ASD and its associated comorbidities have been linked to hypomyelination and oligodendroglial dysfunction. Additionally, the neuromodulator adenosine has been shown to affect certain ASD comorbidities and symptoms, such as epilepsy, impairment of cognitive function, and anxiety.

Enhancing Oligodendrocyte Myelination Rescues Synaptic Loss and Improves Functional Recovery after Chronic Hypoxia.

To address the significance of enhancing myelination for functional recovery after white matter injury (WMI) in preterm infants, we characterized hypomyelination associated with chronic hypoxia and identified structural and functional deficits of excitatory cortical synapses with a prolonged motor deficit. We demonstrate that genetically delaying myelination phenocopies the synaptic and functional deficits observed in mice after hypoxia, suggesting that myelination may possibly facilitate excitatory presynaptic innervation. As a gain-of-function experiment, we specifically ablated the muscarinic receptor 1 (M1R), a negative regulator of oligodendrocyte differentiation in oligodendrocyte precursor cells.

The deletion of dicer in mature myelinating glial cells causes progressive axonal degeneration but not overt demyelination in adult mice.

Myelinating glial cells (MGCs), oligodendrocytes (OLs) in the central nervous system (CNS) and Schwann cells (SCs) in the peripheral nervous system (PNS), generate myelin sheaths that insulate axons. After myelination is completed in adulthood, MGC functions independent from myelin are required to support axon survival, but the underlying mechanisms are still unclear. Dicer is a key enzyme that is responsible for generating functional micro-RNAs (miRNAs).

Promoting oligodendroglial-oriented differentiation of glioma stem cell: a repurposing of quetiapine for the treatment of malignant glioma.

As a major contributor of chemotherapy resistance and malignant recurrence, glioma stem cells (GSCs) have been proposed as a target for the treatment of gliomas. To evaluate the therapeutic potential of quetiapine (QUE), an atypical antipsychotic, for the treatment of malignant glioma, we established mouse models with GSCs-initiated orthotopic xenograft gliomas and subcutaneous xenograft tumors, using GSCs purified from glioblastoma cell line GL261. We investigated antitumor effects of QUE on xenograft gliomas and its underlying mechanisms on GSCs.

Connexin-based channels contribute to metabolic pathways in the oligodendroglial lineage.

Oligodendrocyte precursor cells (OPCs) undergo a series of energy-consuming developmental events; however, the uptake and trafficking pathways for their energy metabolites remain unknown. In the present study, we found that 2-NBDG, a fluorescent glucose analog, can be delivered between astrocytes and oligodendrocytes through connexin-based gap junction channels but cannot be transferred between astrocytes and OPCs. Instead, connexin hemichannel-mediated glucose uptake supports OPC proliferation, and ethidium bromide uptake or increase of 2-NBDG uptake rate is correlated with intracellular Ca(2+) elevation in OPCs, indicating a Ca(2+)-dependent activation of connexin hemichannels.

Advancements in the Underlying Pathogenesis of Schizophrenia: Implications of DNA Methylation in Glial Cells.

Schizophrenia (SZ) is a chronic and severe mental illness for which currently there is no cure. At present, the exact molecular mechanism involved in the underlying pathogenesis of SZ is unknown. The disease is thought to be caused by a combination of genetic, biological, psychological, and environmental factors.

Aspirin Promotes Oligodendroglial Differentiation Through Inhibition of Wnt Signaling Pathway.

Aspirin, one of the most commonly used anti-inflammatory drugs, has been recently reported to display multiple effects in the central nervous system (CNS), including neuroprotection and upregulation of ciliary neurotrophic factor (CNTF) expression in astrocytes. Although it was most recently reported that aspirin could promote the proliferation and differentiation of oligodendrocyte precursor cells (OPCs) after white matter lesion, the underlying mechanisms remain unclear. To dissect the effects of aspirin on oligodendroglial development and explore possible mechanisms, we here demonstrated the following: (i) in vitro treatment of aspirin on OPC cultures significantly increased the number of differentiated oligodendrocytes (OLs) but had no effect on the number of proliferative OPCs, indicating that aspirin can promote OPC differentiation but not proliferation; (ii) in vivo treatment of aspirin on neonatal (P3) rats for 4 days led to a nearly twofold increase in the expression of myelin basic protein (MBP), devoid of change in OPC proliferaion, in the corpus callosum (CC); (iii) finally, aspirin treatment increased the phosphorylation level of β-catenin and counteracted Wnt signaling pathway synergist QS11-induced suppression on OPC differentiation.

Oligodendroglial Development: New Roles for Chromatin Accessibility.

In the central nervous system, the generation of mature oligodendrocytes from their progenitors is a critical step in myelination, which is essential for normal nervous system function. Thus, understanding the regulatory mechanism underlying oligodendroglial development is of great importance, especially for the development of new therapeutic strategies that promote remyelination in demyelinating diseases, such as multiple sclerosis. Previous studies have focused on genetic patterns and revealed a network of cell signaling pathways and related transcription factors involved in oligodendroglial lineage development.