Oligodendrocyte precursor cells engulf synapses during circuit remodeling in mice.
Ontology highlight
ABSTRACT:
SUBMITTER: Auguste YSS
PROVIDER: S-EPMC9534756 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
Publications
Oligodendrocyte precursor cells engulf synapses during circuit remodeling in mice.
Auguste Yohan S S YSS Ferro Austin A Kahng Jessica A JA Xavier Andre M AM Dixon Jessica R JR Vrudhula Uma U Nichitiu Anne-Sarah AS Rosado Daniele D Wee Tse-Luen TL Pedmale Ullas V UV Cheadle Lucas L
Nature neuroscience 20220928 10
Oligodendrocyte precursor cells (OPCs) give rise to myelinating oligodendrocytes throughout life, but the functions of OPCs are not limited to oligodendrogenesis. Here we show that OPCs contribute to thalamocortical presynapse elimination in the developing and adult mouse visual cortex. OPC-mediated synapse engulfment increases in response to sensory experience during neural circuit refinement. Our data suggest that OPCs may regulate synaptic connectivity in the brain independently of oligodendr ...[more]
Similar Datasets
Project description:Many oligodendrocyte precursor cells (OPCs) do not differentiate to form myelin, suggesting additional roles of this cell population. The zebrafish optic tectum contains OPCs in regions devoid of myelin. Elimination of these OPCs impaired precise control of retinal ganglion cell axon arbor size during formation and maturation of retinotectal connectivity and degraded functional processing of visual stimuli. Therefore, OPCs fine-tune neural circuits independently of their canonical role to make myelin.
| S-EPMC8904260 | biostudies-literature
Project description:Following stroke-induced neuronal damage, quiescent oligodendrocyte precursors (OPCs) are activated to proliferate and later to differentiate to myelin-producing cells. GPR17, a receptor transiently expressed on early OPCs, has emerged as a target to implement stroke repair through stimulation of OPC maturation. However, being GPR17 completely downregulated in myelin-producing oligodendrocytes, its actual role in determining the final fate of OPCs after cerebral ischemia is still uncertain. Here, to univocally define the spatiotemporal changes and final fate of GPR17-expressing OPCs, we induced ischemia by middle cerebral artery occlusion (MCAo) in reporter GPR17iCreERT2:CAG-eGreen florescent protein (GFP) mice, in which, upon tamoxifen treatment, cells expressing GPR17 become green and traceable for their entire life. Starting from 3 days and up to 2 weeks after MCAo, GFP+ cells markedly accumulated in regions surrounding the ischemic lesion; several of them proliferated, as shown by co-labeling of the DNA synthesis marker 5-Bromo-2'-deoxyuridine (BrdU). Almost all GFP+/BrdU+ cells expressed the OPC early marker neural/glial antigen 2 (NG2), indicating that they were still precursors. Accumulation of GFP+ cells was also because of OPC recruitment from surrounding areas, as suggested in vivo by acquisition of typical features of migrating OPCs, shown in vitro in presence of the chemoattractant PDGF-AA and confirmed by transplantation of GFP+-OPCs in wild-type MCAo mice. Eight weeks after MCAo, only some of these precociously recruited cells had undergone maturation as shown by NG2 loss and acquisition of mature myelinating markers like GSTpi. A pool of recruited GFP+-OPCs was kept at a precursor stage to likely make it available for further insults. Thus, very early after ischemia, GFP+-OPCs proliferate and migrate toward the lesion; however, most of these cells remain undifferentiated, suggesting functional roles other than myelination.
| S-EPMC5520912 | biostudies-literature
Project description:The myelin sheath, which is wrapped around axons, is a lipid-enriched structure produced by mature oligodendrocytes. Disruption of the myelin sheath is observed in several neurological diseases, such as multiple sclerosis. A crucial component of myelin is sphingomyelin, levels of which can be increased by ABCA8, a member of the ATP-binding cassette transporter family. ABCA8 is highly expressed in the cerebellum, specifically in oligodendroglia. However, whether ABCA8 plays a role in myelination and mechanisms that would underlie this role remain unknown. Here, we found that the absence of Abca8b, a mouse ortholog of ABCA8, led to decreased numbers of cerebellar oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes in mice. We show that in oligodendrocytes, ABCA8 interacts with chondroitin sulfate proteoglycan 4 (CSPG4), a molecule essential for OPC proliferation, migration, and myelination. In the absence of Abca8b, localization of CSPG4 to the plasma membrane was decreased, contributing to reduced cerebellar CSPG4 expression. Cerebellar CSPG4+ OPCs were also diminished, leading to decreased mature myelinating oligodendrocyte numbers and cerebellar myelination levels in Abca8b-/- mice. In addition, electron microscopy analyses showed that the number of nonmyelinated cerebellar axons was increased, whereas cerebellar myelin thickness (g-ratio), myelin sheath periodicity, and axonal diameter were all decreased, indicative of disordered myelin ultrastructure. In line with disrupted cerebellar myelination, Abca8b-/- mice showed lower cerebellar conduction velocity and disturbed locomotion. In summary, ABCA8 modulates cerebellar myelination, in part through functional regulation of the ABCA8-interacting protein CSPG4. Our findings suggest that ABCA8 disruption may contribute to the pathophysiology of myelin disorders.
| S-EPMC8953628 | biostudies-literature
Project description:NG2 protein-expressing oligodendrocyte progenitor cells (OPC) are a persisting and major glial cell population in the adult mammalian brain. Direct synaptic innervation of OPC by neurons throughout the brain together with their ability to sense neuronal network activity raises the question of additional physiological roles of OPC, supplementary to generating myelinating oligodendrocytes. In this study we investigated whether OPC express neuromodulatory factors, typically synthesized by other CNS cell types. Our results show that OPC express two well-characterized neuromodulatory proteins: Prostaglandin D2 synthase (PTGDS) and neuronal Pentraxin 2 (Nptx2/Narp). Expression levels of the enzyme PTGDS are influenced in cultured OPC by the NG2 intracellular region which can be released by cleavage and localizes to glial nuclei upon transfection. Furthermore PTGDS mRNA levels are reduced in OPC from NG2-KO mouse brain compared to WT cells after isolation by cell sorting and direct analysis. These results show that OPC can contribute to the expression of these proteins within the CNS and suggest PTGDS expression as a downstream target of NG2 signaling.
| S-EPMC4429067 | biostudies-literature
Project description:Oligodendrocytes are well known as myelin-forming cells in the central nervous system (CNS). However, detailed mechanisms of oligodendrocyte differentiation and myelination are poorly understood, particularly due to the difficulty of the purification of murine oligodendrocyte precursor cells (OPCs). We have recently established a transgenic mouse line that expresses a fluorescent protein Venus under the promoter of Sox10, whose expression is restricted to OPCs and oligodendrocytes in the CNS. Here, we have characterized Venus-positive cells from the Sox10-Venus mouse brain for analyzing oligodendrocyte differentiation. We first purified Venus-positive cells from the postnatal day 0-2 brain by flow cytometry. Most of the Venus-positive cells expressed NG2, an OPC marker. After induction of differentiation, an increased population of galactocerebroside-positive oligodendrocytes and decrease of OPCs were observed in the Venus-positive culture. Furthermore, a time-lapse analysis showed that Venus-positive oligodendrocytes dynamically changed their morphology with highly branched cell processes during differentiation. In addition, we found that Venus-positive OPCs were able to differentiate to type II astrocytes. In vivo, OPCs and oligodendrocytes express Venus, and some of astrocytes were positive for Venus in the ventral cortex. Taken together, the Sox10-Venus mouse system is useful for analyzing differentiation and multipotency of murine OPCs.
| S-EPMC5658394 | biostudies-literature
Project description:Oligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain, and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective adaptive (re)myelination. OPC differentiation requires significant genetic reprogramming, implicating chromatin remodeling. Mounting evidence indicates that chromatin remodelers play important roles during normal development and their mutations are associated with neurodevelopmental defects, with CHD7 haploinsuficiency being the cause of CHARGE syndrome and CHD8 being one of the strongest autism spectrum disorder (ASD) high-risk-associated genes. Herein, we report on uncharacterized functions of the chromatin remodelers Chd7 and Chd8 in OPCs. Their OPC-chromatin binding profile, combined with transcriptome and chromatin accessibility analyses of Chd7-deleted OPCs, demonstrates that Chd7 protects nonproliferative OPCs from apoptosis by chromatin closing and transcriptional repression of p53 Furthermore, Chd7 controls OPC differentiation through chromatin opening and transcriptional activation of key regulators, including Sox10, Nkx2.2, and Gpr17 However, Chd7 is dispensable for oligodendrocyte stage progression, consistent with Chd8 compensatory function, as suggested by their common chromatin-binding profiles and genetic interaction. Finally, CHD7 and CHD8 bind in OPCs to a majority of ASD risk-associated genes, suggesting an implication of oligodendrocyte lineage cells in ASD neurological defects. Our results thus offer new avenues to understand and modulate the CHD7 and CHD8 functions in normal development and disease.
| S-EPMC6126750 | biostudies-literature
Project description:Movement suppression in Parkinson's disease (PD) is thought to arise from increased efficacy of the indirect pathway basal ganglia circuit, relative to the direct pathway. However, the underlying pathophysiological mechanisms remain elusive. To examine whether changes in the strength of synaptic inputs to these circuits contribute to this imbalance, we obtained paired whole-cell recordings from striatal direct- and indirect-pathway medium spiny neurons (dMSNs and iMSNs) and optically stimulated inputs from sensorimotor cortex or intralaminar thalamus in brain slices from control and dopamine-depleted mice. We found that dopamine depletion selectively decreased synaptic strength at thalamic inputs to dMSNs, suggesting that thalamus drives asymmetric activation of basal ganglia circuitry underlying parkinsonian motor impairments. Consistent with this hypothesis, in vivo chemogenetic and optogenetic inhibition of thalamostriatal terminals reversed motor deficits in dopamine-depleted mice. These results implicate thalamostriatal projections in the pathophysiology of PD and support interventions targeting thalamus as a potential therapeutic strategy.
| S-EPMC4760843 | biostudies-literature
Project description:Human cerebral cortex size and complexity has increased greatly during evolution. While increased progenitor diversity and enhanced proliferative potential play important roles in human neurogenesis and gray matter expansion, the mechanisms of human oligodendrogenesis and white matter expansion remain largely unknown. Here, we identify EGFR-expressing "Pre-OPCs" that originate from outer radial glial cells (oRGs) and undergo mitotic somal translocation (MST) during division. oRG-derived Pre-OPCs provide an additional source of human cortical oligodendrocyte precursor cells (OPCs) and define a lineage trajectory. We further show that human OPCs undergo consecutive symmetric divisions to exponentially increase the progenitor pool size. Additionally, we find that the OPC-enriched gene, PCDH15, mediates daughter cell repulsion and facilitates proliferation. These findings indicate properties of OPC derivation, proliferation, and dispersion important for human white matter expansion and myelination.
| S-EPMC7415734 | biostudies-literature
Project description:BackgroundAnisotropic reentrant excitation occurs in the remodeled substrate of the epicardial border zone (EBZ) of the 5-day infarcted canine heart. Reentry is stabilized because of the formation of functional lines of block. We hypothesized that regional differences of ionic currents in cells of the EBZ form these lines of block. Therefore, we first mapped reentrant circuits of sustained tachycardias, then dispersed cells (infarct zone cells, IZs) from the central common pathway of the circuit (IZc) as well as from the other side of the line of block (outer pathway, IZo) for study.Methods and resultsWe mapped reentrant circuits in the EBZ of infarcted hearts during sustained ventricular tachycardias (>30 seconds, n=17 episodes, cycle lengths=218+/-7.9 ms). INa density was reduced in both IZc and IZo, and the kinetic properties of IZc INa were markedly altered versus IZo. Structural remodeling of the sodium channel protein Nav1.5 occurred in IZs, with cell surface localization differing from normal cells. Both IZc and IZo have similar but reduced ICaL, whereas IZc showed changes in Ca2+ current kinetics with an acceleration of current decay. Computer simulations of the 2D EBZ showed that incorporating only differences between INa in IZc and IZo prevented stability of the reentrant circuit. Incorporating only differences between ICaL in the IZc and IZo cells also prevented stability of the circuit. However, incorporating both INa and ICaL current differences stabilized the simulated reentrant circuit, and lines of block formed between the 2 distinct regions.ConclusionsDespite differences in INa and ICaL properties in cells of the center and outer pathways of a reentrant circuit, the resulting changes in effective refractory periods tend to stabilize reentry in this remodeled substrate.
| S-EPMC4289139 | biostudies-literature
Project description:Oligodendrocyte precursor cell (OPC) migration is a mechanism involved in remyelination; these cells migrate from niches in the adult CNS. However, age and disease reduce the pool of OPCs; as a result, the remyelination capacity of the CNS decreases over time. Several experimental studies have introduced OPCs to the brain via direct injection or intrathecal administration. In this study, we used the nose-to brain pathway to deliver oligodendrocyte lineage cells (human oligodendroglioma (HOG) cells), which behave similarly to OPCs in vitro. To this end, we administered GFP-labelled HOG cells intranasally to experimental animals, which were subsequently euthanised at 30 or 60 days. Our results show that the intranasal route is a viable route to the CNS and that HOG cells administered intranasally migrate preferentially to niches of OPCs (clusters created during embryonic development and adult life). Our study provides evidence, albeit limited, that HOG cells either form clusters or adhere to clusters of OPCs in the brains of experimental animals.
| S-EPMC8509516 | biostudies-literature