Oligodendrocyte Precursor Cells Modulate the Neuronal Network by Activity-Dependent Ectodomain Cleavage of Glial NG2

Sakry, Dominik; Neitz, Angela; Singh, J. B.; Frischknecht, Renato; Marongiu, Daniele; Binamé, Fabien; Perera, Sumudhu S.; Endres, Kristina; Lutz, Beat; Radyushkin, Konstantin; Trotter, Jacqueline; Mittmann, Thomas

doi:10.1371/journal.pbio.1001993

Cited by 169 publications

(196 citation statements)

References 83 publications

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“…Recent studies have shown that myelination is essential for social experience-based cognition and motor skill learning [31][32][33] [34][35][36] , abnormalities of the myelin sheath may contribute to defects of neuronal function. Increasing evidence has shown that the impairment of white matter integrity is prominent in schizophrenic brains [10,11,14,15] and further underscores the importance of the myelin sheath in schizophrenia, pointing to myelin repair as a potential therapeutic strategy for schizophrenia.…”

Section: Resultsmentioning

confidence: 99%

Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination

et al. 2015

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Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia. But it is unknown whether enhancing remyelination is a beneficial approach to schizophrenia. To investigate this hypothesis, we used clemastine, an FDA-approved drug with high potency in promoting oligodendroglial differentiation and myelination, on a cuprizone-induced mouse model of demyelination. The mice exposed to cuprizone (0.2% in chow) for 6 weeks displayed schizophrenia-like behavioral changes, including decreased exploration of the center in the open fi eld test and increased entries into the arms of the Y-maze, as well as evident demyelination in the cortex and corpus callosum. Clemastine treatment was initiated upon cuprizone withdrawal at 10 mg/kg per day for 3 weeks. As expected, myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes (APC-positive) and myelin basic protein. More importantly, the clemastine treatment rescued the schizophrenia-like behavioral changes in the open field test and the Y-maze compared to vehicle, suggesting a beneficial effect via promoting myelin repair. Our fi ndings indicate that enhancing remyelination may be a potential therapy for schizophrenia.

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Section: Resultsmentioning

confidence: 99%

Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination

et al. 2015

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“…The NG2 ectodomain is shed from OPCs in response to neuronal activity, and then the domain in turn modulates the neuronal network. 58 However, oligodendrocyte lineage cells are not always supportive for neurons, especially after injury. Oligodendrocytederived myelin expresses Nogo-A protein, which works as an inhibitory molecule for axonal extension.…”

Section: Oligodendrocyte-neuron Interactionmentioning

confidence: 99%

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

Shindo

Liang

Maki

et al. 2015

J Cereb Blood Flow Metab

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Oligodendrocytes are one of the major cell types in cerebral white matter. Under normal conditions, they form myelin sheaths that encircle axons to support fast nerve conduction. Under conditions of cerebral ischemia, oligodendrocytes tend to die, resulting in white-matter dysfunction. Repair of white matter involves the ability of oligodendrocyte precursors to proliferate and mature. However, replacement of lost oligodendrocytes may not be the only mechanism for white-matter recovery. Emerging data now suggest that coordinated signaling between neural, glial, and vascular cells in the entire neurovascular unit may be required. In this mini-review, we discuss how oligodendrocyte lineage cells participate in signaling and crosstalk with other cell types to underlie function and recovery in various experimental models of subcortical white-matter injury.

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“…Synaptophysin-positive clusters indicative of a 'classical' secretory vesicle accumulation and release machinery have been observed at defined sites along the NG2 glia processes [41]. Other mechanisms of signal transfer have been also reported, including cleavage of fragments of membrane-bound molecules [98] or exosome shedding [99]. Signal transfer through exosomes allows cell-specific targeting by receptor-ligand interactions [100] and assures that a well defined concentration of the signal may be delivered to the target.…”

Section: Ng2 Glia-derived Signals Can Modulate Neuronal and Non-neuromentioning

confidence: 98%

Section: Neuregulinsmentioning

confidence: 99%

“…Sakry et al [98] showed that the ectodomain of the NG2 protein, constitutively released from the NG2 glia surface into the ECM by the ADAM10 secretase, influences AMPA receptor currents and kinetics at glutamatergic synapses of cortical pyramidal neurons. Moreover, the pharmacological inhibition of NG2 cleavage and release from NG2 glia resulted in a large reduction of NMDAR-dependent, long-term potentiation (LTP) at these synapses, indicating a specific role of NG2 in synaptic plasticity [98]. A further neuromodulatory function of NG2 has been attributed to its intracellular domain that regulates the expression of prostaglandin D2 synthase, a secreted enzyme that catalyzes the conversion of prostaglandin H2 to the neuromodulatory form prostaglandin D2 [154].…”

Section: Neuregulinsmentioning

confidence: 99%

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NG2 Glia: Novel Roles beyond Re-/Myelination

Parolisi

Boda

2018

Neuroglia

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Neuron-glia antigen 2-expressing glial cells (NG2 glia) serve as oligodendrocyte progenitors during development and adulthood. However, recent studies have shown that these cells represent not only a transitional stage along the oligodendroglial lineage, but also constitute a specific cell type endowed with typical properties and functions. Namely, NG2 glia (or subsets of NG2 glia) establish physical and functional interactions with neurons and other central nervous system (CNS) cell types, that allow them to constantly monitor the surrounding neuropil. In addition to operating as sensors, NG2 glia have features that are expected for active modulators of neuronal activity, including the expression and release of a battery of neuromodulatory and neuroprotective factors. Consistently, cell ablation strategies targeting NG2 glia demonstrate that, beyond their role in myelination, these cells contribute to CNS homeostasis and development. In this review, we summarize and discuss the advancements achieved over recent years toward the understanding of such functions, and propose novel approaches for further investigations aimed at elucidating the multifaceted roles of NG2 glia.

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Oligodendrocyte Precursor Cells Modulate the Neuronal Network by Activity-Dependent Ectodomain Cleavage of Glial NG2

Abstract: This study shows that the activity of neurons can trigger shedding of a protein, NG2, from the surface of oligodendrocyte precursor cells; this protein in turn modulates synaptic transmission, revealing a two-way conversation between neurons and glia.

Cited by 169 publications

References 83 publications

Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination

Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

NG2 Glia: Novel Roles beyond Re-/Myelination

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