NMDA Receptor Signaling in Oligodendrocyte Progenitors Is Not Required for Oligodendrogenesis and Myelination

The Solomon H. Snyder Department of Neuroscience and Department of Neurology, Johns Hopkins University, Baltimore, Maryland 21205, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/2011; 31(35):12650-62. DOI: 10.1523/JNEUROSCI.2455-11.2011
Source: PubMed


Oligodendrocyte precursor cells (OPCs) express NMDA receptors (NMDARs) and form synapses with glutamatergic neurons throughout the CNS. Although glutamate influences the proliferation and maturation of these progenitors in vitro, the role of NMDAR signaling in oligodendrogenesis and myelination in vivo is not known. Here, we investigated the consequences of genetically deleting the obligatory NMDAR subunit NR1 from OPCs and their oligodendrocyte progeny in the CNS of developing and mature mice. NMDAR-deficient OPCs proliferated normally, achieved appropriate densities in gray and white matter, and differentiated to form major white matter tracts without delay. OPCs also retained their characteristic physiological and morphological properties in the absence of NMDAR signaling and were able to form synapses with glutamatergic axons. However, expression of calcium-permeable AMPA receptors (AMPARs) was enhanced in NMDAR-deficient OPCs. These results suggest that NMDAR signaling is not used to control OPC development but to regulate AMPAR-dependent signaling with surrounding axons, pointing to additional functions for these ubiquitous glial cells.

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    • "Right: Nonsynaptically released neurotransmitters from axons or astrocytes can exert a more generalized effect on multiple NG2 cells in the micro-region. and remyelination after cuprizone induced demyelination (Li et al., 2013), whereas NG2 cell-specific knockout of NMDA receptor NR1 subunit did not alter NG2 cell morphology, membrane properties, proliferation, or oligodendrocyte differentiation with the exception of altering the expression of calcium permeable AMPA receptors (De Biase et al., 2011). "
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    ABSTRACT: NG2 cells (polydendrocytes) are the fourth major non-neuronal cell type in the central nervous system parenchyma. They exhibit diverse properties, ranging from their well-established role as oligodendrocyte precursors to their ability to respond to neurotransmitters released by synaptic and non-synaptic mechanisms. The functional diversity of NG2 cells has prompted the question of whether they represent a single cellular entity or multiple distinct cell populations. This review first summarizes recent findings on the nature and mechanism underlying the diversity of NG2 cells with regard to their proliferative and differentiation behavior. This will be followed by a synopsis of observations on how their microenvironment, particularly neuronal activity, influences their dynamic behavior, and how these changes in NG2 cells could in turn influence neural function and animal behavior. GLIA 2014
    Glia 08/2014; 62(8). DOI:10.1002/glia.22664 · 6.03 Impact Factor
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    • "When using NG2-DsRed mice to identify NG2 cells in cerebellar white matter at postnatal day 7–8 in our laboratory, we did not observe action potentials (n = 6, Kukley and Dietrich, unpublished observation) and the current clamp responses obtained were well in line with what is known from NG2 cells (Lin and Bergles, 2002). A number of other publications analyzing current clamp recordings of NG2 cells in different brain regions of rats and mice also did not observe action potentials in NG2 cells (Bergles et al., 2000; Chittajallu et al., 2004; Lin and Bergles, 2004; Lin et al., 2005; Ziskin et al., 2007; Mangin et al., 2008; Ge et al., 2009; Tong et al., 2009; De Biase et al., 2010, 2011). Nevertheless, it is clear that NG2 cells express a variable amount of voltage-activated sodium channels (Steinhauser et al., 1992; Gallo et al., 1996; Bergles et al., 2000; Diers-Fenger et al., 2001; Chittajallu et al., 2004; Lin and Bergles, 2004; Ge et al., 2006; Karadottir et al., 2008; Kukley et al., 2008; Ge et al., 2009; De Biase et al., 2010; Kukley et al., 2010; Clarke et al., 2012). "
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    ABSTRACT: NG2 expressing oligodendrocyte precursor cells stand out from other types of glial cells by receiving classical synaptic contacts from many neurons. This unconventional form of signaling between neurons and glial cells enables NG2 cells to receive information about the activity of presynaptic neurons with high temporal and spatial precision and has been postulated to be involved in activity-dependent myelination. While this still unproven concept is generally compelling, how NG2 cells may integrate synaptic input has hardly been addressed to date. Here we review the biophysical characteristics of synaptic currents and membrane properties of NG2 cells and discuss their capabilities to perform complex temporal and spatial signal integration and how this may be important for activity-dependent myelination.
    Frontiers in Cellular Neuroscience 12/2013; 7:255. DOI:10.3389/fncel.2013.00255 · 4.29 Impact Factor
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    • "The exact role of NMDA receptors during oligodendrocyte maturation is unclear (Matute et al., 2006; Cavaliere et al., 2012). There is evidence suggesting that NMDA receptor signaling in oligodendrocyte progenitors is not required for oligodendrogenesis and myelination (De Biase et al., 2011). Thus, genetic deletion of structural GluN1 from OPCs does not result in changes in proliferation, differentiation, or myelination. "
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    ABSTRACT: Multipotent cells from the juvenile subventricular zone (SVZ) possess the ability to differentiate into new neural cells. Depending on local signals, SVZ can generate new neurons, astrocytes, or oligodendrocytes. We previously demonstrated that activation of NMDA receptors in SVZ progenitors increases the rate of oligodendrocyte differentiation. Here we investigated the mechanisms involved in NMDA receptor-dependent differentiation. Using functional studies performed with the reporter gene luciferase we found that activation of NMDA receptor stimulates PKC. In turn, stimulation of PKC precedes the activation of NADPH oxidase (NOX) as demonstrated by translocation of the p67phox subunit to the cellular membrane. We propose that NOX2 is involved in the transduction of the signal from NMDA receptors through PKC activation as the inhibitor gp91 reduced their pro-differentiation effect. In addition, our data and that from other groups suggest that signaling through the NMDA receptor/PKC/NOX2 cascade generates ROS that activate the PI3/mTOR pathway and finally leads to the generation of new oligodendrocytes.
    Frontiers in Cellular Neuroscience 12/2013; 7:261. DOI:10.3389/fncel.2013.00261 · 4.29 Impact Factor
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