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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    • "This body of evidence raises the possibility that direct neuron-glia signaling through synaptic connections could underlie myelin plasticity, potentially via the release of glutamate from axonal vesicles and the subsequent synthesis of MBP (Wake et al. 2011). However, conditional deletion of an NMDA receptor subunit in mouse oligodendroglial lineage cells did not cause deficits in developmental myelination in vivo; of note, possible compensation through AMPA receptor upregulation was observed (De Biase et al. 2011). More recent work has attempted to reconcile the diverse hypotheses surrounding glutamatergic signaling in oligodendroglial lineage cells. "
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    • "Ionotropic Glu receptors have primarily been associated with excitotoxicity (Matute, 2011) but they have also been implicated in the regulation of myelination (Lundgaard et al., 2013) and the preservation of neuronal integrity (Fruhbeis et al., 2013). Nevertheless, conditional deletion of the key receptor subunit of the NMDA subtype of iontropic Glu receptors in cells of the oligodendrocyte lineage was not found to lead to an apparent phenotype (De Biase et al., 2011; Guo et al., 2012). Thus, sodium-dependent Glu transporters emerge as good candidates for mediating Glu-evoked responses related to the maturation of differentiating oligodendrocytes. "

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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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