Glutamate regulates intracellular calcium and gene expression in oligodendrocyte progenitors through the activation of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors.

Abstract

Oligodendrocytes and their progenitors (0-2A) express functional kainate-and DL-a-amino-3-hydroxy-5-methyl-4-isoxazoleproplonlc acid (AMPA)-preferring glutamate receptors. The physiological consequences of activation of these receptors were studied In pified rat cortical 0-2A progenitors and In the primary oligodendrocyte cell line Changes in the mRNA levels of a set of immediate early genes were studied and were correlated to Intracellular Ca2+ concentration, as measured by fura-2 Ca+ imaging. Both in CG-4 and in cortical 0-2A progenitors, basal mRNA levels of NGFI-A were much higher than c-fos, c-jun, or jun-b. In the forebrain and cerebellum, oligodendrocytes develop from progenitor cells that originate in the subventricular zone and migrate into gray and white matter in early postnatal life (1, 2). The developmental potential of oligodendrocyte progenitors (0-2A) is maintained when these cells are isolated, purified, and cultured in the presence of appropriate growth factors (3-5). 0-2A development depends on homologous and heterologous interactions with other cells in the central nervous system (6), including neurons, which may synthesize and release factors that are essential for 0-2A progenitor cell division and differentiation (7). Recently, a primary oligodendrocyte cell line (CG-4) has been described (5). CG-4 cells can be fully induced to differentiate into myelinating oligodendrocytes with the same time schedule as 0-2A progenitors purified and cultured from different parts ofthe brain (5). CG-4 progenitors sequentially express oligodendrocytespecific markers throughout their development (5, 8) and respond to the same growth factors that regulate 0-2A proliferation and differentiation (5).Cells of the oligodendrocyte lineage have been shown to express both ligand-and voltage-gated ionic channels (9-11). We have demonstrated, by electrophysiological and molecular analyses in CG-4 cells and cortical glia, that functional kainate-and DL-a-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid (AMPA)-preferring glutamate receptors are coexpressed in cells ofthe oligodendrocyte lineage (8,12). In 0-2A progenitor cells and mature oligodendrocytes, glutamate and structurally related compounds generated large depolarizing currents due to the opening of membrane cationic channels (8,12 Vellis (16). Both CG-4 and primary progenitors were grown in Dulbecco's modified Eagle's medium (DME)-N1, supplemented with 30% B-104 conditioned medium. Cultures enriched in 01+ oligodendrocytes were obtained by replacing the B-104 conditioned medium after 3 days with DME-N1 plus 0.5% fetal bovine Abbreviations: AMPA, DL-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; DNQX, 6,7-dinitroquinoxaline-2,3-dione; 1S,3R-ACPD, 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid;[Ca2+]i, intracellular calcium concentration; IEG, immediate early gene; NMDA, N-methyl-D-aspartate.

Diversity of Functional Astroglial Properties in the Respiratory Network

“…High expression of A-type K ϩ channels, ionotropic glutamate receptors from the AMPA type, and expression of the NG2 proteoglycan are characteristics of migrating and proliferating progenitor cells (Pende et al, 1994;Knutson et al, 1997;Wang et al, 2000;Diers-Fenger et al, 2001). We observed outwardly rectifying astrocytes in the ventral respiratory group and the hypoglossal nucleus of brainstem preparations, independent of their age.…”

“…Concerted action of ionotropic glutamate receptor-mediated depolarization and outwardly rectifying, voltage-gated potassium channel activation was found to be involved in the gene regulation of glial progenitor cells (Pende et al, 1994). AMPA receptor and outward rectifier expression could therefore serve as a marker for immature, undifferentiated, or progenitor cells [but see Matthias et al (2003)].…”

Glutamate receptor-mediated toxicity in optic nerve oligodendrocytes

“…And lastly, kainate induces oligodendrocyte death at concentrations that mainly activate kainate-selective receptors (18,21). In addition to toxicity, previous findings indicated that kainate actions, such as the induction of early genes, in cells of the oligodendroglial lineage can be mediated by both AMPA and kainate receptors (22). Thus, it appears that activation of these two receptor classes may contribute to the same overall biological effects in oligodendroglial cells.…”

“…The depolarization caused by activated AMPA and kainate receptors may open Ca 2ϩ channels located in the vicinity of these receptors. Because of that, we examined whether blocking of Ca 2ϩ channels with nimodipine, at concentrations known to block all voltage-gated Ca 2ϩ channels in at least oligodendrocyte progenitors (22), had a protective effect on the viability of these cells. Indeed, we found that this blocker only partially reversed the toxicity induced by kainate application.…”

Oligodendrocytes and Ischemic Brain Injury

“…Although mRNA encoding the N-methyl-Daspartate (NMDA) type of glutamate receptor subunits can be also detected in oligodendroglia (Yoshioka et al, 1995), most studies suggest that these cells lack expression of functional NMDA receptors (Wyllie et al, 1991;Borges et al, 1994;Pende et al, 1994;Liu and Almazan, 1995). AMPA and kainate receptor expression is especially prominent in oligodendrocyte progenitor cells (Barres et al, 1990;Wyllie et al, 1991;Kastritsis and McCarthy, 1993;Holzwarth et al, 1994), and there are fewer descriptions of functional glutamate receptors in differentiated oligodendrocytes.…”