Oligodendrocyte progenitor cell proliferation and lineage progression are regulated by glutamate receptor-mediated K+ channel block

Abstract

We have analyzed the role of glutamate and its receptors (GluRs) in regulating the development of oligodendrocytes. Activation of AMPA-preferring GluRs with selective agonists inhibited proliferation of purified cortical oligodendrocyte progenitor (O-2A) cells cultured with different mitogens, as measured by [3H]thymidine incorporation or bromodeoxyuridine staining. In contrast, activation of GABA or muscarinic receptors did not affect O-2A proliferation. Cell viability and apoptosis assays demonstrated that the inhibition of O-2A proliferation was not attributable to a cytotoxic action of GluR agonists, and was reversible. Activation of GluRs prevented lineage progression from the O-2A (GD3+/nestin+) stage to the prooligodendroblast (O4+) stage, but did not affect O-2A migration. Additional experiments examined the membrane ionic channels mediating these GluR activation effects. We found that proliferating O-2A cells expressed functional delayed rectifier K+ channels, which were absent in pro-oligodendroblasts. GluR agonists and the K+ channel blocker tetraethylammonium (TEA) strongly inhibited delayed rectifier K+ currents in O-2A cells. TEA reproduced the effects of GluR activation on O-2A proliferation and lineage progression in the same concentration range that blocked delayed rectifier K+ currents. These results indicate that glutamate regulates oligodendrogenesis specifically at the O-2A stage by modulating K+ channel activity.

Initiation of Oligodendrocyte Progenitor Cell Migration by a PDGF-A Activated Extracellular Regulated Kinase (ERK) Signaling Pathway

“…2b). Our finding is consistent with previously published data [22]. This confirms that observed PDGF induced OP migration cannot be due to proliferation of cells distributed away from areas of high cell density.…”

“…1c). To further confirm that this PDGF-induced migration measure was not skewed by proliferation of OP cells, the glutamate receptor antagonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) was used to inhibit OP proliferation [22]. In our study, 200 μM AMPA had no effect on the extent of migration (Fig.…”

Electrophysiological Changes That Accompany Reactive GliosisIn Vitro

“…Specifically, the expression and/or activity of potassium channels have been linked to glial proliferation. Thus in O2-A cells (Gallo et al, 1996), Schwann cells (Chiu and Wilson, 1989), retinal glial cells (Puro et al, 1989), and spinal cord astrocytes (Pappas et al, 1994), blockade of K ϩ channels retards proliferation. Underlying mechanisms are not well understood, but studies suggest that intracellular pH (Pappas et al, 1994) or intracellular Na ϩ (Knutson et al, 1997) are critically important.…”

Prostaglandin E2 and 4‐Aminopyridine Prevent the Lipopolysaccharide‐Induced Outwardly Rectifying Potassium Current and Interleukin‐1β Production in Cultured Rat Microglia

“…The K+ OR is K+-selective, shows time-and voltage-dependent activation and inactivation, is blocked by Cs', and is inhibited by both 4-AP and tetraethylammonium (Niirenberg et al, 1994). Others have shown that a change in current profile is necessary for activation or proliferation of astrocytes (Pappas et al, 1994;MacFarlane and Sontheimer, 1997) and other cells (Chiu and Wilson, 1989;Puro et al, 1989;Gallo et al, 1996). The expression of the K+ OR is also thought to be necessary to counteract the depolarizing effects of certain metabolites present during inflammation, such as ATP and IgG (Young et al, 1983;Niirenberg et al, 1992;Illes et al, 1996).…”