Neurotrophin-3 (NT-3) diminishes susceptibility of the oligodendroglial lineage to AMPA glutamate receptor-mediated excitotoxicity

Abstract

Prior reports demonstrated that cells of the oligodendroglial lineage are susceptible to excitotoxic necrosis mediated by α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid glutamate receptors (AMPA‐GluR), and also showed that these cells express the high affinity neurotrophin receptors, TrkC and TrkA. We now report that: a) oligodendroglial progenitors (OP) and immature oligodendroglia are more vulnerable to AMPA‐GluR‐mediated excitotoxicity than are mature oligodendroglia; b) TrkC expression falls substantially during differentiation of cultured OP to mature oligodendroglia, whereas TrkA expression increases markedly; and c) neurotrophin‐3, and to a lesser extent, nerve growth factor, protect the oligodendroglial lineage against AMPA‐GluR‐mediated excitotoxicity. J. Neurosci. Res. 60:725–732, 2000. © 2000 Wiley‐Liss, Inc.

Diminished calcium homeostasis and increased susceptibility to excitotoxicity of JS 3/16 progenitor cells after differentiation to oligodendroglia

“…Compared with primary OLC cultures with respect to the expression of surface markers and of AMPA-GluR subunits, JS 3/16 OP and ImO correspond to an intermediate phenotype between primary preprogenitors and progenitors, and that between primary progenitors and immature oligodendrocytes, respectively (Grinspan et al, 1990;authors' unpublished observations). Despite these discrepancies in differentiation behavior, JS 3/16 showed similar vulnerability to AMPA-GluR-mediated excitotoxicity as A2B5-immunopanned primary oligodendroglial cultures, in which we observed 33% death of progenitor cells and 57% death of immature oligodendrocytes after a 24-h incubation with AMPAϩCYZ (Kavanaugh et al, 2000). The important advantages of the JS 3/16 cells are homogeneity and ready availability in quantities sufficient for all forms of molecular analysis.…”

Oligodendroglial Cells and Neurotrophins: A Polyphonic Cantata in Major and Minor

“…In addition, truncated TrkB and TrkC isoforms were found (Cohen et al 1996;Kumar and deVellis 1996). A slightly different picture was reported by Kavanaugh et al (2000), where TrkC and TrkA were also demonstrated but with an increase of TrkA expression in more mature OL. A variation of the theme was noted by Robinson and Miller (1996) in that optic nerve OLP expressed TrkC, while those from the spinal cord did not.…”

“…However, NTs are also protective in other conditions that cause oligodendroglial cell death. For example, NGF prevented TNF-α-mediated oligodendroglial cell death by activating the Akt pathway (Takano et al 2000) while NT-3 and, to a lesser extent, NGF protected the cells against AMPA-GluR-induced excitotoxicity at least partially (Kavanaugh et al 2000). It is interesting to note that AMPA does not induce a significant percentage of cell death of mature pig OL (Althaus et al, unpublished observation).…”

Disorders of intermediary metabolism: Toxic leukoencephalopathies

“…Excitotoxicity in the oligodendroglial lineage is independent of NMDA receptors. Instead it is mediated by a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors (Kavanaugh et al 2000, Matute et al 1997, McDonald et al 1998. These are the only ionotropic glutamate receptors expressed by this cell type (Figure 2) (McDonald et al 1998;Patneau et al 1994;Puchalski et al 1994).…”

“…It has only recently been demonstrated that overstimulation of AMPA/kainate receptors causes excitotoxic damage in oligodendroglia in vitro and in vivo (Kavanaugh et al 2000;Matute et al 1997;McDonald et al 1998). Receptor-mediated cell death, which is induced by the activation of AMPA/kainate glutamate receptors, a¡ects exclusively the developing oligodendrocyte and can be prevented by speci¢c receptor antagonists (Follett et al 2004;Rosenberg et al 2003), highlighting a particular vulnerability of fetuses, neonates and infants to white-matter injury.…”