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

JS 3/16, derived from passaged oligodendroglial cultures prepared from rat cerebral white matter, differentiate from progenitors (OP) into complex pro cess-bearing, galactocerebroside-positive but myelin basic protein-negative immature oligodendrocyte-like cells (ImO) after withdrawal of trophic fact ors. We found that JS 3/16 ImO are markedly more susceptible than OP to cel l death after sustained alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionat e glutamate receptor (AMPA-GluR) activation. This excitotoxicity is precede d by loss of intracellular Ca2+ homeostasis, which is more marked in ImO th an OF. We identified three factors likely to contribute to the diminished C a2+ homeostatic capacity of ImO. First, signal intensities of immunoreactiv e GluR2, GluR3, and GluR4 AMPA-GluR subunits are increased 1.3- to 2.2-fold in ImO over OP without comparable changes in RNA editing and alternative s plicing. Second, transcriptional levels of genes encoding Na+-Ca2+ exchange r proteins and a plasma membrane ATPase (PMCA1), which are necessary for Ca 2+ extrusion across the plasma membrane, are lower in ImO than in OF. Third , ImO have more depolarized basal mitochondrial membrane potential (Delta P si) than OF, and Delta Psi collapses within 15 min after onset of AMPA-GluR activation in almost all ImO, but not in the majority of OF. This Delta Ps i collapse limits the capacity of ImO mitochondria to buffer the rise in in tracellular Ca2+ caused by AMPA-GluR activation. The JS 3/16 line provides a valuable system for analysis of intracellular Ca2+ homeostasis and AMPA-G luR-mediated excitotoxicity in the oligodendroglial lineage. (C) 2000 Wiley -Liss, Inc.