Ca2+ Influx through AMPA or Kainate Receptors Alone Is Sufficient to Initiate Excitotoxicity in Cultured Oligodendrocytes

Abstract

Oligodendrocytes are vulnerable to excitotoxic insults mediated by AMPA receptors and by low and high affinity kainate receptors, a feature that is dependent on Ca2+ influx. In the current study, we have analyzed the intracellular concentration of calcium [Ca2+]i as well as the entry routes of this cation, upon activation of these receptors. Selective activation of either receptor type resulted in a substantial increase (up to fivefold) of [Ca2+]i, an effect which was totally abolished by the non-NMDA receptor antagonist CNQX or by removing Ca2+ from the culture medium. Blockade of voltage-gated Ca2+ channels with La3+ or nifedipine, reduced the amplitude of the Ca2+ current triggered by AMPA receptor activation by ∼65%, but not that initiated by low and high affinity kainate receptors. In contrast, KB-R7943, an inhibitor of the plasma membrane Na+–Ca2+ exchanger, solely attenuated the rise in [Ca2+]i by ∼25% due to activation of low affinity kainate receptors. However, oligodendroglial death by glutamate receptor overactivation was largely unaffected in the presence of La3+ or KB-R7943. These findings indicate that Ca2+ influx via AMPA and kainate receptors alone is sufficient to initiate cell death in oligodendrocytes, which does not require the entry of calcium via other routes such as voltage-activated calcium channels or the plasma membrane Na+–Ca2+ exchanger.