Neuron is the primary target of Ca2+ paradox-type insult-induced cell injury in neuron/astrocyte co-cultures

“Ca2+ paradox” is the phenomenon whereby the intracellular concentration of Ca2+ paradoxically increases during reperfusion with normal Ca2+-containing media after brief exposure to a Ca2+-free solution. The present study aims to characterize the Ca2+ paradox induced cell injury in neuron/astrocyte co-cultures. Prior exposure of the co-cultures to a low Ca2+ solution for 60 min significantly injured only neurons after reperfusion with a normal Ca2+ medium for 24 h, but astrocytes remained intact. An analysis of the Ca2+ paradox-induced changes in the intracellular concentration of Na+ revealed that the concentration in astrocytes increased significantly during the reperfusion episode, resulting in a reversal of the operation of the astrocytic Na+-dependent glutamate transporter GLT-1. These results suggested that Ca2+ paradox-induced accumulation of Na+ in astrocytes was crucially involved in the excitotoxic neuronal injury resulting from the reversed astrocytic GLT-1 during the reperfusion episode. Previous studies have suggested that Ca2+ paradox-induced injury in the brain occurs first in astroglial cells and only later in neurons resulting from the prior damage of astrocytes. Here we show that if “Ca2+ paradox” occurs in the brain, neurons would be the primary target of Ca2+ paradox-induced cell injury in the central nervous system.