Strain-Dependent Differences in Calcium Signaling Predict Excitotoxicity in Murine Hippocampal Neurons

Abstract

Commonly used inbred murine strains differ substantially in their vulnerability to excitotoxic insults. We investigated whether differences in dendritic Ca(2+) signaling could underlie the differential vulnerability of C57BL/6 (resistant to kainate excitotoxicity) and C57BL/10 strains (vulnerable). A striking difference was found in fine dendrite Ca(2+) responses after kainate exposure. Ca(2+) signals in distal dendrites were large in C57BL/10 neurons, and, if a threshold concentration of approximately 1.5 microm was reached, a region of sustained high Ca(2+) was established in the distal dendritic tree. This region then served as an initiation site for a degenerative cascade, producing high Ca(2+) levels that slowly spread to involve the entire neuron and led to cell death. Dendritic Ca(2+) signals in C57BL/6 neurons were much smaller and did not trigger these propagating secondary responses. Strain differences in dendritic Ca(2+) signaling were also evident after tetanic stimulation of Schaffer collaterals. Ca(2+) responses were much larger and peaked earlier in distal dendrites of C57BL/10 compared with those in C57BL/6. Neurons from both strains had similar membrane properties and responded to kainate with intense action potential firing. Degenerative Ca(2+) responses were seen in both strains if soma Ca(2+) could be sustained above 1.5 microm. The early phases of secondary Ca(2+) responses were attributable to Ca(2+) influx and were abolished rapidly by buffered zero Ca(2+) saline. Taken together, these data indicate that the substantial difference in Ca(2+) signals in fine distal dendrites and in the initiation of spreading secondary responses may underlie the selective vulnerability of these neurons to excitotoxic insults.