Strain-dependent differences in calcium signaling predict excitotoxicity in murine hippocampal neurons

Commonly used inbred murine strains differ substantially in their vulnerability to excitotoxic insults. We investigated whether differences in dendritic Ca2+ 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 Ca2+ responses after kainate exposure. Ca2+ signals in distal dendrites were large in C57BL/10 neurons, and, if a threshold concentration of similar to1.5 muM was reached, a region of sustained high Ca2+ was established in the distal dendritic tree. This region then served as an initiation site for a degenerative cascade, producing high Ca2+ levels that slowly spread to involve the entire neuron and led to cell death. Dendritic Ca2+ signals in C57BL/6 neurons were much smaller and did not trigger these propagating secondary responses. Strain differences in dendritic Ca2+ signaling were also evident after tetanic stimulation of Schaffer collaterals. Ca2+ 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 Ca2+ responses were seen in both strains if soma Ca2+ could be sustained above 1.5 muM. The early phases of secondary Ca2+ responses were attributable to Ca2+ influx and were abolished rapidly by buffered zero Ca2+ saline. Taken together, these data indicate that the substantial difference in Ca2+ signals in fine distal dendrites and in the initiation of spreading secondary responses may underlie the selective vulnerability of these neurons to excitotoxic insults.