title: 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.
authors.affiliation: Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131, USA. bshuttleworth@salud.unm.edu
authors.forename: C W
authors.initials: CW
authors.lastname: Shuttleworth
authors.forename: J A
authors.initials: JA
authors.lastname: Connor
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D002614:Chelating Agents / Q000494:pharmacology; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism*; D004351:Drug Resistance / Q000235:genetics; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D005456:Fluorescent Dyes; D016257:Fura-2; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D012684:Sensory Thresholds / Q000187:drug effects / Q000502:physiology; D013045:Species Specificity
chemical_list: D002614:Chelating Agents; D005456:Fluorescent Dyes; D004533:Egtazic Acid; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D007608:Kainic Acid; D002118:Calcium; D016257:Fura-2