Calcium dependence of damage to mouse motor nerve terminals following oxygen/glucose deprivation

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Motor nerve terminals are especially sensitive to an ischemia/reperfusion stress. We applied an in vitro model of this stress, oxygen/glucose deprivation (OGD), to mouse neuromuscular preparations to investigate how Ca2+ contributes to stress-induced motor terminal damage. Measurements using an ionophoretically-injected fluorescent [Ca2+] indicator demonstrated an increase in intra-terminal [Ca2+] following OGD onset. When OGD was terminated within 20–30 min of the increase in resting [Ca2+], these changes were sometimes reversible; in other cases [Ca2+] remained high and the terminal degenerated. Endplate innervation was assessed morphometrically following 22 min OGD and 120 min reoxygenation (32.5 °C). Stress-induced motor terminal degeneration was Ca2+-dependent. Median post-stress endplate occupancy was only 26% when the bath contained the normal 1.8 mM Ca2+, but increased to 81% when Ca2+ was absent. Removal of Ca2+ only during OGD was more protective than removal of Ca2+ only during reoxygenation. Post-stress endplate occupancy was partially preserved by pharmacological inhibition of various routes of Ca2+ entry into motor terminals, including voltage-dependent Ca2+ channels (ω-agatoxin-IVA, nimodipine) and the plasma membrane Na+/Ca2+ exchanger (KB-R7943). Inhibition of a Ca2+-dependent protease with calpain inhibitor VI was also protective. These results suggest that most of the OGD-induced motor terminal damage is Ca2+-dependent, and that inhibition of Ca2+ entry or Ca2+-dependent proteolysis can reduce this damage. There was no significant difference between the response of wild-type and presymptomatic superoxide dismutase 1 G93A mutant terminals to OGD, or in their response to the protective effect of the tested drugs.


▸ An oxygen/glucose deprivation stress was applied to mouse neuromuscular preparations. ▸ This stress elevated [Ca2+] and depolarized mitochondria within motor terminals. ▸ Removal of bath Ca2+ during the stress preserved motor terminals and axons. ▸ Inhibitors of Ca2+ influx and of calpain activation preserved endplate innervation. ▸ Motor terminal degeneration following oxygen/glucose deprivation is Ca2+-dependent.

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