ISCHEMIA-INDUCED NEURONAL DAMAGE - A ROLE FOR CALCIUM CALMODULIN-DEPENDENT PROTEIN-KINASE-II

Calcium/calmodulin-dependent protein kinase II (CaM-kinase) is a centr al enzyme in regulating neuronal processes. Imbalances in the activity and distribution of this enzyme have been reported following in vivo ischemia, and sustained decreases in activity correlate with subsequen t neuronal death. In this report, mice that had been rendered deficien t in the alpha subunit of CaM-kinase using gene knock-out technology w ere utilized to determine whether this enzyme is causally related to i schemic damage. Using a focal model of cerebral ischemia, we showed th at homozygous knock-out mice lacking the alpha subunit exhibited an in farct volume almost twice that of wild-type litter mates. Heterozygous mice exhibited slightly less damage following ischemia than did homoz ygous mice, but infarct volumes remained significantly larger than tho se of wild-type litter mates. We conclude that reduced amounts of the alpha subunit of CaM-kinase predisposes neurons to increased damage fo llowing ischemia and that any perturbation that decreases the amount o r activity of the enzyme will produce enhanced susceptibility to neuro nal damage.