Behavioral, Electrophysiological, and Biochemical Consequences of Chronic Cytochrome Oxidase Inhibition in Rats

Abstract

The mitochondrial enzyme cytochrome oxidase (C.O.) is an essential catalyst for electron transfer in oxidative phosphorylation. Recent clinical studies have shown that C.O. activity is reduced in both blood platelets and in the brains of patients with Alzheimer’s disease (A.D.), suggesting that a decline in the efficiency of this enzyme could impair cognition. We explored this idea by chronically treating rats with sodium azide, using doses that inhibited C.O. but not other electron transport chain enzymes. Our initial studies demonstrated that selective C.O. inhibition produced deficits in learning tasks, including spatial learning, but did not alter basic sensorimotor function. Azide treatment also disrupted hippocampal long-term potentiation, a potential memory encoding mechanism. Both these effects may have been the consequence of a reduction in membrane bound protein kinase C activity that was observed in the hippocampus, but not in frontal or temporal cortex or cerebellum. Further work revealed that the stress hormone, corticosterone, potentiated azide-induced inhibition of C.O. and the resulting cognitive deficits. Thus, manipulation of C.O. activity in rats to mimic biochemical conditions observed in patients with A.D. caused impairments in learning and memory.