Synaptic aging as revealed by changes in membrane potential and decreased activity of Na+,K(+)-ATPase

Age-related changes in the membrane potential of nerve terminals were investigated by monitoring the accumulation of tritium-labeled triphenylmethylphosphonium ion, [3H]TPMP+, in mouse cortical synaptosomes. The resting membrane potential became less negative with advancing age, that is, it changed from -64.5 +/- 0.8 to -58.1 +/- 2.3 mV between 6 and 27 months of age. The intrasynaptosomal potassium concentration was found to decrease concomitantly by 13% in aged mice (56.6 +/- 0.9 mM) as compared to young-adult mice (64.9 +/- 0.5 mM). The ouabain-sensitive Na+,K(+)-ATPase activity of synaptic plasma membranes decreased in late senescence to 82% of the adult level. To examine the correlation with the decreased Na+,K(+)-ATPase activity, the membrane lipid composition was analyzed. Among the membrane phospholipids, only the content of phosphatidylcholine decreased in the course of senescence. The changes in the Na+,K(+)-ATPase activity were found to be positively correlated with the changes in the phospholipid content, and more specifically with the changes in the phosphatidyl-choline content. These results suggest that age-related alterations in the microenvironment constructed by phospholipids may decrease the activity of Na+,K+-ATPase, resulting in neuronal ion imbalance and decreased membrane potential. This might be responsible in part for altered functions of nerve terminals in aging brain.