Impaired synaptic functions with aging as characterized by decreased calcium influx and acetylcholine release

Age-related alterations of presynaptic functions were studied in terms of acetylcholine (ACh) synthesis and release using synaptosomes isolated from mouse brain cortices. The following three findings were obtained: 1) Choline acetyltransferase activity and ACh production rate remained constant throughout all ages tested. This observation, obtained with synaptosomes, was not consistent with data reported for brain slices (Gibson GE, Peterson C: J Neurochem 37:978-984, 1981). Various conditions, such as low glucose or membrane depolarization, modulated ACh synthesis to similar extents in young and aged synaptosomes. 2) Depolarization-induced release of ACh from synaptosomes significantly decreased in the senescent stage. The fraction of ACh released from aged synaptosomes was less than that released from young synaptosomes, although the ACh contents in the synaptosomes did not change with age. 3) Calcium influx induced by depolarization was lower in the synaptosomal preparations from aged mice than in those from young mice. A strong positive correlation was observed between the amounts of ACh released and the increased calcium levels when the data for all preparations, both from young and aged mice, were plotted. This indicates that diminished calcium influx may cause the reduced ACh release by aged synapses. The present study provides evidence for an age-related decrease in presynaptic functions, that is, a reduction in calcium influx via voltage-dependent calcium channels followed by a decreased ACh release from synapses despite an abundance of ACh within the synapses.