Glutamatergic neurotransmission in aging: a critical perspective

The effects of aging on glutamate neurotransmission in the brain is reviewed and evaluated. Glutamate is the neurotransmitter in most of the excitatory synapses and appears to be involved in functions such as motor behaviour, cognition and emotion, which alter with age. However, relatively few studies have been conducted to study the relationship between glutamate and aging of the brain. The studies presented here indicate the existence of a number of changes in the glutamatergic system during the normal process of aging. First, an age-related decrease of glutamate content in tissue from cerebral cortex and hippocampus has been reported, although it may be mainly a consequence of changes in metabolic activity rather than glutamatergic neurotransmission. On the other hand, studies in vitro and in vivo have shown no changes in glutamate release during aging. Since glutamate sampled in most of these studies is the result of a balance between release and uptake processes, the lack of changes in glutamate release may be due to compensatory changes in glutamate uptake. In fact, a reduced glutamate uptake capacity, as well as a loss in the number of high affinity glutamate transporters in glutamatergic terminals of aged rats, have been described. However, the most significant and consistent finding is the decrease in the density of glutamatergic NMDA receptors with age. A new perspective, in which glutamate interacts with other neurotransmitters to conform the substrates of specific circuits of the brain and its relevance to aging, is included in this review. In particular, studies from our laboratory suggest the existence of age-related changes in the interaction between glutamate and other neurotransmitters, e.g. dopamine and GABA, which are regionally specific.