Effects of age on axon terminals forming axosomatic and axodendritic inhibitory synapses in prefrontal cortex

Much of the cognitive decline shown by aging primates can be attributed to dysfunction of prefrontal cortex and, as shown previously, about 30% of asymmetric (excitatory) and symmetric (inhibitory) axodendritic synapses are lost from the neuropil of layer 2/3 in prefrontal area 46 with age [Peters A, Sethares C, Luebke JI (2008) Neuroscience 152:970-981]. Whether there is a similar loss of inhibitory axosomatic synapses from this cortex has not been determined, but a study in primate motor cortex suggests that axosomatic synapses are not lost with age [Tigges J, Herndon JG, Peters A (1992) Anat Rec 232:305-315]. The present study is focused upon whether the remaining axon terminals forming inhibitory synapses in old monkeys hypertrophy to compensate for any age-related loss. Analysis of electron micrographs show that in layer 2/3 of area 46 in both young and old monkeys, axon terminals forming axosomatic synapses are significantly larger and contain more mitochondria than those forming axodendritic synapses and both axodendritic and axosomatic terminals become larger with age. However, while mitochondria in axodendritic terminals do not change in either size or amount with age, the mitochondria in axosomatic terminals become larger. Similarly, in terminals forming axodendritic synapses, the mean numbers of synaptic vesicle profiles is the same in young and old monkeys, whereas in terminals forming axosomatic synapses there is an increase in the numbers of synaptic vesicles with age. We also show that among these age-related changes, only the numbers of synaptic vesicles in axosomatic synapses are significantly correlated with the cognitive impairment indices displayed by the same monkeys. In summary, the data provide original evidence that axosomatic axon terminals increase in size and in their content of mitochondria and synaptic vesicles. Furthermore, based on our and previously published results, we speculate that these changes are linked to age-related cognitive decline.