Multiple changes in noradrenergic mechanisms in the coeruleo-hippocampal pathway during aging. Structural and functional correlates in intraocular double grafts

Age-related changes of the coeruleo-hippocampal noradrenergic system were investigated using intraocular double transplants. Pieces of fetal hippocampus were grafted into the anterior chamber of the eye and placed into contact with previously inserted locus coeruleus grafts. Ages of both transplants and hosts were varied to enable studies of intrinsic versus extrinsic determinants of aging in an isolated neuronal circuit. Four different experimental groups, with the approximate age in months of grafts/hosts at the time of recording given in parentheses, were studied; young grafts in the eyes of young hosts ( 3 7), young grafts in the eyes of old hosts ( 3 23), mature transplants in adult host rats ( 8 12) and aged transplants in the eyes of aged rats ( 21 25). Extracellular recordings from the hippocampal part of the double grafts were performed. Superfusion with α-adrenergic antagonists and the α₂-agonist clonidine elicited significant increases in the discharge rate of the grafted hippocampal neurons in all groups except the aged transplants in the aged hosts ( 21 25), where a small excitation was elicited with clonidine and no effect at all was seen with α-adrenergic antagonists. The host age did not seem to be important since young transplants in the old hosts ( 3 23) showed a similar increase in discharge rate as transplants in the young and adult hosts. Tyrosine hydroxylase immunohistochemistry and high-performance liquid chromatography revealed that hippocampal transplants remaining in oculo for a minimum of 6-10 months became permanently hyperinnervated by noradrenergic fibers from the locus coeruleus grafts. The density of noradrenergic fibers was significantly lower in young transplants. In conclusion, the present results indicate an age-related disturbance in both pre- and postsynaptic noradrenergic mechanisms in intraocular locus coeruleo-hippocampal double transplants. This decline in noradrenergic transmission is dependent on transplant age rather than host age and thus appears to be triggered primarily by factors intrinsic to the hippocampal graft.