Cholinergic deficits in the septal-hippocampal pathway of the SAM-P/8 senescence accelerated mouse

Senescence accelerated prone mouse strains (SAM-P) and resistant strains (SAM-R) have proven useful in elucidating aspects of the aging process. The senescence accelerated mouse SAM-P/8 strain exhibits severe age-related learning and memory impairments well before the median age of survival. Disruption of the brain cholinergic system produces learning and memory impairments as severe as those seen in aging SAM-P/8 mice. Therefore, we compared the effects of aging on cholinergic parameters in the septal-hippocampal pathway, a region known to play a role in learning and memory, in SAM-P/8 mice and mice of the senescence resistant SAM-R/1 strain. Between 4 and 12 months of age we observed a 40-50% decrease in choline acetyltransferase (ChAT) activity in two of three subregions of the hippocampus in the SAM-P/8, but not the SAM-R/1 strain. Between 4 and 12 months, SAM-P/8 mice also showed a 40-50% decrease in ChAT activity in the septal region that was maximal by 8 months of age. By contrast, these age-related changes were not observed in the control SAM-R/1 mouse strain. The changes in ChAT in the SAMP/8 mouse strain were limited to the septal-hippocampal cholinergic pathway. There were no differences in ChAT activity in the nucleus basalis of Meynert, nor any of several neocortical areas to which it projects. To determine the neurochemical specificity of these alterations, the activity of glutamic acid decarboxylase (GAD), was also measured in the septum and hippocampus of SAM-P/8 mice. There were no age-related alterations in the hippocampus, but a significant 50% increase in GAD activity in the septal nucleus at 12 months of age. There were no age-related alterations in either nicotinic (3H-cytisine) or muscarinic (3H-QNB) cholinergic receptor binding in the cortex or hippocampus of SAM-P/8 mice. However, there were significant strain differences. At 2 months of age, 3H-QNB binding was higher in hippocampus of the SAM-R/1 than in SAM-P/8 mice. Similarly, 3H-cytisine binding in cortex of SAM-R/1 mice was higher at both 2 and 13 months than in SAM-P/8 mice. The results suggest that a compromised septal-hippocampal cholinergic pathway may contribute to the previously reported early onset of impaired learning and memory in the SAM-P/8 mouse strain.