| In certain species, an inability to acquire and maintain a neural representation of spatial relationships in the environment may occur when efficiency of the hippocampal system deteriorates with age. However, hippocampal function, and, consequently, spatial memory, may not necessarily deteriorate as a result of chronological aging. Rather, memory function that demonstrates an age-dependent lability may decline at a markedly variable rate. These age-related individual differences are seen in both rodents and humans. The cholinergic basal forebrain network plays a critical role in memory function and includes the hippocampal formation, neocortex and amygdala. An age-related degeneration of the cholinergic transmitter system plays a critical role in altering hippocampal-dependent neural plasticity. Several muscarinic cholinergic receptor subtypes are coupled by G-proteins to the phosphoinositide (PI) signal transduction pathway that has been shown to be essential to neural plasticity-related events. One muscarinic cholinergic receptor in particular, the postsynaptically localized M1 receptor, does not change in density throughout the aging process in the hippocampal formation (HF). Rather, the M1-muscarinic-receptor-G-protein complex may demonstrate an age-sensitive uncoupling in this region potentially resulting in impaired acquisition and retention of certain types of new information. Furthermore, a deficit in protein kinase C (PKC) activation, an intermediate PI pathway enzyme normally activated by M1 muscarinic stimulation may occur in age-related memory impairment. The work herein demonstrates a disconnection of a G-protein link between the M1 receptor and the PI system in aged F344 rats separated by choice accuracy using a spatial memory task that stresses memory load, i.e., the eight-arm radial-maze. The data show a striking relationship between an age-dependent spatial memory deficit and the functional integrity of the initial segment of the M1 muscarinic cholinergic signal transduction pathway in both the HF and neocortex, but not amygdala. In addition, this uncoupling of the M1-receptor-G-protein complex is associated with an apparent alteration of the immunoreactivity of the PKCγ subtype across spatial domains of CA1 pyramidal neurons. The implication is that conventional cholinomimetic pharmacotherapies that target the cholinergic receptor itself without entering the cell may not provide an optimal strategy to ameliorate the memory impairment that can occur as a consequence of aging. |
