Muscarinic receptor-mediated GTP–Eu binding in the hippocampus and prefrontal cortex is correlated with spatial memory impairment in aged rats

The present study examined muscarinic receptor/G-protein coupling in the hippocampus and the prefrontal cortex of young and aged Long-Evans rats characterized for spatial learning ability in the Morris water maze. In a highly sensitive time-resolved fluorometry GTP–Eu binding assay, muscarinic-mediated GTP–Eu binding was severely blunted in hippocampus (−32%) and prefrontal cortex (−34%) as a consequence of aging. Furthermore, the magnitude of decreased muscarinic-mediated GTP–Eu binding was significantly correlated with the severity of spatial learning impairment in hippocampus and prefrontal cortex of aged rats and was specifically decreased in the subset of aged rats that were spatial learning impaired when compared to the aged unimpaired and the young rats. Western blot data indicated a preservation of the membrane-bound M1 receptor and the Gαq/11 protein in both brain regions. These data demonstrate that muscarinic signaling is severely impaired as a consequence of normal aging in a manner that is closely associated with age-related cognitive decline.