GABAergic systems in a model of age-related cognitive impairment

Abstract

With medical advancements extending the life span, age-related cognitive decline is a growing problem for the United States. A rat model of cognitive aging was used to investigate the GABAergic neurotransmitter system in relation to changes in learning and memory functions. Confocal stereology was used to determine the number of GABAergic and cholinergic projection neurons in the rostral basal forebrain of spatially characterized young and aged male F344 rats. The GABAergic system was then assessed as a potential target for improving age-related cognitive decline using an odor discrimination task sensitive to decline in aging. Performance of aged rats was impaired compared to young rats on the spatial version of the Morris water maze. Notably, a high degree of variability in individual abilities was observed among aged rats such that some aged rats performed on par with young (aged-unimpaired) and others performed outside the range of young, demonstrating impairment (aged-impaired). The number of basal forebrain neurons expressing multiple immunomarkers for GABAergic septohippocampal projection cells was selectively increased in aged-impaired rats in comparison to both young and aged-unimpaired rats. Indeed, among aged rats, worse performance in the water maze was reliably associated with higher GABAergic cell number. The number of cholinergic neurons, quantified in adjacent sections did not differ as a function of chronological age or cognitive status. These data suggest that aging can dysregulate GABAergic systems in circuitry important for learning and memory and such alterations may contribute to age-related cognitive decline. To test whether the GABAergic system may be a viable target for treating age-related cognitive decline, a second cohort of young and aged rats was characterized in an odor discrimination task. Similar to aged rat water maze performance, some aged rats performed odor learning discrimination problems on par with the young cohort (i.e. aged-unimpaired) and some aged rats were impaired compared to young (i.e. aged-impaired). Using a within-subjects design, the GABA(B) antagonist, CGP 55845 completely ameliorated odor discrimination learning deficits in aged-impaired rats in a dose-dependent manner. These data support the hypothesis that the GABAergic system should be a novel target for therapies aimed at treating age-related cognitive decline.