Keele Research Repository

Retinoic acid (RA), a metabolite of vitamin A, has many physiological functions, and mounting evidence points to important roles in cognition. In vitro experiments indicate that RA is involved in homeostatic synaptic scaling in the hippocampus, which supports overall network stability during learning. It has been previously determined that disrupted RA signaling in the hippocampus causes deterioration of memory, that RA signaling declines with age in brain, and that application of RA reverses this decline. Here we explore whether RA signaling is altered in an animal model of neurocognitive aging. We utilized a Morris water maze protocol to study cognitive decline in aged rats, which assesses hippocampus-dependent spatial memory and reveals substantial inter-individual differences in aged animals. Aged unimpaired (AU) rats perform on par with young, while aged impaired (AI) animals exhibit spatial memory deficits. We show that the major substrate for RA, retinol binding protein 4, is decreased in AU rats, and retinol cell surface receptor declines with chronological age. Other affected components of RA signaling include selective increases in AI animals in hippocampal synthesis (RALDH1) and catabolism of RA (CYP26B1), RA receptor α, the RA regulated ionotropic glutamate receptor (GluR1), as well as fragile X mental retardation protein. The results support the conclusion that, surprisingly, increased RA signaling in the aged hippocampus is associated with poor cognitive outcome.SIGNIFICANCE STATEMENTGrowing evidence indicates that retinoic acid (RA) function extends well beyond metabolic control and includes the regulation of memory-related synaptic plasticity. Here we explore whether RA signaling is altered in an animal model of neurocognitive aging. We show that in fact RA function is altered at nearly all levels examined, and these results are unrelated to metabolic aging. Overall, the net effect points in the direction of increased RA signaling in impaired aged animals, which may contribute to disruption in excitation/inhibition balance, a prominent feature of age-related cognitive impairment and suspected early event in the pathogenesis of Alzheimer's disease.