Differential Retinoic Acid Signaling in the Hippocampus of Aged Rats with and without Memory Impairment

Abstract

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 used a Morris water maze protocol to study cognitive decline in aged rats, which assesses hippocampus-dependent spatial memory and reveals substantial interindividual differences in aged animals. Aged unimpaired (AU) rats perform on par with young (Y), while aged impaired (AI) animals exhibit spatial memory deficits. We show that the major substrate for RA, retinol binding protein 4 (RBP4), 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 (FMRP). The results support the conclusion that, surprisingly, increased RA signaling in the aged hippocampus is associated with poor cognitive outcome.

General and specific patterns of cortical gene expression as spatial correlates of complex cognitive functioning

“…Loss of GABRQ *‐containing neurons is an indicator of early social–emotional cognitive decline in frontotemporal dementia (Gami‐Patel et al, 2022), IL6R* has been associated with memory domain scores, and Alzheimer's disease pathology (cerebrospinal fluid pTau and Aβ42/40 ratio) (Quillen et al, 2023), and DTNB is an indicator of extent of neuronal injury and inflammation in Alzheimer's disease (Neumann et al, 2022). CYP26B1 is upregulated in the prefrontal cortex (Shibata et al, 2021), and there are links between its catabolism in the hippocampus and poor cognitive outcomes in mice (Wołoszynowska‐Fraser et al, 2021).…”

General and specific patterns of cortical gene expression as spatial correlates of complex cognitive functioning

“…Additionally, SEMA5A * has previously been associated with hippocampal volume and performance on cognitive tests ( 85 ). CYP26B1 is upregulated in the prefrontal cortex ( 86 ), and there are links between its catabolism in the hippocampus and poor cognitive outcomes in mice ( 87 ).…”

“…GNB5 plays a key role in several neurodevelopmental cognitive disabilities (83,84). CYP26B1 is upregulated in the prefrontal cortex (85), and there are links between its catabolism in the hippocampus and poor cognitive outcomes in mice (86).…”

Re‐remembering the influence of randomized β‐carotene on cognitive decline

“…The most potent form of vitamin A is the nuclear receptor agonist, retinoic acid. In the hippocampus, a primary region implicated in multiple pathways of cognitive decline 21,22 and early AD, 21 retinoic acid is synthesized locally from retinol 23 . Studies in rodents have shown that retinoic acid induces hippocampal neurogenesis and neuronal differentiation, 24,25 rescues vitamin‐A deficiency‐induced spatial memory impairment, 26,27 and reverses age‐related memory deficits 28,29 .…”

“…In the hippocampus, a primary region implicated in multiple pathways of cognitive decline 21,22 and early AD, 21 retinoic acid is synthesized locally from retinol. 23 Studies in rodents have shown that retinoic acid induces hippocampal neurogenesis and neuronal differentiation, 24,25 rescues vitamin-A deficiencyinduced spatial memory impairment, 26,27 and reverses age-related memory deficits. 28,29 Rodent models have also demonstrated that vitamin A deficiency reduces hippocampal volume and plasticity, and increases amyloid-β deposition, as compared to vitamin A replete controls.…”