Retinoid Hyposignaling Contributes to Aging-Related Decline in Hippocampal Function in Short-Term/Working Memory Organization and Long-Term Declarative Memory Encoding in Mice

Abstract

An increasing body of evidence indicates that the vitamin A metabolite retinoic acid (RA) plays a role in adult brain plasticity by activating gene transcription through nuclear receptors. Our previous studies in mice have shown that a moderate downregulation of retinoidmediated transcription contributed to aging-related deficits in hippocampal long-term potentiation and long-term declarative memory (LTDM). Here, knock-out, pharmacological, and nutritional approaches were used in a series of radial-arm maze experiments with mice to further assess the hypothesis that retinoid-mediated nuclear events are causally involved in preferential degradation of hippocampal function in aging. Molecular and behavioral findings confirmed our hypothesis. First, a lifelong vitamin A supplementation, like shortterm RA administration, was shown to counteract the aging-related hippocampal (but not striatal) hypoexpression of a plasticity-related retinoid target-gene, GAP43 (reverse transcription-PCR analyses, experiment 1), as well as short-term/working memory (STWM) deterioration seen particularly in organization demanding trials (STWM task, experiment 2). Second, using a two-stage paradigm of LTDM, we demonstrated that the vitamin A supplementation normalized memory encoding-induced recruitment of (hippocampo-prefrontal) declarative memory circuits, without affecting (striatal) procedural memory system activity in aged mice (Fos neuroimaging, experiment 3A) and alleviated their LTDM impairment (experiment 3B). Finally, we showed that (knock-out, experiment 4) RA receptor ␤ and retinoid X receptor ␥, known to be involved in STWM (Wietrzych et al., 2005), are also required for LTDM. Hence, aging-related retinoid signaling hypoexpression disrupts hippocampal cellular properties critically required for STWM organization and LTDM formation, and nutritional vitamin A supplementation represents a preventive strategy. These findings are discussed within current neurobiological perspectives questioning the historical consensus on STWM and LTDM system partition.

Vitamin A regulates hypothalamic–pituitary–adrenal axis status in LOU/C rats

“…In relation to their leanness, their long life expectancy and their preserved cognitive capacities with age, we previously characterized a HPA axis hypoactive and hyporesponsive to environmental or metabolic challenges in LOU/C rats (Marissal-Arvy et al 2007. The phenotype of LOU/C rats may be related to the functional properties of the retinoid system, with vitamin A mediating a reduction in adipogenesis (Mercader et al 2006, Ziouzenkova et al 2007) and protective effects against memory impairments during ageing (Etchamendy et al 2001, Bonnet et al 2008, Mingaud et al 2008. We then aimed to test whether vitamin A could be a regulator of the HPA axis in LOU/C rats.…”

“…During adulthood, retinoids have been shown to modulate metabolic (Mercader et al 2006, Ziouzenkova et al 2007) and memory (Lane & Bailey 2005, Bonnet et al 2008 functions. During ageing in rats, the naturally occurring hypoactivity of the retinoid signalling pathway impairs spatial memory and long-term potentiation in the hippocampus, which is alleviated by the normalization of brain retinoid signalling by treatment with RA or nutritional vitamin A supplementation (Etchamendy et al 2001, Mingaud et al 2008. Glucocorticoid (GC) levels increase during ageing in rodents and humans, and this endocrine alteration results in prolonged exposure to excess GCs that compromise hippocampal plasticity and functions such as memory processes (Lupien et al 2009).…”

Vitamine A et vieillissement cérébral

“…En effet, des donnees recentes ont montre que des modifications du statut en retinoïdes induisent la mise en place d'alterations dans l'expression des proteines neuro-nales cibles et en consequence, affectent le maintien des processus physiologiques dans le cerveau adulte (Malik et al, 2000). Ainsi, des alterations de la plasticite cerebrale et des deficits de memoire ont ete decrits chez l'animal carence en vitamine A. Il a aussi ete demontre que les souris Knockout pour les recepteurs RARb et RXRb-RXRg presentaient une alteration de la LTP (potentialisation a long terme, une forme de plasticite synaptique) ainsi que des deficits substantiels des performances mnesiques, mis en evidence dans un test de memoire spatiale dependante de l'hippocampe (Chiang et al, 1998 ;Mingaud et al, 2008). La mutation du RARb avec, soit celle du RXRb, soit celle du RXRg, entraîne des deficits de locomotion caracteristiques d'une fonction anormale du striatum et probablement lies a une diminution de l'expression des recepteurs a la dopamine dans les neurones striataux (Krezel et al, 1998 ;Alfos et al, 2001).…”

“…Enfin, plus recemment, la demonstration de l'efficacite d'une supplementation nutritionnelle en vitamine A chez les animaux adultes, permettant a la fois le maintien de l'activite de la voie de signalisation et la prevention de l'apparition de troubles mnesiques specifiques lies au vieillissement, a ete faite (Mingaud et al, 2008). Il est donc aujourd'hui bien admis qu'il existe une relation etroite entre le niveau d'activite cerebrale de la voie d'action des retinoïdes, l'expression de genes cibles codant pour des proteines neuronales impliquees dans certains processus de plasticite (Husson et al, 2004), et les performances mnesiques au cours du vieillissement (Mingaud et al, 2008). L'ensemble de ces donnees suggerent qu'une regulation precise de l'expression des genes contrôles par les retinoïdes est fondamentalement importante pour le fonctionnement optimal du cerveau et pour le maintien des performances de memoire.…”

Concise synthesis of the retinoic acid receptor (RAR) agonist AGN-193836 utilizing a photochemical benzylic oxidation

“…Our interest was in the evaluation of subtype selective RAR and RXR agonists for promoting neuroregeneration (3,4) and decided to create a 'toolbox' of suitable RAR and RXR agonists for use in biological experiments (5). A search of the literature identified AGN-193836 (1) as a potent, selective RAR-a agonist which was assessed to be a suitable 'chemical probe' for evaluating the role of RAR-a (6, 7).…”