title: 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 retinoid-mediated 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 short-term 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 beta and retinoid X receptor gamma, 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.
authors.affiliation: Centre Neurosciences Intégratives et Cognitives, Université Bordeaux 1, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5228, 33405 Talence, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Mingaud
authors.forename: Cécile
authors.initials: C
authors.lastname: Mormede
authors.forename: Nicole
authors.initials: N
authors.lastname: Etchamendy
authors.forename: Nicole
authors.initials: N
authors.lastname: Mons
authors.forename: Betty
authors.initials: B
authors.lastname: Niedergang
authors.forename: Marta
authors.initials: M
authors.lastname: Wietrzych
authors.forename: Véronique
authors.initials: V
authors.lastname: Pallet
authors.forename: Robert
authors.initials: R
authors.lastname: Jaffard
authors.forename: Wojciech
authors.initials: W
authors.lastname: Krezel
authors.forename: Paul
authors.initials: P
authors.lastname: Higueret
authors.forename: Aline
authors.initials: A
authors.lastname: Marighetto
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal; D019922:GAP-43 Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D007641:Keratolytic Agents / Q000008:administration & dosage; D018782:Maze Learning; D008569:Memory Disorders / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D008570:Memory, Short-Term / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018168:Receptors, Retinoic Acid / Q000172:deficiency; D047488:Retinoid X Receptors / Q000172:deficiency; D012176:Retinoids / Q000378:metabolism*; D013997:Time Factors; D014212:Tretinoin / Q000008:administration & dosage; D014801:Vitamin A / Q000627:therapeutic use
chemical_list: D019922:GAP-43 Protein; D007641:Keratolytic Agents; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; C082925:retinoic acid receptor beta; D014801:Vitamin A; D014212:Tretinoin