Retinoid hyposignaling contributes to aging-related decline in hippocampal function in short-term/working memory organization and long-term declarative memory encoding in mice.
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.
Mingaud
Frédérique
F
Centre Neurosciences Intégratives et Cognitives, Université Bordeaux 1, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5228, 33405 Talence, France.
Mormede
Cécile
C
Etchamendy
Nicole
N
Mons
Nicole
N
Niedergang
Betty
B
Wietrzych
Marta
M
Pallet
Véronique
V
Jaffard
Robert
R
Krezel
Wojciech
W
Higueret
Paul
P
Marighetto
Aline
A
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
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