title: Alleviation of a selective age-related relational memory deficit in mice by pharmacologically induced normalization of brain retinoid signaling.
abstract: Vitamin A and its derivatives, the retinoids, have been implicated recently in the synaptic plasticity of the hippocampus and might therefore play a role in associated cognitive functions. Acting via transcription factors, retinoids can regulate gene expression via their nuclear receptors [retinoic acid receptors (RARs) and retinoid X receptors]. In a series of experiments, the present study investigated the possible role of age-related downregulation of retinoid-mediated transcription events in the cognitive decline seen in aged mice. We observed that the brain (and hippocampal) levels of retinoid receptors and the expression of specific associated target genes were restored to presenescent (adult) levels in aged mice after acute administration (150 microg/kg, s.c.) of retinoic acid (RA). These effects of RA, however, could be abolished by the coadministration of an RAR antagonist. RA was also demonstrated to alleviate the age-related deficit in the CA1 long-term potentiation efficacy of aged mice in vivo. Moreover, RA was found to alleviate completely the performance deficit of aged mice to the control level in a two-stage spatial discrimination paradigm designed to assess relational memory. This promnesic effect of RA was again susceptible to abolition by RAR antagonist treatment. The parallel molecular, cellular, and behavioral correlates associated with the decrease of retinoid receptor expression and its normalization demonstrated here suggest that the fine regulation of retinoid-mediated gene expression is fundamentally important to optimal brain functioning and higher cognition. Specifically, a naturally occurring dysregulation of retinoid-mediated molecular events might be a potential etiological factor for cognitive deterioration during senescence.
authors.affiliation: Laboratory of Cognitive Neurosciences, Unité Mixte de Recherche Centre National de la Recherche Scientifique 5106, University of Bordeaux 1, 33405 Talence Cedex, France.
authors.forename: N
authors.initials: N
authors.lastname: Etchamendy
authors.forename: V
authors.initials: V
authors.lastname: Enderlin
authors.forename: A
authors.initials: A
authors.lastname: Marighetto
authors.forename: R M
authors.initials: RM
authors.lastname: Vouimba
authors.forename: V
authors.initials: V
authors.lastname: Pallet
authors.forename: R
authors.initials: R
authors.lastname: Jaffard
authors.forename: P
authors.initials: P
authors.lastname: Higueret
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D001923:Brain Chemistry / Q000187:drug effects; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004558:Electric Stimulation; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects / Q000503:physiopathology; D007279:Injections, Subcutaneous; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051579:Neurogranin; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors; D012176:Retinoids / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000008:administration & dosage
chemical_list: D002148:Calmodulin-Binding Proteins; D009419:Nerve Tissue Proteins; C496650:Nrgn protein, mouse; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; D051579:Neurogranin; D014212:Tretinoin