Working memory deficits in retinoid X receptor γ-deficient mice

Abstract

Retinoid signaling has been recently shown to be required for mnemonic functions in rodents. To dissect the behavioral and molecular mechanisms involved in this requirement, we have analyzed the spatial and recognition working memory in mice carrying null mutations of retinoid receptors RAR␤ and RXR␥. Double mutants appeared deficient in spatial working memory as tested in spontaneous alternation in the Y-maze and delayed nonmatch to place (DNMTP) test in the T-maze. These mutant mice did acquire, however, spatial place reference or right/left discrimination tasks in the T-maze set-up, indicating that basic sensorimotor functions, spatial orientation, and motivational factors are unlikely to account for deficits in working memory-sensitive tasks. Double-mutant mice were also deficient in novel object recognition at intermediate, but not short delays. RXR␥ appeared to be the functionally predominant receptor in modulation of the working memory, as RXR␥, but not RAR␤ single null mutant mice exhibited deficits similar to those observed in the double mutants. The mechanism of this modulation is potentially related to functions of RXR␥ in frontal and perirhinal cortex, structures in which we detected RXR␥ expression and which are functionally implicated in working memory processes.Retinoic acid (RA, the major active form of vitamin A) is involved in the control of functions of several adult organs, including brain. Diet-induced or age-related reduction of retinoic acid levels was recently reported to lead to mnemonic deficits in spatial learning and memory in rats (Cocco et al. 2002) or relational memory in mice (Etchamendy et al. 2001(Etchamendy et al. , 2003. In view of the pleiotropic effects of RA, several dysfunctions may be involved in the generation of these deficits. Thus, one of the first steps in elucidating the molecular mechanisms underlying the modulation of mnemonic functions by retinoids is to determine which RA-signaling pathway(s) is implicated in this control.In vertebrates, the retinoid signal is mediated by two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), each family comprising three isotypes, ␣ ␤, and ␥ with several isoforms for each isotype (Chambon 1996). These receptors are ligand-dependent transcriptional regulators acting as RAR/RXR heterodimers (Chambon 1996;Kastner et al. 1997). As RARs and RXRs are expressed in the adult mouse brain (Krezel et al. 1999;Zetterstrom et al. 1999) they can be directly implicated in control of brain functions. The concomitant null mutation of RAR␤ and RXR␥ or the null mutation of RAR␤ alone have been linked with spatial long-term memory deficits observed in the place-reference version of the Morris water-maze task (Chiang et al. 1998). Whether the inability of RAR␤/RXR␥ double mutants to learn this task could be related to deficits in the working memory, which actually would be the primary origin of deficient performance of these mutants in the water-maze task, was not investigated in this latter study....

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

“…Here we demonstrated that RAR␤/RXR␥, which were shown previously to be involved in STWM (Wietrzych et al, 2005), are required for LTDM and that, like RA treatment, nutritional vitamin A supplementation prevents the age-related decline in both STWM and LTDM performances, as well as in molecular markers of hippocampal function. The present findings support the hypothesis that hippocampal retinoid receptor signaling is critically implicated in cellular mechanisms sustaining STWM organization and LTDM formation.…”

“…Functional implication of retinoid signaling in hippocampal plasticity and spatial memory was demonstrated in rodents by knock-out of RAR␤ or RXR␤/␥ receptors (Chiang et al, 1998;Wietrzych et al, 2005), vitamin A deprivation (Misner et al, 2001;Cocco et al, 2002;Etchamendy et al, 2003b), and RA administration (Crandall et al, 2004). Furthermore, dysfunction of retinoid signaling pathway has been hypothesized to be involved in human neurodevelopmental pathologies such as schizophrenia or late-onset Alzheimer's disease (for review, Goodman, 1998Goodman, , 2006Goodman and Pardee, 2003;Palha and Goodman, 2006).…”

“…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.…”

Stress during a Critical Postnatal Period Induces Region-Specific Structural Abnormalities and Dysfunction of the Prefrontal Cortex via CRF1

“…In addition, antalarmin treatment normalized stress-increased same arm return ratio (treatment: F 1, 24 ¼ 8.757, p ¼ 0.007; interaction: F 1, 24 ¼ 4.663, p ¼ 0.041; Figure 5b), which reflects certain aspects of attention (Wall and Messier, 2002;Wietrzych et al, 2005). In each sample phase of the temporal order memory test, all groups of mice explored the two copies of an identical object similarly (Supplementary Figure S7d).…”

“…The total distance traveled, number of arm entries, spontaneous alternation ratio (Wang et al, 2013), and same arm return ratio (Wall and Messier, 2002;Wietrzych et al, 2005) were measured.…”