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.

Fig. 1.

Design of the behavioral procedure.

Fig. 2.

a, Representative records of the population spike in the CA1 region of the hippocampus before and after HFS of the contralateral ventral hippocampal commissure.b, The average amplitude of the population spike normalized to the average baseline value before HFS.

Fig. 3.

Left, Progression of the go–no-go discriminative performance evaluated by the no-go/go enter-latency ratio over the first six (1–6) sessions (i.e., the presently observed minimum number of sessions required to attain the criterion) and the last six (n − 5 to n) sessions of training before reaching criterion in stage 1. Middle, Mean no-go/go enter-latency ratio over the last two sessions (n − 1, n) of stage 1.Right, Two-choice discriminative performance expressed as the mean percentage correct over the two daily sessions of stage 2 (n + 1, n + 2). Post hocScheffe test: ***p < 0.001 versus aged + vehicle group; °°°p < 0.001 versus chance (50%).

Fig. 4.

a, Whole-brain mRNAs in mice killed 24 hr after the fourth daily drug treatment. b, Hippocampal mRNAs in mice killed either 24 hr after the fourth daily administration of treatments (i.e., before the beginning of behavioral training) or after completion of testing in stage 2 (i.e., the day after the 25th daily administration of treatments). All values are expressed as the mean ± SEM of measures derived from three independent samples (n = 3). Each sample unit consisted of two pooled whole brains or two pooled hippocampi (i.e., a total of 6 animals). Post hoc Fisher tests: *p < 0.05; **p < 0.01; ***p < 0.001; all significantly different from the aged + vehicle group.