Alleviation of a selective age-related relational memory deficit in mice by pharmacologically induced normalization of brain retinoid signaling

Vitamin A and its derivatives, the retinoids, have been implicated recently in the synaptic plasticity of the hippocampus and might therefore play a r ole in associated cognitive functions. Acting via transcription factors, re tinoids 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 downregul ation of retinoid-mediated transcription events in the cognitive decline se en in aged mice. We observed that the brain (and hippocampal) levels of ret inoid receptors and the expression of specific associated target genes were restored to presenescent (adult) levels in aged mice after acute administr ation (150 mug/kg, s.c.) of retinoic acid (RA). These effects of RA, howeve r, 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 alle viate completely the performance deficit of aged mice to the control level in a two-stage spatial discrimination paradigm designed to assess relationa l 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 an d its normalization demonstrated here suggest that the fine regulation of r etinoid-mediated gene expression is fundamentally important to optimal brai n functioning and higher cognition. Specifically, a naturally occurring dys regulation of retinoid-mediated molecular events might be a potential etiol ogical factor for cognitive deterioration during senescence.