HDAC3-Mediated Repression of the Family Contributes to Age-Related Impairments in Long-Term Memory

Aging is accompanied by cognitive deficits, including impairments in long-term memory formation. Understanding the molecular mechanisms that support preserved cognitive function in aged animals is a critical step toward identifying novel therapeutic targets that could improve memory in aging individuals. One potential mechanism is the family of genes, a group of CREB-dependent nuclear orphan receptors that have previously been shown to be important for hippocampal memory formation. Here, using a cross-species approach, we tested the role of and in age-related memory impairments. Using a rat model designed to identify individual differences in age-related memory impairments, we first identified as a key gene that fails to be induced by learning in cognitively impaired male aged rats. Next, using a mouse model that allows for genetic manipulations, we determined that histone deacetylase 3 (HDAC3) negatively regulates in the aged male and female hippocampus. Finally, we show that overexpression of , , or both transcripts in the male mouse dorsal hippocampus can ameliorate age-related impairments in object location memory. Together, our results suggest that may be a key mechanism that promotes preserved cognitive function in old age, with HDAC3-mediated repression of contributing to age-related cognitive decline. More broadly, these results indicate that therapeutic strategies to promote gene expression or function may be an effective strategy to improve cognitive function in old age. Aging is accompanied by memory impairments, although there is a great deal of variability in the severity of these impairments. Identifying molecular mechanisms that promote preserved memory or participate in cognitive reserve in old age is important to develop strategies that promote healthy cognitive aging. Here, we show that learning-induced expression of the CREB-regulated nuclear receptor gene is selectively impaired in aged rats with memory impairments. Further, we show that is regulated by histone deacetylase HDAC3 in the aged mouse hippocampus. Finally, we demonstrate that hippocampal overexpression of either or its family member, , can ameliorate age-related memory impairments. This suggests that promoting expression may be a novel strategy to improve memory in aging individuals.