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Histone deacetylases (HDACs) are promising therapeutic targets for neurological and psychiatric disorders that impact cognitive ability, but the relationship between various HDAC isoforms and cognitive improvement is poorly understood, particularly in mouse models of memory impairment. A goal shared by many is to develop HDAC inhibitors with increased isoform selectivity in order to reduce unwanted side effects, while retaining procognitive effects. However, studies addressing this tack at the molecular, cellular and behavioral level are limited. Therefore, we interrogated the biological effects of class I HDAC inhibitors with varying selectivity and assessed a subset of these compounds for their ability to regulate transcriptional activity, synaptic function and memory. The HDAC-1, -2, and -3 inhibitors, RGFP963 and RGFP968, were most effective at stimulating synaptogenesis, while the selective HDAC3 inhibitor, RGFP966, with known memory enhancing abilities, had minimal impact. Furthermore, RGFP963 increased hippocampal spine density, while HDAC3 inhibition was ineffective. Genome-wide gene expression analysis by RNA sequencing indicated that RGFP963 and RGFP966 induce largely distinct transcriptional profiles in the dorsal hippocampus of mature mice. The results of bioinformatic analyses were consistent with RGFP963 inducing a transcriptional program that enhances synaptic efficacy. Finally, RGFP963, but not RGFP966, rescued memory in a mouse model of Alzheimer's Disease. Together, these studies suggest that the specific memory promoting properties of class I HDAC inhibitors may depend on isoform selectivity and that certain pathological brain states may be more receptive to HDAC inhibitors that improve network function by enhancing synapse efficacy.

Interference theory refers to the idea that forgetting occurs because the recall of certain items interferes with the recall of other items. Recently, it has been proposed that interference is due to an inhibitory control mechanism, triggered by competing memories, that ultimately causes forgetting [Anderson MC (2003) Rethinking interference theory: Executive control and the mechanisms of forgetting. J Mem Lang 49:415-4453]. In the present research we study the interference process by submitting CD1 mice to two different hippocampal-dependent tasks: a place object recognition task (PORT) and a step-through inhibitory avoidance task (IA). Our results show a mutual interference between PORT and IA. To elucidate the possible neural mechanism underlying the interference process, we submit hippocampus- and prefrontal cortex-lesioned mice to PORT immediately before IA training. Results from these experiments show that prefrontal cortex lesions completely revert the impairing effect exerted by PORT administration on IA memory, while hippocampus lesions, that as expected impair memory for both PORT and IA, increase this effect. Altogether our results suggest that interference-induced forgetting is driven by an inhibitory control mechanism through activation of hippocampus-prefrontal cortex circuitry. The hippocampus seems to be crucial for storing information related to both behavioral tasks. Competition between memories triggers the inhibitory control mechanism, by activating prefrontal cortex, and induces memory suppression.