A novel non‐toxic histone deacetylase inhibitor enhances spatial memory consolidation in male mice

Abstract

AbstractBackgroundMemory dysfunction is a hallmark of Alzheimer’s disease (AD) and other dementias, yet truly effective treatments for memory loss do not exist. Memory dysfunction stems in part from reduced gene expression that leads to decreased levels of proteins essential for neural plasticity. Gene expression is facilitated by histone acetylation, an epigenetic mechanism that regulates chromatin accessibility. Compounds that maintain histone acetylation, called histone deacetylase inhibitors (HDACi), enhance memory by preventing deacetylation of core histone proteins, which allows for transcriptional machinery to bind open chromatin and increase gene expression. Although HDACi are promising therapeutics that could be used to prevent or delay memory loss associated with AD and other dementias, existing HDACi have poor solubility and undesirable toxicity. To address these shortcomings, our group has developed a novel HDACi compound, MJM‐1, that is brain‐penetrant and shows no evidence of toxicity. Here, we determine the extent to which MJM‐1can enhance memory.MethodsMale C57BL/6 mice were tested in object placement (OP) and object recognition (OR) tasks, which were used to assess spatial and object recognition memory consolidation, respectively. Mice received a post‐training intraperitoneal (i.p.) injection of either negative control (100% DMSO), positive HDACi control (sodium butyrate; 0.6 g/kg NaBu), or one of three doses of MJM‐1(20, 30, or 40 µg/g). During testing, one training object was moved to a new location in the open field (OP task) or was replaced with a novel object (OR task). Mice who remember the training objects should spend more time with the moved and/or novel objects.ResultsMice receiving NaBu, 20 µg/g MJM‐1, or 40 µg/g MJM‐1 spent significantly more time with the moved object, whereas DMSO‐treated controls mice did not, suggesting that the established HDACi NaBu and two doses of the novel HDACi MJM‐1 enhanced spatial memory consolidation. Mice receiving the 30 µg/g dose of MJM‐1 also tended to prefer the moved object. Conversely, none of the doses of MJM‐1 affected object recognition memory.ConclusionThe novel non‐toxic brain penetrant HDACi MJM‐1 can enhance spatial memory consolidation, suggesting encouraging proof of principle for future testing in models of aging and AD.