Reassessing the effects of histone deacetylase inhibitors on hippocampal memory and cognitive aging

Abstract

Converging results link histone acetylation dynamics to hippocampus-dependent memory, including evidence that histone deacetylase inhibitor (HDACi) administration enhances long-term memory. Previously we demonstrated that aging disrupts the coordinated epigenetic response to recent experience observed in the young adult hippocampus. Here we extended that work to test the cognitive effects of a novel, brain-penetrant HDACi (EVX001688; EVX) that we confirmed yields robust, relatively long lasting dose-dependent increases in histone acetylation in the hippocampus. In young rats, acute systemic EVX administration, scheduled to yield elevated histone acetylation levels during training in a contextual fear conditioning (CFC) task, had no effect on memory retention at 24 hours at any dose examined (10, 30, or 60 mg/kg). Pretraining injection of another HDACi, sodium butyrate, also failed to affect fear memory, and CFC training itself had no influence on hippocampal histone acetylation at 1 hour in mice or two strains of rats. EVX administration before water maze training in young rats yielded a modest effect such that the middle dose produced marginally better 24-hour retention than either the low or high dose, but only a small numerical benefit relative to vehicle. Guided by those findings, a final experiment tested the influence of pretraining EVX treatment on age-related spatial memory impairment. The results, revealing no effect on performance, are consistent with the idea that effective procognitive HDACi treatments in aging may require intervention aimed at restoring coordinated epigenetic regulation rather than bulk increases in hippocampal histone acetylation.

7T Brain MRS in HIV Infection: Correlation with Cognitive Impairment and Performance on Neuropsychological Tests

“…However, we do not expect morphometric differences to significantly affect results, since metabolite ratios (relative to Cr) are relatively insensitive to voxel composition (particularly CSF contamination). Finally, no significant changes were observed in the hippocampus in this study, despite the well-known importance of this structure for memory and other age-related cognitive dysfunction 40, 54, 55 . Lack of significant findings may be in part due to the generally lower spectral quality obtained in this region due to magnetic susceptibility effects from bone/air/tissue interfaces proximal to the anterior temporal lobe, as well as partial volume with surrounding tissue due to the small size of the hippocampus.…”

Histone deacetylases in memory and cognition

“…Consistently, treatment with TSA, SAHA, or CI-994 either reduced the threshold for LTP induction or increased the magnitude of potentiation in the hippocampus and amygdala (17,19,24,27,30,32), although these effects were not always observed (33). Furthermore, multiple HDAC inhibitors improved performance in fear conditioning, object location, novel object recognition, food preference, and spatial memory tasks (24-27, 29-32, 34-38), again with some exceptions (19,33,39,40). Thus, endogenous HDAC activity clearly plays a critical role in cognitive performance and appears to normally restrain both structural and functional synaptic plasticity.…”

Epigenetic contributions to cognitive aging: disentangling mindspan and lifespan

“…For example, Castellano et al (2014) reported that 24-h retention of fear memory is unaffected in young rats provided pretraining injection of a potent, brain penetrant HDAC inhibitor (i.e., EVX001688, FORUM Pharmaceuticals) that they directly confirmed yields robust increases in hippocampal histone acetylation at the time of fear conditioning. Negative results were also obtained with the more commonly used HDAC inhibitor, sodium butyrate, and indeed in this case there was a clear trend toward impaired memory with treatment.…”

“…Castellano et al (2014), Epigenetic contributions to cognitive aging www.learnmem.org for example, reported that, rather than uniformly increasing histone H3 and H4 acetylation, behavioral training in multiple animal models, including strains and testing procedures adopted from earlier work (Levenson et al 2004;Peleg et al 2010), led to modest decreases or no change in hippocampal histone acetylation. Indeed other work from the same group suggests that bidirectional and subregion-specific regulation of experience-dependent histone acetylation might contribute to the different pattern of results observed across studies (Castellano et al 2012).…”

“…In contrast, performance in aged rats with impaired memory was entirely uncoupled from the status of the epigenetic modifications examined. A follow-up study taking advantage of this model examined the potential benefit of HDAC inhibitor administration, testing whether the marked increases in bulk hippocampal histone acetylation induced by pretraining injections of EVX001688 (EVX) are sufficient to rescue age-related impairment on a redundant placecue variant of the water maze (Castellano et al 2014). Unlike the benefit reported in aged mice that were provided other compounds (Peleg et al 2010), EVX had no effect on age-related memory deficits, despite confirmation that treatment induced robust increases in hippocampal histone acetylation at the time of learning.…”