A collaborative international study between researchers at Duke University and two different Japanese universities has recently yielded important insight into the role of histone deacetylases (Hdacs) in the normal emotional centers of the brain. This research, which was published last week in the journal PLoS, provides evidence that these enzymes may be responsible for a significantly greater number of cellular and physiological processes than what has been previously recognized, and provides a novel target for the potential therapeutic intervention in emotional disorders such as schizophrenia, depression and anxiety.

The role of Hdacs in cellular processes was initially investigated with regard to these enzymes’ interactions with nuclear histones. Histones are the protein component of chromatin, and essentially act as “spools” to which DNA is spun around. To access the genetic data encoded in the DNA, different types of enzymes involved in the processes of replication, repair, and transcription must be able to access the DNA component, a feat which requires differential accessibility of the genetic data to specific factors. A number of different enzymes have been shown to alter this accessibility, and a great deal of research has been devoted to deciphering the “histone code” which allows access to certain DNA regions based on combinations of specific post-translational modifications such as methylation, acetylation, SUMOylation, and ubiquitination. In particular, the influence of acetylation (which serves to make DNA more accessible) and methylation (which has variable effects) on these processes has been rigorously investigated, and an adequate understanding of these modifications has been achieved.

Through these studies, the histone deacetylase enzymes have been well characterized based on their effects on chromatin access, but their roles in interactions with non-histone proteins is still not well understood. These enzymes share the common characteristic of removing acetyl groups from lysine residues on various proteins, and this removal is thought to play an important role in a variety of processes such as interactions between different protein complexes, protein degradation, cellular motility, autophagic and apoptotic cell death, and vesicular transport. Specifically, the interaction of these Hdacs with the proteins α-tubulin, cortactin, and Hsp90 are thought to be of significant importance, and could underlie a number of these integral cellular processes.

In the published study, the researchers were interested specifically in the role of Hdac6, which they were able to show is localized to the dorsal and median raphe nuclei of the brainstem, a region which has been identified as playing an important role in the regulation of emotional activity. This brain region is the center of serotonergic innervations to the rest of the brain, and so the role of Hdac6 in these cells could play an important role in the modulation of emotional behavior, possibly through modulating neuronal projections to the limbic system. As this region seems to be related to neurological defects which occur during the onset of schizophrenia, depression, and a number of anxiety disorders, an understanding of the intracellular actions of Hdac6 could be especially helpful to those afflicted by such illnesses.

Through a number of different behavioral studies in mice, these researchers were able to show that the loss of Hdac6 in raphe nuclei leads to an increase in physical activity, as well as a decrease in both anxiety and depression-like symptoms. These behavioral changes were attributed to a general increase in emotional arousal, which was presumably altered by the changes to Hdac6 activity. As this type of arousal is generally considered to parallel various stress responses, the mice were also measured for increases to serum glucocorticoid levels, a marker of increased HPA (hypothalamic-pituitary-adrenal) axis activation. These results appeared to be negative, suggesting that the knockout mice were not exhibiting any sort of increase in basal stress levels. Further, it was shown that knockout mice which did not express the Hdac6 gene were able to develop and function normally, without any measurable deficits to other physiological processes.

Finally, when normal mice were exposed to NCT-14b, an inhibitor of Hdac6, it was shown that antidepressant-like activity was produced, and that NCT-14B could effectively modulate this effect in mouse models. Collectively, these results suggest a novel role for Hdac6 which has not been previously appreciated. Through unknown actions in raphe nuclei (the authors showed that serotonin synthesis was not affected), Hdac6 seems to play some sort of role in emotional arousal, and therapeutic blockade of this enzyme can result in changes to behavioral characteristics related to a variety of emotional disorders.

Though these results have only been demonstrated in mouse models, this new information concerning the role of Hdac6 with non-histone proteins could provide important implications for future therapies directed at curtailing the emotional arousal associated with a variety of emotional disorders, including depression, schizophrenia, and anxiety disorders.

Original Research Paper