Histone deacetylases (HDACs) are part of a vast family of enzymes that have crucial roles in numerous biological processes, largely through their repressive influence on transcription. The expression of many HDAC isoforms in eukaryotic cells raises questions about their possible specificity or redundancy, and whether they control global or specific programmes of gene expression. Recent analyses of HDAC knockout mice have revealed highly specific functions of individual HDACs in development and disease. Mutant mice lacking individual HDACs are a powerful tool for defining the functions of HDACs in vivo and the molecular targets of HDAC inhibitors in disease.

The many roles of histone deacetylases in development and physiology: Implications for disease and therapy

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within ...

The Microbiota-Gut-Brain Axis

This report builds on a highly valued predecessor, the 1994 Institute of Medicine (IOM) report entitled Reducing Risks for Mental Disorders: Frontiers for Preventive Intervention Research. That report provided the basis for understanding prevention science, elucidating its then-existing research base, and contemplating where it should go in the future. This report documents that an increasing number of mental, emotional, and behavioral problems in young people are in fact preventable. The proverbial ounce of prevention will indeed be worth a pound of cure: effectively applying the evidence-based prevention interventions at hand could potentially save billions of dollars in associated costs by avoiding or tempering these disorders in many individuals. Furthermore, devoting significantly greater resources to research on even more effective prevention and promotion efforts, and then reliably implementing the findings of such research, could substantially diminish the human and economic toll.

Preventing Mental, Emotional, and Behavioral Disorders Among Young People: Progress and Possibilities

Alzheimer mechanisms and therapeutic strategies.

Chromatin modifications, especially histone-tail acetylation, have been implicated in memory formation. Increased histone-tail acetylation induced by inhibitors of histone deacetylases (HDACis) facilitates learning and memory in wild-type mice as well as in mouse models of neurodegeneration. Harnessing the therapeutic potential of HDACis requires knowledge of the specific HDAC family member(s) linked to cognitive enhancement. Here we show that neuron-specific overexpression of HDAC2, but not that of HDAC1, decreased dendritic spine density, synapse number, synaptic plasticity and memory formation. Conversely, Hdac2 deficiency resulted in increased synapse number and memory facilitation, similar to chronic treatment with HDACis in mice. Notably, reduced synapse number and learning impairment of HDAC2-overexpressing mice were ameliorated by chronic treatment with HDACis. Correspondingly, treatment with HDACis failed to further facilitate memory formation in Hdac2-deficient mice. Furthermore, analysis of promoter occupancy revealed an association of HDAC2 with the promoters of genes implicated in synaptic plasticity and memory formation. Taken together, our results suggest that HDAC2 functions in modulating synaptic plasticity and long-lasting changes of neural circuits, which in turn negatively regulates learning and memory. These observations encourage the development and testing of HDAC2-selective inhibitors for human diseases associated with memory impairment.

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HDAC2 negatively regulates memory formation and synaptic plasticity

Neurodegenerative diseases of the central nervous system are often associated with impaired learning and memory, eventually leading to dementia An important aspect in pre-clinical research is the exploration of strategies to re-establish learning ability and access to long-term memories By using a mouse model that allows temporally and spatially restricted induction of neuronal loss, we show here that environmental enrichment reinstated learning behaviour and re-established access to long-term memories after significant brain atrophy and neuronal loss had already occurred Environmental enrichment correlated with chromatin modifications (increased histone-tail acetylation) Moreover, increased histone acetylation by inhibitors of histone deacetylases induced sprouting of dendrites, an increased number of synapses, and reinstated learning behaviour and access to long-term memories These data suggest that inhibition of histone deacetylases might be a suitable therapeutic avenue for neurodegenerative diseases associated with learning and memory impairment, and raises the possibility of recovery of long-term memories in patients with dementia

Recovery of learning and memory is associated with chromatin remodelling

The pathogenesis of emotional disorders often involves associative learning that links anxiogenic stimuli to certain life experiences. Among these are phobias and post-traumatic stress disorders that severely affect the life of patients and are an increasing burden to our societies. Treatment of such disorders generally involves the promotion of extinction processes, which are defined as the reduction of an aversively motivated behavior. Therefore, understanding the molecular mechanisms underlying extinction may help to develop therapeutic strategies for emotional disorders. Here, we discuss recent advances in the understanding of the molecular machinery that regulates the extinction of learned fear in mice. On this basis, we suggest that extinction is regulated by counteracting signaling pathways that either promote or prevent extinction of fear. Targeting such pathways should be beneficial for the treatment of patients suffering from anxiety disorders.

Counteracting Molecular Pathways Regulating the Reduction of Fear: Implications for the Treatment of Anxiety Diseases

PROBLEM TO BE SOLVED: To provide a compound useful for inhibition of histone deacetylase (HDAC), a pharmaceutically acceptable salt, hydrate and solvate thereof.SOLUTION: There is provided a compound represented by the formula (I). U is a single bond, NR, NR-NRor O, J is NHor SH, V is C or N, when V is N, one of Rto Rdoes not exist, X each independently is H, D, methyl, CFor halogen, two of Rto Rjoint together to be C3 to 8 cycloalkyl, C4 to C8 cycloalkenyl or 3 to 8-membered saturated/partially unsaturated heterocyclic and remaining Rto Rdo not exist or is H, halogen, OH, NHor C1 to 8 alkyl and t is an integer of 0 to 2.SELECTED DRAWING: None

Histone deacetylase inhibitor

Verwendung von ci-994 und dinalin zur behandlung von gedächtnis-/kognitiven und angststörungen

L'invention concerne des procedes et des compositions pour favoriser la fonction cognitive et/ou traiter des troubles et deficiences de la fonction cognitive. En particulier, les procedes sont accomplis par l'administration a un sujet de CI-994 ou d'un sel, ester, promedicament ou metabolite pharmaceutiquement acceptable de celui-ci.

Li-Huei Tsai

Papers

Recovery of learning and memory is associated with chromatin remodelling

Counteracting Molecular Pathways Regulating the Reduction of Fear: Implications for the Treatment of Anxiety Diseases

Histone deacetylase inhibitor

Verwendung von ci-994 und dinalin zur behandlung von gedächtnis-/kognitiven und angststörungen

Utilisation de ci-994 et de dinaline pour le traitement de troubles de la mémoire/cognition et de l'anxiété