Epigenetics is one of the most rapidly expanding fields in biology. The recent characterization of a human DNA methylome at single nucleotide resolution, the discovery of the CpG island shores, the finding of new histone variants and modifications, and the unveiling of genome-wide nucleosome positioning maps highlight the accelerating speed of discovery over the past two years. Increasing interest in epigenetics has been accompanied by technological breakthroughs that now make it possible to undertake large-scale epigenomic studies. These allow the mapping of epigenetic marks, such as DNA methylation, histone modifications and nucleosome positioning, which are critical for regulating gene and noncoding RNA expression. In turn, we are learning how aberrant placement of these epigenetic marks and mutations in the epigenetic machinery is involved in disease. Thus, a comprehensive understanding of epigenetic mechanisms, their interactions and alterations in health and disease, has become a priority in biomedical research.

Epigenetic modifications and human disease

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

All antidepressants in use today act via the monoamine neurotransmitters However, only ∼50% of individuals with depression show full remission Berton and Nestler review recent development of alternative, non-monoamine-based antidepressants, highlighting the obstacles and some of the most promising strategies All available antidepressant medications are based on serendipitous discoveries of the clinical efficacy of two classes of antidepressants more than 50 years ago These tricyclic and monoamine oxidase inhibitor antidepressants were subsequently found to promote serotonin or noradrenaline function in the brain Newer agents are more specific but have the same core mechanisms of action in promoting these monoamine neurotransmitters This is unfortunate, because only ∼50% of individuals with depression show full remission in response to these mechanisms This review summarizes the obstacles that have hindered the development of non-monoamine-based antidepressants, and provides a progress report on some of the most promising current strategies

New approaches to antidepressant drug discovery: beyond monoamines

| All available antidepressant medications are based on serendipitous discoveries of the clinical efficacy of two classes of antidepressants more than 50 years ago. These tricyclic and monoamine oxidase inhibitor antidepressants were subsequently found to promote serotonin or noradrenaline function in the brain. Newer agents are more specific but have the same core mechanisms of action in promoting these monoamine neurotransmitters. This is unfortunate, because only ∼50% of individuals with depression show full remission in response to these mechanisms. This review summarizes the obstacles that have hindered the development of non-monoamine-based antidepressants, and provides a progress report on some of the most promising current strategies.

New approaches to antidepressant drug discovery : beyond monoamines

Many neurological and most psychiatric disorders are not due to mutations in a single gene; rather, they involve molecular disturbances entailing multiple genes and signals that control their expression. Recent research has demonstrated that complex 'epigenetic' mechanisms, which regulate gene activity without altering the DNA code, have long-lasting effects within mature neurons. This review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in neurons that have been implicated in the regulation of complex behaviour, including abnormalities in several psychiatric disorders such as depression, drug addiction and schizophrenia.

https://focus.psychiatryonline.org/doi/pdf/10.1176/foc.8.3.foc435

Epigenetic regulation in psychiatric disorders

https://www.cell.com/neuron/pdf/S0896-6273(04)00302-2.pdf

Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration.

A Role in Learning for SRF: Deletion in the Adult Forebrain Disrupts LTD and the Formation of an Immediate Memory of a Novel Context

Prior work has shown that sweet taste–deficient T1R3 knockout (KO) mice developed significant sucrose preferences when given long-term sugar versus water tests. The current study investigated the role of olfaction in this experience-conditioned sucrose preference. T1R3 KO and C57BL/6 wild-type (WT) mice were given 24-h sugar versus water tests with ascending concentrations of sucrose (0.5–32%), after which the mice received olfactory bulbectomy (OBx) or sham surgery. When retested with sucrose, the Sham-KO mice preferred all sugar solutions to water, although their intake and preference were less than those of the Sham-WT mice. The OBx-KO mice, in contrast, showed no or weak preferences for dilute sucrose solutions (0.5–8%) although they strongly preferred concentrated sugar solutions (16–32%). OBx-WT mice displayed only a partial reduction in their sucrose preference. Although the OBx mice of both genotypes underconsumed dilute sucrose solutions relative to Sham mice, they overconsumed concentrated sucrose. These results indicate that olfaction plays a critical role in the conditioned preference of T1R3 KO mice for dilute sugar solutions. Further, the fact that OBx-KO mice preferred concentrated sucrose solutions in the absence of normal sweet taste and olfactory sensations underscores the potency of postoral nutritive signals in promoting ingestion.

Role of olfaction in the conditioned sucrose preference of sweet-ageusic T1R3 knockout mice.

Rats with lesions of the area postrema (APX) or sham lesions were trained to associate flavored solutions with positive or negative postingestive consequences. The APX rats were similar to controls in learning preferences for flavors paired with concurrent intragastric infusions of maltodextrin or corn oil and for a flavor paired with delayed maltodextrin infusions. In contrast, the APX rats displayed impaired aversion learning for flavors paired with toxic drug treatments (lithium chloride infusion or methylscopolamine injection). The aversion learning deficit ranged from mild to total, depending on training procedures. These findings confirm the important role of the area postrema in flavor-toxin learning but provide no evidence for its involvement in flavor-nutrient conditioning.

Khalid Touzani

Papers

Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration.

A Role in Learning for SRF: Deletion in the Adult Forebrain Disrupts LTD and the Formation of an Immediate Memory of a Novel Context

Role of olfaction in the conditioned sucrose preference of sweet-ageusic T1R3 knockout mice.

Area postrema lesions impair flavor-toxin aversion learning but not flavor-nutrient preference learning.

Ghrelin signaling is not essential for sugar or fat conditioned flavor preferences in mice.