Epigenetic regulation of learning and memory

Memories are recollections of actual events stored within our brains. But how is our brain able to form and store these memories? Epigenetic mechanisms influence genomic activities in the brain to produce long-term changes in synaptic signaling, organization, and morphology, which in turn support learning and memory (Day & Sweatt, 2011).

Neuronal activity in the hippocampus of mice is associated with changes in DNA methylation (Guo et al., 2011), and disruption to genes encoding the DNA methylation machinery cause learning and memory impairments (Feng et al., 2010). DNA methylation has also been implicated in the maintenance of long-term memories, as pharmacological inhibition of DNA methylation and impaired memory (Day & Sweatt, 2011; Miller et al., 2010). These findings indicate the importance of DNA methylation in mediating synaptic plasticity and cognitive functions, both of which are disturbed in psychological illness.

Changes in histone modifications can also influence long-term memory formation by altering chromatin accessibility and the expression of genes relevant to learning and memory. Memory formation and the associated enhancements in synaptic transmission are accompanied by increases in histone acetylation (Guan et al., 2002) and alterations in histone methylation (Schaefer et al., 2009), which promote gene expression. Conversely, a neuronal increase in histone deacetylase activity, which promotes gene silencing, results in reduced synaptic plasticity and impairs memory (Guan et al., 2009). Pharmacological inhibition of histone deacetylases augments memory formation (Guan et al., 2009; Levenson et al., 2004), further suggesting that histone (de)acetylation regulates this process.

In humans genetic defects in genes encoding the DNA methylation and chromatin machinery exhibit profound effects on cognitive function and mental health (Jiang, Bressler, & Beaudet, 2004). The two best-characterized examples are Rett syndrome (Amir et al., 1999) and Rubinstein-Taybi syndrome (RTS) (Alarcon et al., 2004), which are profound intellectual disability disorders. Both MECP2 and CBP are highly expressed in neurons and are involved in regulating neural gene expression (Chen et al., 2003; Martinowich et al., 2003).

Rett syndrome patients have a mutation in their DNA sequence in a gene called MECP2. MECP2 plays many important roles within the cell: One of these roles is to read the DNA sequence, checking for DNA methylation, and to bind to areas that contain methylation, thereby preventing the wrong proteins from being present. Other roles for MECP2 include promoting the presence of particular, necessary, proteins, ensuring that DNA is packaged properly within the cell and assisting with the production of proteins. MECP2 function also influences gene expression that supports dendritic and synaptic development and hippocampus-dependent memory (Li, Zhong, Chau, Williams, & Chang, 2011; Skene et al., 2010). Mice with altered MECP2 expression exhibit genome-wide increases in histone acetylation, neuron cell death, increased anxiety, cognitive deficits, and social withdrawal (Shahbazian et al., 2002). These findings support a model in which DNA methylation and MECP2 constitute a cell-specific epigenetic mechanism for regulation of histone modification and gene expression, which may be disrupted in Rett syndrome.

RTS patients have a mutation in their DNA sequence in a gene called CBP. One of these roles of CBP is to bind to specific histones and promote histone acetylation, thereby promoting gene expression. Consistent with this function, RTS patients exhibit a genome-wide decrease in histone acetylation and cognitive dysfunction in adulthood (Kalkhoven et al., 2003). The learning and memory deficits are attributed to disrupted neural plasticity (Korzus, Rosenfeld, & Mayford, 2004). Similar to RTS in humans, mice with a mutation of CBP perform poorly in cognitive tasks and show decreased genome-wide histone acetylation (for review, see Josselyn, 2005). In the mouse brain CBP was found to act as an epigenetic switch to promote the birth of new neurons in the brain. Interestingly, this epigenetic mechanism is disrupted in the fetal brains of mice with a mutation of CBP, which, as pups, exhibit early behavioral deficits following removal and separation from their mother (Wang et al., 2010). These findings provide a novel mechanism whereby environmental cues, acting through histone modifying enzymes, can regulate epigenetic status and thereby directly promote neurogenesis, which regulates neurobehavioral development.

Together, these studies demonstrate that misregulation of epigenetic modifications and their regulatory enzymes is capable of orchestrating prominent deficits in neuronal plasticity and cognitive function. Knowledge from these studies may provide greater insight into other mental disorders such as depression and suicidal behaviors.

Epigenetic mechanisms in psychological disorders

Epigenome-wide studies have identified several dozen sites with DNA methylation alterations in genes involved in brain development and neurotransmitter pathways, which had previously been associated with mental illness (Mill et al., 2008). These disorders are complex and typically start at a young age and cause lifelong disability. Often, limited benefits from treatment make these diseases some of the most burdensome disorders for individuals, families, and society. It has become evident that the efforts to identify the primary causes of complex psychiatric disorders may significantly benefit from studies linking environmental effects with changes observed within the individual cells.

Epigenetic events that alter chromatin structure to regulate programs of gene expression have been associated with depression-related behavior and action of antidepressant medications, with increasing evidence for similar mechanisms occurring in post-mortem brains of depressed individuals. In mice, social avoidance resulted in decreased expression of hippocampal genes important in mediating depressive responses (Tsankova et al., 2006). Similarly, chronic social defeat stress was found to decrease expression of genes implicated in normal emotion processing (Lutter et al., 2008). Consistent with these findings, levels of histone markers of increased gene expression were down regulated in human post-mortem brain samples from individuals with a history of clinical depression (Covington et al., 2009).

Administration of antidepressants increased histone markers of increased gene expression and reversed the gene repression induced by defeat stress (Lee, Wynder, Schmidt, McCafferty, & Shiekhattar, 2006; Tsankova et al., 2006; Wilkinson et al., 2009). These results provide support for the use of HDAC inhibitors against depression. Accordingly, several HDAC inhibitors have been found to exert antidepressant effects by each modifying distinct cellular targets (Cassel et al., 2006;Schroeder, Lin, Crusio, & Akbarian, 2007).

There is also increasing evidence that aberrant gene expression resulting from altered epigenetic regulation is associated with the pathophysiology of suicide (McGowan et al., 2008; Poulter et al., 2008). Thus, it is tempting to speculate that there is an epigenetically determined reduced capacity for gene expression, which is required for learning and memory, in the brains of suicide victims.

Epigenetic strategy to understanding gene-environment interactions

While the cellular and molecular mechanisms that influence on physical and mental health have long been a central focus of neuroscience, only in recent years has attention turned to the epigenetic mechanisms behind the dynamic changes in gene expression responsible for normal cognitive function and increased risk for mental illness. The links between early environment and epigenetic modifications suggest a mechanism underlying gene-environment interactions. Early environmental adversity alone is not a sufficient cause of mental illness, because many individuals with a history of severe childhood maltreatment or trauma remain healthy. It is increasingly becoming evident that inherited differences in the segments of specific genes may moderate the effects of adversity and determine who is sensitive and who is resilient through a gene-environment interplay. Genes such as the glucocorticoid receptor appear to moderate the effects of childhood adversity on mental illness. Remarkably, epigenetic DNA modifications have been identified that may underlie the long-lasting effects of environment on biological functions. This new epigenetic research is pointing to a new strategy to understanding gene-environment interactions.

The next decade of research will show if this potential can be exploited in the development of new therapeutic options that may alter the traces that early environment leaves on the genome. However, as discussed in this module, the epigenome is not static and can be molded by developmental signals, environmental perturbations, and disease states, which present an experimental challenge in the search for epigenetic risk factors in psychological disorders (Rakyan, Down, Balding, & Beck, 2011). The sample size and epigenomic assay required is dependent on the number of tissues affected, as well as the type and distribution of epigenetic modifications. The combination of genetic association maps studies with epigenome-wide developmental studies may help identify novel molecular mechanisms to explain features of inheritance of personality traits and transform our understanding of the biological basis of psychology. Importantly, these epigenetic studies may lead to identification of novel therapeutic targets and enable the development of improved strategies for early diagnosis, prevention, and better treatment of psychological and behavioral disorders.