Major depressive disorder is one of the most common mental illnesses as it affects more than 350 million people globally. Major depressive disorder is etiologically complex and disabling. Genetic ...factors play a role in the etiology of major depression. However, identical twin studies have shown high rates of discordance, indicating non‐genetic mechanisms as well. For instance, stressful life events increase the risk of depression. Environmental stressors also induce stable changes in gene expression within the brain that may lead to maladaptive neuronal plasticity in regions implicated in disease pathogenesis. Epigenetic events alter the chromatin structure and thus modulate expression of genes that play a role in neuronal plasticity, behavioral response to stress, depressive behaviors, and response to antidepressants. Here, we review new information regarding current understanding of epigenetic events that may impact depression. In particular, we discuss the roles of histone acetylation, DNA methylation, and non‐coding RNA. These novel mechanisms of action may lead to new therapeutic strategies for treating major depression.
•Synaptically localized transcriptional regulators, CRTC1, HDAC4 and NF-κB, can move to the nucleus upon neuronal stimulation.•Their phosphorylation status regulates their synaptic or nuclear ...localization.•These transcriptional regulators are unique, providing means of direct link between synaptic activity and gene transcription.
At the neuronal cell level, long-term memory formation emerges from interactions between initial activity-dependent molecular changes at the synapse and subsequent regulation of gene transcription in the nucleus. This in turn leads to strengthening of the connections back at the synapse that received the initial signal. However, the mechanisms through which this synapse-to-nucleus molecular exchange occurs remain poorly understood. Here we discuss recent studies that delineate nucleocytoplasmic transport of a special class of synaptically localized transcriptional regulators that upon receiving initial external signal by the synapse move to the nucleus to modulate gene transcription.
Stressful events during adulthood are potent adverse environmental factors that can predispose individuals to psychiatric disorders, including depression; however, many individuals exposed to ...stressful events can adapt and function normally. While stress vulnerability may influence depression, the molecular mechanisms underlying the susceptibility and adaptation to chronic stress within the brain are poorly understood. In this study, two genetically distinct mouse strains that exhibit different behavioral responses to chronic stress were used to demonstrate how the differential epigenetic status of the glial cell-derived neurotrophic factor (
Gdnf) gene in the ventral striatum modulates susceptibility and adaptation to chronic stress. Our results suggest that the histone modifications and DNA methylation of the
Gdnf promoter have crucial roles in the control of behavioral responses to chronic stress. Our data provide insights into these mechanisms, suggesting that epigenetic modifications of
Gdnf, along with genetic and environmental factors, contribute to behavioral responses to stress.
► Stress-induced impairment of GDNF synthesis increases depression-related behaviors ► HDAC2 is required for stress-induced Gdnf repression and behavioral deficits ► DNA methylation is required for stress-susceptible and stress-resilient phenotypes ► MeCP2-HDAC2 complexes contribute to stress-induced Gdnf repression
Postpartum depression is an important mental health issue not only for the mother but also for the child's development, other family members, and the society. An appropriate animal model is desired ...to elucidate the pathogenesis of postpartum depression. However, methods for stress loading during pregnancy have not been established. Behavioral experiments to investigate postpartum depression-like behaviors should be conducted without stress because behavioral tests affect rearing behaviors such as lactation. Therefore, we developed a new mouse model of postpartum depression using a psychological stress method. Mating partners were made to witness their partners experiencing social defeat stress and then listen to their cries. Emotional stress loading during pregnancy significantly increased postpartum depression-like behaviors. Postpartum depression also affected nurturing behaviors and caused disturbances in pup care. Furthermore, nesting behavior was impaired in the stressed group, suggesting that the observation of nesting behavior may be useful for assessing social dysfunction in postpartum depression. These results demonstrate the utility of this new mouse model of postpartum depression.
There is growing evidence suggesting that early life events have long-term effects on the neuroendocrine and behavioral developments of rodents. However, little is known about the involvement of ...early life events in the susceptibility to subsequent stress exposure during adulthood. The present study characterized the effect of maternal separation, an animal model of early life adversity, on the behavioral response to repeated restraint stress in adult rats and investigated the molecular mechanism underlying behavioral vulnerability to chronic stress induced by the maternal separation. Rat pups were separated from the dams for 180 min per day from postnatal day 2 through 14 (HMS180 rats). We found that, as young adults, HMS180 rats showed a greater hypothalamic-pituitary-adrenal axis response to acute restraint stress than nonseparated control rats. In addition, repeatedly restrained HMS180 rats showed increased depression-like behavior and an anhedonic response compared with nonrestrained HMS180 rats. Furthermore, HMS180 rats showed increased expression of REST4, a neuron-specific splicing variant of the transcriptional repressor REST (repressor element-1 silencing transcription factor), and a variety of REST target gene mRNAs and microRNAs in the medial prefrontal cortex (mPFC). Finally, REST4 overexpression in the mPFC of neonatal mice via polyethyleneimine-mediated gene transfer enhanced the expression of its target genes as well as behavioral vulnerability to repeated restraint stress. In contrast, REST4 overexpression in the mPFC of adult mice did not affect depression-like behaviors after repeated stress exposure. These results suggest that the activation of REST4-mediated gene regulation in the mPFC during postnatal development is involved in stress vulnerability.
Major depressive disorder (MDD) is a debilitating disease characterized by depressed mood, loss of interest or pleasure, suicidal ideation, and reduced motivation or hopelessness. Despite ...considerable research, mechanisms underlying MDD remain poorly understood, and current advances in treatment are far from satisfactory. The antidepressant effect of ketamine is among the most important discoveries in psychiatric research over the last half-century. Neurobiological insights into the ketamine’s effects have shed light on the mechanisms underlying antidepressant efficacy. However, mechanisms underlying the rapid and sustained antidepressant effects of ketamine remain controversial. Elucidating such mechanisms is key to identifying new therapeutic targets and developing therapeutic strategies. Accumulating evidence demonstrates the contribution of the glutamatergic pathway, the major excitatory neurotransmitter system in the central nervous system, in MDD pathophysiology and antidepressant effects. The hypothesis of a connection among the calcium signaling cascade stimulated by the glutamatergic system, neural plasticity, and epigenetic regulation of gene transcription is further supported by its associations with ketamine’s antidepressant effects. This review briefly summarizes the potential mechanisms of ketamine’s effects with a specific focus on glutamatergic signaling from a multiscale perspective, including behavioral, cellular, molecular, and epigenetic aspects, to provide a valuable overview of ketamine’s antidepressant effects.
The heterogeneity of major depressive disorder (MDD) is attributed to the fact that diagnostic criteria (e.g., DSM-5) are only based on clinical symptoms. The discovery of blood biomarkers has the ...potential to change the diagnosis of MDD. The purpose of this study was to identify blood biomarkers of DNA methylation by strategically subtyping patients with MDD by onset age. We analyzed genome-wide DNA methylation of patients with adult-onset depression (AOD; age ≥ 50 years, age at depression onset < 50 years; N = 10) and late-onset depression (LOD; age ≥ 50 years, age at depression onset ≥ 50 years; N = 25) in comparison to that of 30 healthy subjects. The methylation profile of the AOD group was not only different from that of the LOD group but also more homogenous. Six identified methylation CpG sites were validated by pyrosequencing and amplicon bisulfite sequencing as potential markers for AOD in a second set of independent patients with AOD and healthy control subjects (N = 11). The combination of three specific methylation markers achieved the highest accuracy (sensitivity, 64%; specificity, 91%; accuracy, 77%). Taken together, our findings suggest that DNA methylation markers are more suitable for AOD than for LOD patients.
Major depressive disorder (MDD) is a leading cause of disability worldwide. Although the etiology and pathophysiology of MDD remain poorly understood, aberrant neuroplasticity mediated by the ...epigenetic dysregulation of gene expression within the brain, which may occur due to genetic and environmental factors, may increase the risk of this disorder. Evidence has also been reported for sex-related differences in the pathophysiology of MDD, with female patients showing a greater severity of symptoms, higher degree of functional impairment, and more atypical depressive symptoms. Males and females also differ in their responsiveness to antidepressants. These clinical findings suggest that sex-dependent molecular and neural mechanisms may underlie the development of depression and the actions of antidepressant medications. This review discusses recent advances regarding the role of epigenetics in stress and depression. The first section presents a brief introduction of the basic mechanisms of epigenetic regulation, including histone modifications, DNA methylation, and non-coding RNAs. The second section reviews their contributions to neural plasticity, the risk of depression, and resilience against depression, with a particular focus on epigenetic modulators that have causal relationships with stress and depression in both clinical and animal studies. The third section highlights studies exploring sex-dependent epigenetic alterations associated with susceptibility to stress and depression. Finally, we discuss future directions to understand the etiology and pathophysiology of MDD, which would contribute to optimized and personalized therapy.
•The role of histone modification and DNA methylation in memory formation.•Transcription cofactor CRTC1 and its target gene Fgf1b is required for memory enhancement.•Epigenetic regulation of Fgf1 ...transcription modulated by CRTC1 is associated with memory strength.•CRTC1-dependent substitution of histone acetyltransferases following learning leads to memory enhancement.•CRTC1 and FGF1 may be involved in memory-related disorders.
Recent evidence demonstrates that epigenetic regulation of gene transcription is critically involved in learning and memory. Here, we discuss the role of histone acetylation and DNA methylation, which are two best understood epigenetic processes in memory processes. More specifically, we focus on learning-strength-dependent changes in chromatin on the fibroblast growth factor 1 (Fgf1) gene and on the molecular events that modulate regulation of Fgf1 transcription, required for memory enhancement, with the specific focus on CREB-regulated transcription coactivator 1 (CRTC1).
•Learning induces early and late phases in stathmin activity and microtubule stability.•Contextual fear conditioning is controlled by dentate gyrus stathmin.•In the late phase stathmin and ...microtubules control synaptic localization of AMPARs.•Aging and mental disorders may involve stathmin and microtubule changes.
Microtubules, one of the major cytoskeletal structures, were previously considered stable and only indirectly involved in synaptic structure and function in mature neurons. However, recent evidence demonstrates that microtubules are dynamic and have an important role in synaptic structure, synaptic plasticity, and memory. In particular, learning induces changes in microtubule turnover and stability, and pharmacological manipulation of microtubule dynamics alters synaptic plasticity and long-term memory. These learning-induced changes in microtubules are controlled by the phosphoprotein stathmin, whose only known cellular activity is to negatively regulate microtubule formation. During the first eight hours following learning, changes in the phosphorylation of stathmin go through two phases causing biphasic shifts in microtubules stability/instability. These shifts, in turn, regulate memory formation by controlling in the second phase synaptic transport of the GluA2 subunit of AMPA receptors. Improper regulation of stathmin and microtubule dynamics has been observed in aged animals and in patients with Alzheimer’s disease and depression. Thus, recent work on stathmin and microtubules has identified new molecular players in the early stages of memory encoding.
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