SLC6A4 (solute carrier family 6, member 4) gene encodes a serotonin transporter (5-hydroxytryptamine transporter, HTT) , whose epigenetic regulation is assumed to be related to occurrence of mental disorders such as major depression and bipolar disorder. DNA methylation at the promoter CpG island and CpG island shore region inversely correlates with gene expression level. A functional polymorphism, HTT- linked polymorphic region (HTTLPR) and DNA methylation are thought to regulate gene expression of SLC6A4 cooperatively. By examining brain and peripheral blood samples, hypermethylation of SLC6A4 at the CpG island shore in bipolar disorder was identified. DNA methylation at the same CpG site was down- regulated in human neuroblastoma cells treated with mood stabilizers. DNA methylation of SLC6A4 at the CpG island shore can become sensitive marker of gene- environment interaction in mental disorders.

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DNA methylation is one of the major epigenetic mechanisms. We will introduce clinical DNA methylation studies of schizophrenia in this article. Attention to its role of DNA methylation in schizophrenia has recently increased because it has been shown that the environmental factors can influence the DNA methylation status, and the altered DNA methylation can affect gene expressions and behaviors. Like genetic studies, technological advances in DNA methylation enable us to perform genome - wide methylome analyses using a microarray and a next - generation sequencing. These epigenetic approaches will be useful to reveal novel molecular mechanisms of schizophrenia.

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Early-life stress affects brain development and contributes to psychiatric disorders. Adult neurogenesis in the dentate gyrus (DG) is also involved in psychiatric disorders and early-life stress decreases adult neurogenesis in DG. These suggest that early-life stress might contribute to psychiatric disorders via adult neurogenesis in DG. Here we examined the effects of maternal separation (MS) in early-life on adult rat DG-derived neural precursors (ADP) . In MS group, pups were separated from mothers for 3 hours daily from postnatal day (PND) 2 to 14. At PND 56, ADP were isolated from both groups. Effects of MS on ADP were examined with immunocytochemistry. An epigenetic mechanism underlying them was investigated with DNA methyltransferase inhibitor (DNMT-i) . MS attenuated ADP differentiation into neuron. DNMT-i recovered MS-attenuated neural differentiation. MS decreased DNMT1 expression. These suggest that MS-increased DNA methylation might be involved in MS-attenuated ADP neural differentiation. Next, we focused on RARα as a candidate gene in which DNA methylation is altered by MS. MS decreased RARα expression. RARα agonist and antagonist reciprocally affected neural differentiation. DNMT-i recovered MS-decreased RARα expression. MS increased DNA methylation in RARαpromoter. Therefore, MS may attenuate ADP neural differentiation via increasing DNMT1 expression and DNA methylation in RARα promoter.

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Disruptions of epigenetic mechanisms are known to be causative for several neurodevelopmental disorders such as autism, rett syndrome (RTT) , attention deficit hyperactive disorder (ADHD) . RTT is caused by mutation in the X- linked gene methyl- CpG binding protein 2 (MECP2) . MeCP2 has a lot of targets and complex roles that encompass activating or repressing gene transcription, regulating chromatin remodeling, and altering non - coding RNAs. Although MeCP2 is important for neuronal function, recent studies suggest that glial cells, such as astrocytes, oligodendrocytes and microglia, likely control the progression of RTT. Recently, several works have described the generation and characterization of iPSC- derived neurons from autism and RTT patients. Neurons differentiated from RTT- iPSCs showed the recapitulation of RTT phenotypes. The iPSCs make a contribution to not only underlying of RTT pathology but also development of new therapeutic agents. Furthermore, early- life adversity increases the risk for neurodevelopmental disorders. The underlying mechanism suggests that prenatal exposures to tobacco smoke, alcohol and persistent organic pollutants cause aberrant DNA methylation patterns. Because epigenetic mechanisms are intrinsically reversible, there are great hopes that epigenetic drugs have been conducting for treatment of neurodevelopmental disorder.

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We previously reported that a certain subtype of schizophrenic patients exhibit idiopathic carbonyl stress with high plasma pentosidine levels and serum vitamin B6 depletion, which is referred to as carbonyl stress, without underlying diabetes or chronic kidney disease that are the two major cause of elevation of advanced glycation end products (AGEs) . Furthermore, we found the correlation between carbonyl stress and clinical features such as high ratio of inpatients, long duration of hospitalization, higher daily doses of anti - psychotics and lower educational status, suggesting that those patients might be treatment - registrant cases. We attempted to find associations between cognitive impairments and biochemical data. Schizophrenics were divided into four groups by their levels of pentosidine and vitamin B6, and we assessed the symptom severity by the Manchester Scale Japanese version, the cognitive function by Wechsler Adult Intelligence Scale 3rd version and Wisconsin card sorting test. We found that symptoms in high - risk group with high pentosidine and low vitamin B6 had a tendency to severe incoherence of thought and lower performance for digit span compared to that of other groups. Our preliminary data suggest that carbonyl stress might be associated with impaired working memory in schizophrenia. The comprehensive information covering in vitro and in vivo studies is important for evidence- based personalized for schizophrenic patients.

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Accumulating evidence suggests that oxidative stress and inflammation play a role in the pathophysiology of schizophrenia. Blood levels of pro - inflammatory cytokines in patients with schizophrenia were significantly higher than those of healthy controls. Furthermore, brain imaging studies using positron emission tomography (PET) suggest that microglial activation is detected in the brain of patients with schizophrenia. Taken together, antioxidants and anti - inflammatory compounds have been proposed as the novel therapeutic drugs for schizophrenia. Here the author would like to discuss the possibility of antioxidants (N-acetyl cysteine and sulforaphane) as prophylactic compounds for the onset of schizophrenia.

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Nonresolving low - grade inflammation is supposed to underly the basis of chronic disorders including cancer, type 2 diabete, cardiovascular diseases, obesity and psychiatric disorders such as depression. There is increasing evidence suggesting that pathophysiology of psychiatric disorders is related to the inflammatory responses mediated by microglial cells. Elevation of intracellular Ca2+ is important in activation of microglial cell functions, including proliferation, release of NO, cytokines and BDNF. It has been shown that alteration of intracellular Ca2+ signaling underlies the pathophysiology of psychiatric disorders, including schizophrenia, depression and bipolar disorders. Microglial cells are able to respond to BDNF, which may be important for the regulation of inflammator y responses, and may also be involved in the pathophysiology and/or the treatment of psychiatric disorders.

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Carbonyl group of reducing sugar non - enzymatically react with amino groups of amino acids and proteins, causing a condensation reaction. This reaction is named the Maillard reaction because French food chemist, Louis Camille Maillard, discovered the reaction. This reaction is divided into roughly two steps, Amadori rearrangement products typified by hemoglobin A1c (HbA1c) that is already measured worldwide as a clinical marker for blood glucose level in patients with diabetes. This early product is converted into Advanced Glycation End- products (AGEs) by oxidation and condensation reaction. Although the reaction was primarily considered to progress slowly from glucose in vivo, recent studies demonstrate that highly reactive carbonyl compounds produced from the glycolysis, lipid peroxidation by inflammatory responses generate AGEs more rapidly than glucose. Although AGEs is mainly studied in the field of age- related diseases and lifestyle-related diseases, the involvement of AGEs for mental illness, including schizophrenia has been reported as the measurement system of AGEs is gradually established.

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Growing evidence has implicated nutritional impairments in depressive disorder. However, nutritional data in Japanese patients with major depressive disorder (MDD) is scarce. Here we present our preliminary results from our survey on MDD patients and healthy controls. We found that overweight and dyslipidemia were more frequent in MDD patients compared with controls. Low level of serum folate (< 4.0 ng/mL) was more common in patients than in controls. Plasma tryptophan concentration was decreased in MDD patients, which was consolidated by our meta - analysis on previous studies. Against our expectation, we obtained no significant difference in blood levels of n - 3 polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid) , ferritin (marker for stored iron) , or zinc between the two groups. Interestingly, green tea consumption was less frequent in the patients than in the controls. These results indicate the importance of nutritional approach to depressive disorder.

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Chronic stress is the main risk factor in the development of depression and may cause hippocampal dysfunction resulting in memory deficits and HPS - axis hyperactivity. The reduction of adult hippocampal neurogenesis (AHN) and resultant hippocampal atrophy would also occur in patients with major depression. As a complementary therapy, stress - free mild exercise would be possible candidate, since even acute mild exercise below lactate threshold (LT) activates hippocampal neurons and its two weeks exercise training resulted in enhanced AHN, like antidepressant treatment and electroconvulsive therapy, which might be beneficial for depression. In our current study using rats, we found that 2 weeks of ME, that is defined below the LT enhanced AHN in mediating neurosteroid, dihydrotestosterone (DHT) , which is synthesized in hippocampus via de novo synthesis, and BDNF and IGF-Ⅰ may also be associated with its promoting AHN. Furthermore, in the six - week of mild exercise model that enhanced both AHN and spatial memory, we found that AHN are related to lipid metabolism (APOE) , protein synthesis (IGF2, IRS1) , and inflammatory response (IL1B, TNF) , known to be facilitatory factor for AHN. These results might serve in further elucidating the main pathway behind mild exercise - enhanced AHN and spatial memory. Collectively, it is tempting to conclude that even mild exercise, which is useful for anybody even vulnerable peoples, could have potential clinical impacts for depression, like depressants.

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In Japan, the number of patients with depression is increasing. Although psychotherapy, drug therapy, environmental manipulation, and other strategies are applied in treating depression, the remission rates are not necessarily high. Furthermore, even if remission is achieved and allows patients to return to work, the rates of repeated work absences are also known to be high. In addition to the current therapeutic strategies, non - drug therapies are also expected to be important. Among such treatments, exercise therapy has a large role. In the treatment of depression, exercise therapy may contribute to relieving psychiatric symptoms through the noradrenergic nervous system and to allow continuation of work through the maintenance of high physical activity. In terms of preventing depression, exercise therapy is also considered to play a large role and expected to be effective in alleviating depressive symptoms and improving the sleep rhythm.

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