In this study, we investigated the pathophysiology of major depressive disorder (MDD) and of bipolar disorder (BD) by using near- infrared spectroscopy (NIRS) and magnetoencephalography (MEG). The study participants were segregated into 3 groups : the MDD, BD, and healthy control (HC) groups. During the verbal fluency task, compared to the HC group, the MDD group showed hypoactivation in the frontal lobe and the BD group showed delayed activation. During the talk and listen phases of the conversation task, the MDD group showed hypoactivation in the frontal lobe while the BD group did not show rhythmic [oxy - Hb] changes. The MDD and BD groups had lower mismatch field (MMNm) amplitudes indexing automatic attention; the duration of MMNm was prolonged only in the BD group. These results indicate that frontal activation decreased in the MDD group and was delayed in the BD group. The altered frontal activation in the MDD and BD groups may have been caused by the impairment at the level of automatic attention; however, further studies are required to confirm this issue.

View full abstract

We explained a general view about blood (serum or plasma) BDNF levels in depressed patients. Blood BDNF levels in depressed patients were significantly lower than those in age-and sex-matched healthy controls. A significantly negative correlation was found between serum BDNF levels and the HAMD-17 scores in depressed patients. Blood BDNF levels reflect both BDNF dynamics in the brain and the release from platelets. The specificity, but not sensitivity of blood BDNF is problematic. It might be ideal to combine matured BDNF with proBDNF which is involved in long-term depression and apoptosis for evaluating the depressive state.

View full abstract

Recent research has raised the notion that epigenetic mechanisms (e.g., DNA methylation and histone modifications), which exert lasting control over gene expression without altering the genetic code, could mediate stable changes in brain function. However, the role of environmental factors along with genetic factors in the epigenetic regulation of the pathogenesis of depression is largely unknown. Two genetically distinct mice strains that exhibit different behavioral responses to chronic stress were used to demonstrate how the differential epigenetic status of glial cell- derived neurotrophic factor (GDNF) gene in the ventral striatum modulates susceptibility and adaptation to chronic stress. Our results indicate crucial roles of histone modifications and DNA methylation by histone deacetylase2 (HDAC2) and MeCP2 for the control of GDNF expression and subsequent behavioral responses to chronic stress. In addition, we also investigated the effect of antidepressants on the epigenetic regulation of GDNF expression. We found that the antidepressants enhance the induction of GDNF transcription by the increased histone acetylation of GDNF gene promoter. Furthermore, HDAC4 inhibited the induction of GDNF by antidepressant. Finally, we investigated whether the expressions of GDNF and epigenetic- related molecules would be altered in mood disorder patients. We found the aberrant expression of GDNF, HDAC2, HDAC4 in mood disorder patients. Thus, our data provide novel insights, suggesting that epigenetic mechanisms of GDNF contribute to pathogenesis or pathophysiology of depression.

View full abstract

The role of genetic factors in bipolar disorder has been established. Recently, genome- wide association studies, relying on the common disease- common variant hypothesis, showed the association of several SNPs with bipolar disorder but the P- values and odds ratios were very low. With the development of DNA sequencing technology, an alternative hypothesis, common disease- rare variant hypothesis, becomes testable. We focused on the POLG1 gene and searched for rare variants in 505 patients with bipolar disorder and 550 controls obtained from multi - center collaborative study in Japan. POLG1 encodes mitochondrial DNA polymerase and is one of causative genes for chronic progressive external ophthalmoplegia (CPEO), which is a mitochondrial disease and occasionally accompanied by mood disorders. We identified dozens of nonsynonymous variants of POLG1. We are now screening them for deleterious variants by using several methods : biochemical experiments (in vitro), referring to clinical data of CPEO patients with POLG1 variants (in vivo), and computer prediction tools (in silico). In this article, we also discuss important issues with rare variant studies, which were noticed in the course of our study.

View full abstract

A growing evidence of the stress vulnerability in response to early adversities, maternal care plays an important role in the development of susceptibility to mental disorders. In this article, we would like to show the involvement of early adversi-ty in the development of the stress vulnerability, using neonatal isolation, postpartum depression model, and early lighting condition. In addition, we would like to demonstrate how environmental enrichment after weaning ameliorates the stress vulnerability in response to early adversities.

View full abstract

We hypothesized that dysfunction of mitochondria in the brain is involved in the pathophysiology of bipolar disorder (BD). We previously reported that neuron - specific mutant Polg1 (mitochondria DNA polymerase) transgenic (Tg) mice exhibited BD- like phenotypes and proposed that the Tg mice would be an animal model of bipolar disorder. We examined gene expression profiles in the brains of the Tg mice using DNA microarray analysis and the obtained data were compared with the data in the postmortem brains of patients with bipolar disorder. We found that PPIF showed similar changes. PPIF encodes cyclophilin D (CypD), a component of the mitochondrial permeability transition pore. A CypD inhibitor, NIM811, significantly improved the abnormal behavior of the Tg mice. These findings suggest that CypD is a promising target for a new drug for BD and our model mouse is useful for the development of new mood stabilizers.

View full abstract

The forced swim test (FST) is a behavioral test widely used to evaluate the potential efficacy of antidepressant drugs in rats or mice. Here we reviewed the results of preceding researches on the neuronal responses and the mechanisms of antidepressant actions in the FST. Several brain regions have been implicated in behavioral control during the FST; the cingulate cortex, bed nucleus of stria terminalis, lateral septal nucleus, amygdala, hippocampal formation, hypothalamus, periaqueductal gray, raphe nuclei and locus coeruleus. The results were highly complex, and further research will be needed on functional neuroanatomy of the FST.

View full abstract

The pathological mechanisms underlying schizophrenia are unclear in spite of the numerous successful findings from human genetics. Although genetic susceptibility factors for schizophrenia likely influence neurodevelopmental processes, the onset of the disease is in adolescence and young adulthood. Here we overview recent literatures implicating neurodevelopmental deficits in schizophrenia and discuss how genetic factors function during late neurodevelopment. We emphasize the importance of postnatal glutamate synapse development in the pathology of the disorder, particularly focusing on the synaptic function of DISC1 (Disrupted- In- Schizophrenia- 1) . These genetic risk factors contribute to the process possibly in a synergistic manner, which might be involved in the processes toward onset of the disease. The notion of signal pathways involving more than one genetic factor is in accord with the multifactorial nature of schizophrenia.

View full abstract