22q11 deletion syndrome frequently accompanies schizophrenia. 22q11.2 deletion syndrome model mice showed schizophrenia - like behavioral abnormalities, which can be normalized by a GABAA receptor agonist, bretazenile or a GABAA α2/α3 receptor agonist, SL651498. Catechol-O- methytransferase (COMT) is in the 22q11 - deleted region. Virus - mediated- reintroduction of Comt, to the prefrontal cortex rescued behavioral abnormalities of 22q11.2 deletion syndrome model mice. Comt overexpression and Comt inhibition caused an abnormal responsiveness to a GABAA receptor agonist and affected interneuronal activation and GABA release. Our data suggest that Comt - mediated regulation of GABAergic system might be involved in the behavioral pathogenesis of 22q11.2 deletion syndrome model mice.

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Abnormalities in cortical GABAergic interneurons have been reported repeatedly in a number of postmortem studies of schizophrenia. Although the neurodevelopmental hypothesis is one of the most plausible etiological hypothesis of schizophrenia, it remains to be elucidated whether the GABAergic interneuron abnormalities is a primary cause of the disease or not. To examine this possibility, we utilized a mouse model of 22q11 deletion syndrome, which is associated with high prevalence of schizophrenia. We showed migration deficits of GABAergic interneurons in the developing cortex of the model mice. Neuregulin1-ErbB4 and Cxcl12-Cxcr4 signaling are indispensable for cortical interneuron migration. We demonstrated the expression of Cxcr4 decreased in 22q11 deletion syndrome model mice, leading to the migration deficits. These findings suggest a possible involvement of the developmental abnormalities of GABAergic interneurons in the pathogenesis of schizophrenia.

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Neuronal inhibition is essential for cognitive processes in the brain, but molecular mechanisms mediating activity - dependent regulation of inhibitory GABAergic interneurons remain unclear. Neuropsin proteolytically cleaved mature neuregulin 1 (NRG1) bound to extracellular glycosaminoglycans, liberating the soluble ligand, which activated its receptor, ErbB4. Processed NRG1 was directed to ErbB4 - and parvalbumin - expressing interneurons and subsequently activated GABAergic transmission. Neuropsin- knockout mice exhibited disruption of the excitation- inhibition balance (E/I balance) and impairments in long- term potentiation, both of which are essential in processing and storing information, reversed by application of the NRG1 ligand moiety. These results suggest that neuropsin regulates GABAergic interneurons through NRG1 - ErbB4 signaling during network activity and reveal mechanisms linking neuropsin/NRG1/ErbB4 signaling with network balance control that may be altered in patients with schizophrenia.

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Cognitive deficits of schizophrenia may be due at least in part to lower expression of the 67-kDa isoform of glutamic acid decarboxylase (GAD67) , a key enzyme for GABA synthesis, in the dorsolateral prefrontal cortex of individuals with schizophrenia. However, little is known about the molecular regulation of lower cortical GAD67 levels in schizophrenia. The GAD67 promoter region contains a conserved Zif268 binding site, and Zif268 activation is accompanied by increased GAD67 expression. Consequently, using postmortem brain tissues from 62 matched pairs of schizophrenia and healthy comparison subjects preser ved in the Department of Psychiatr y, University of Pittsburgh, USA, we examined whether altered expression of Zif268 may contribute to lower levels of GAD67 mRNA in the dorsolateral prefrontal cortex in schizophrenia. We found that GAD67 and Zif268 mRNA levels were significantly lower and were positively correlated in the schizophrenia subjects. In addition, these findings were robust to the effects of the confounding variables examined. Deficient Zif268 mRNA expression may contribute to lower cortical GAD67 levels in schizophrenia, suggesting a potential mechanistic basis for altered cortical GABA synthesis and impaired cognition in schizophrenia.

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Recent advances in electroneurophysiology (EEG/MEG, Optogenetics) and postmortem studies have revealed that cortical neural oscillation deficit play critical roles in the pathophysiology of schizophrenia. A growing body of evidence is accumulating to show that such synchronous oscillations especially within the γband which relates to perception, cognition and consciousness, exhibit deficits in schizophrenia. Impairments in γband oscillation have been hypothesized to arise from disruption of GABAergic inhibitory interneuron one act as a rhythm maker in neural circuit, and excitatory neuron (NMDAR hypofunction), as well as abnormal neuronal balance of excitation and inhibition (E/I balance). Moreover, these phenomena are believed to be observed across species and can be obtained from animal models of schizophrenia. Thus, γ band oscillation deficit have attracted a lot of attention as a new pathophysiological model of schizophrenia and its therapeutic target.

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Evidence from observational studies suggests that there is an association between depression and brain - derived neurotrophic factor (BDNF), polyunsaturated fatty acids (PUFAs), and folate; however, this association has yet to be examined in childhood and adolescent depression. The objective was to determine whether the BDNF, PUFAs, and folate in serum differ between first - episode childhood and adolescent depressed patients and healthy controls. We measured the serum levels of BDNF, PUFAs, and folate of cases admitted to the hospital for depression (n = 24) and compared it to that of controls (n = 26) . Subjects and their parents were informed about the nature and the purpose of this study, and a consent form was signed by parents. The ethics committee of Hirosaki University Graduate School of Medicine approved the study protocol. There were significant differences in the docosahexanoic acid (DHA) , arachidonic acid (AA) , and folate levels between cases and controls. Serum levels of DHA, AA, and folate levels in the patients group were statistically lower than those in the control group, while serum levels of BDNF were not different between cases and controls. These results are in line with findings of previous studies involving adult and elderly subjects, demonstrating lower levels of PUFAs and folate in patients with depression than healthy controls. However, further studies using a larger sample size are warranted.

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Genome- wide association studies (GWASs) have provided new insights of susceptibility genes for complex disorders, including psychiatric disorders. This review highlights the GWAS results of mood disorders. For Major depressive disorders (MDD), a number of GWASs have not detected the susceptibility genes so thus; this review will also present the issues regarding the phenotype and the gene- environment interaction of MDD.

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Blood (plasma or/and serum) levels were lower in patients with major depressive disorder (MDD) than those with healthy controls. In addition, a negative correlation was observed between the HAMD scores and blood BDNF levels. In the present study, we predicted the relapse of major depressive episode based on plasma BDNF levels, and we found plasma BDNF levels in relapse group decreased at least 6 months after the follow up point (baseline), however, those in remission group did not. The decrease in blood BDNF is an objective biological marker for relapse of majar depressive episode.

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Depression is not only a disorder of mood and affect but also a form of cognitive impairment. Patients with depression are shown to be impaired in a range of cognitive domains, including psychomotor speed, memory, attention, and executive function. Cognitive dysfunction also reportedly remains unresolved even after remission of depressive symptoms. Recent studies have found that cognitive impairments in depression predict treatment responsiveness, recurrence, and relapse. Furthermore, cognitive impairment may be a key factor affecting the patientʼs occupational and social functioning. Given that some antidepressants may cause drug - induced cognitive impairment, clinicians should be cautious in their use. Further investigations of these issues are needed because there is still a lack of good- quality studies.

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Besides the positive and negative symptoms, the cognitive deficits are now recognized as a core domain of schizophrenia (SZ). Here, we introduce recent advances in “The kynurenic acid (KYNA)hypothesis of SZ” based especially on the abnormally elevated levels of KYNA, a tryptophan metabolite on the kynurenine pathway, in the SZ prefrontal cortex and the cerebrospinal fluid possibly due to the decreased activity of kynurenine 3 -monooxygenase (KMO) . KYNA modulates glutamate, dopamine, and acetylcholine (Ach) signaling via NMDA- Receptor and α 7nAch-Receptor. The regulation of the kynurenine pathway by inflammatory mediators suggests immunological alterations and neuroinflammation-mediated dysregulation of kynurenine pathway which pertains partly to psychiatric disorders including SZ. Novel therapeutic targets for SZ are discussed according to this hypothesis, regarding especially the cognitive deficits in SZ.

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