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      Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders

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          Abstract

          Although the brains of patients with schizophrenia and bipolar disorder exhibit decreased brain pH relative to those of healthy controls upon postmortem examination, it remains controversial whether this finding reflects a primary feature of the diseases or is a result of confounding factors such as medication and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models that can be studied without confounds inherent in human studies. In the present study, we first reevaluated the pH of the postmortem brains of patients with schizophrenia and bipolar disorder by conducting a meta-analysis of existing data sets from 10 studies. We then measured pH, lactate levels, and related metabolite levels in brain homogenates from five neurodevelopmental mouse models of psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorder. All mice were drug naive with the same agonal state, postmortem interval, and age within each strain. Our meta-analysis revealed that brain pH was significantly lower in patients with schizophrenia and bipolar disorder than in control participants, even when a few potential confounding factors (postmortem interval, age, and history of antipsychotic use) were considered. In animal experiments, we observed significantly lower pH and higher lactate levels in the brains of model mice relative to controls, as well as a significant negative correlation between pH and lactate levels. Our findings suggest that lower pH associated with increased lactate levels is not a mere artifact, but rather implicated in the underlying pathophysiology of schizophrenia and bipolar disorder.

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          Interneuron dysfunction in psychiatric disorders.

          Schizophrenia, autism and intellectual disabilities are best understood as spectrums of diseases that have broad sets of causes. However, it is becoming evident that these conditions also have overlapping phenotypes and genetics, which is suggestive of common deficits. In this context, the idea that the disruption of inhibitory circuits might be responsible for some of the clinical features of these disorders is gaining support. Recent studies in animal models demonstrate that the molecular basis of such disruption is linked to specific defects in the development and function of interneurons - the cells that are responsible for establishing inhibitory circuits in the brain. These insights are leading to a better understanding of the causes of schizophrenia, autism and intellectual disabilities, and may contribute to the development of more-effective therapeutic interventions.
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            Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression.

            The dopamine system is unique among the brain's modulatory systems in that it has discrete projections to specific brain regions involved in motor behaviour, cognition and emotion. Dopamine neurons exhibit several activity patterns - including tonic and phasic firing - that are determined by a combination of endogenous pacemaker conductances and regulation by multiple afferent systems. Emerging evidence suggests that disruptions in these regulatory systems may underlie the pathophysiology of several psychiatric disorders, including schizophrenia and depression.
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              AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo.

              AMPK is a metabolic sensor that helps maintain cellular energy homeostasis. Despite evidence linking AMPK with tumor suppressor functions, the role of AMPK in tumorigenesis and tumor metabolism is unknown. Here we show that AMPK negatively regulates aerobic glycolysis (the Warburg effect) in cancer cells and suppresses tumor growth in vivo. Genetic ablation of the α1 catalytic subunit of AMPK accelerates Myc-induced lymphomagenesis. Inactivation of AMPKα in both transformed and nontransformed cells promotes a metabolic shift to aerobic glycolysis, increased allocation of glucose carbon into lipids, and biomass accumulation. These metabolic effects require normoxic stabilization of the hypoxia-inducible factor-1α (HIF-1α), as silencing HIF-1α reverses the shift to aerobic glycolysis and the biosynthetic and proliferative advantages conferred by reduced AMPKα signaling. Together our findings suggest that AMPK activity opposes tumor development and that its loss fosters tumor progression in part by regulating cellular metabolic pathways that support cell growth and proliferation. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Neuropsychopharmacology
                Neuropsychopharmacology
                Neuropsychopharmacology
                Nature Publishing Group
                0893-133X
                1740-634X
                February 2018
                04 August 2017
                06 September 2017
                1 February 2018
                : 43
                : 3
                : 459-468
                Affiliations
                [1 ]Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University , Toyoake, Japan
                [2 ]Schizophrenia Research Laboratory, Neuroscience Research Australia , Randwick, NSW, Australia
                [3 ]School of Psychiatry, University of New South Wales , Sydney, NSW, Australia
                [4 ]Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University , Fukuoka, Japan
                [5 ]Institute for Developmental Research, Aichi Human Service Center , Kasugai, Japan
                [6 ]RIKEN Tsukuba Institute , Tsukuba, Japan
                [7 ]Program of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institute of Health , Bethesda, MD, USA
                [8 ]Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University , Kyoto, Japan
                [9 ]Department of Pathology, Stanford University School of Medicine , Stanford, CA, USA
                Author notes
                [* ]Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Kutsukake-cho , Toyoake, Aichi 470-1192, Japan, Tel: +81 562 93 9376, Fax: +81 562 92 5382, E-mail: miyakawa@ 123456fujita-hu.ac.jp
                Author information
                http://orcid.org/0000-0003-0137-8200
                Article
                npp2017167
                10.1038/npp.2017.167
                5770757
                28776581
                46d2d631-84dd-447a-b00b-32b33d5fccf5
                Copyright © 2018 The Author(s)

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

                History
                : 04 May 2017
                : 14 July 2017
                : 01 August 2017
                Categories
                Original Article

                Pharmacology & Pharmaceutical medicine
                Pharmacology & Pharmaceutical medicine

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