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      • Record: found
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      Serotonin rebalances cortical tuning and behavior linked to autism symptoms in 15q11-13 CNV mice

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          Abstract

          Serotonin enhancement during developmental stages restores autism symptoms in a mouse model of human 15q11-13 duplication.

          Abstract

          Serotonin is a critical modulator of cortical function, and its metabolism is defective in autism spectrum disorder (ASD) brain. How serotonin metabolism regulates cortical physiology and contributes to the pathological and behavioral symptoms of ASD remains unknown. We show that normal serotonin levels are essential for the maintenance of neocortical excitation/inhibition balance, correct sensory stimulus tuning, and social behavior. Conversely, low serotonin levels in 15q dup mice (a model for ASD with the human 15q11-13 duplication) result in impairment of the same phenotypes. Restoration of normal serotonin levels in 15q dup mice revealed the reversibility of a subset of ASD-related symptoms in the adult. These findings suggest that serotonin may have therapeutic potential for discrete ASD symptoms.

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          Most cited references37

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          Neocortical excitation/inhibition balance in information processing and social dysfunction.

          Ofer Yizhar, Lief Fenno, Matthias Prigge … (2011)
          Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30-80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms.
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            How inhibition shapes cortical activity.

            Jeffry S. Isaacson, Massimo Scanziani (2011)
            Cortical processing reflects the interplay of synaptic excitation and synaptic inhibition. Rapidly accumulating evidence is highlighting the crucial role of inhibition in shaping spontaneous and sensory-evoked cortical activity and thus underscores how a better knowledge of inhibitory circuits is necessary for our understanding of cortical function. We discuss current views of how inhibition regulates the function of cortical neurons and point to a number of important open questions. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Model of autism: increased ratio of excitation/inhibition in key neural systems.

              J. Rubenstein, M M Merzenich (2003)
              Autism is a severe neurobehavioral syndrome, arising largely as an inherited disorder, which can arise from several diseases. Despite recent advances in identifying some genes that can cause autism, its underlying neurological mechanisms are uncertain. Autism is best conceptualized by considering the neural systems that may be defective in autistic individuals. Recent advances in understanding neural systems that process sensory information, various types of memories and social and emotional behaviors are reviewed and compared with known abnormalities in autism. Then, specific genetic abnormalities that are linked with autism are examined. Synthesis of this information leads to a model that postulates that some forms of autism are caused by an increased ratio of excitation/inhibition in sensory, mnemonic, social and emotional systems. The model further postulates that the increased ratio of excitation/inhibition can be caused by combinatorial effects of genetic and environmental variables that impinge upon a given neural system. Furthermore, the model suggests potential therapeutic interventions.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Sci Adv
                Journal ID (iso-abbrev): Sci Adv
                Journal ID (publisher-id): SciAdv
                Journal ID (hwp): advances
                Title: Science Advances
                Publisher: American Association for the Advancement of Science
                ISSN (Electronic): 2375-2548
                Publication date Collection: June 2017
                Publication date (Electronic): 21 June 2017
                Volume: 3
                Issue: 6
                Electronic Location Identifier: e1603001
                Affiliations
                [1 ]RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
                [2 ]Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima 734-8553, Japan.
                [3 ]Graduate School of Biostudies, Kyoto University, Sakyo, Kyoto 606-8501, Japan.
                [4 ]Graduate School of Medicine, Nippon Medical School, Bunkyo, Tokyo 113-8602, Japan.
                [5 ]Department of Clinical Neurobiology, University Hospital and German Cancer Research Center, Heidelberg 69120, Germany.
                [6 ]RIKEN Center for Life Science Technologies, Chuo, Kobe 650-0047, Japan.
                [7 ]Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
                [8 ]Department of Anatomy and Embryology, Hokkaido University Graduate School of Medicine, Kita, Sapporo 060-8638, Japan.
                [9 ]Graduate School of Medicine, University of Tokyo, Bunkyo, Tokyo 113-8654, Japan.
                [10 ]Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan.
                Author notes
                [*]

                These authors contributed equally to this work.

                [† ]Corresponding author. Email: toru.takumi@ 123456riken.jp (T.T.); hsuzuki@ 123456nms.ac.jp (H.S.); y.watanabe@ 123456dkfz-heidelberg.de (Yasuhito Watanabe)
                Author information
                http://orcid.org/0000-0001-6270-049X
                http://orcid.org/0000-0001-5037-7138
                Article
                Publisher ID: 1603001
                DOI: 10.1126/sciadv.1603001
                PMC ID: 5479676
                PubMed ID: 28691086
                SO-VID: 714d9a39-51ba-4c93-92dc-a25ad97e1a18
                Copyright © Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                Date received : 30 November 2016
                Date accepted : 26 April 2017
                Categories
                Subject: Research Article
                Subject: Research Articles
                Subject: SciAdv r-articles
                Subject: Neuroscience
                Custom metadata
                Copyeditor Nova Morabe

                Keywords: autism spectrum disorder,mouse model,cnv,serotonin,behavior,15q duplication
                Data availability:
                Keywords: autism spectrum disorder, mouse model, cnv, serotonin, behavior, 15q duplication

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