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      Relaxin-3/RXFP3 networks: an emerging target for the treatment of depression and other neuropsychiatric diseases?

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          Abstract

          Animal and clinical studies of gene-environment interactions have helped elucidate the mechanisms involved in the pathophysiology of several mental illnesses including anxiety, depression, and schizophrenia; and have led to the discovery of improved treatments. The study of neuropeptides and their receptors is a parallel frontier of neuropsychopharmacology research and has revealed the involvement of several peptide systems in mental illnesses and identified novel targets for their treatment. Relaxin-3 is a newly discovered neuropeptide that binds, and activates the G-protein coupled receptor, RXFP3. Existing anatomical and functional evidence suggests relaxin-3 is an arousal transmitter which is highly responsive to environmental stimuli, particularly neurogenic stressors, and in turn modulates behavioral responses to these stressors and alters key neural processes, including hippocampal theta rhythm and associated learning and memory. Here, we review published experimental data on relaxin-3/RXFP3 systems in rodents, and attempt to highlight aspects that are relevant and/or potentially translatable to the etiology and treatment of major depression and anxiety. Evidence pertinent to autism spectrum and metabolism/eating disorders, or related psychiatric conditions, is also discussed. We also nominate some key experimental studies required to better establish the therapeutic potential of this intriguing neuromodulatory signaling system, including an examination of the impact of RXFP3 agonists and antagonists on the overall activity of distinct or common neural substrates and circuitry that are identified as dysfunctional in these debilitating brain diseases.

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          Most cited references217

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

          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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            Animal models of neuropsychiatric disorders.

            Modeling of human neuropsychiatric disorders in animals is extremely challenging given the subjective nature of many symptoms, the lack of biomarkers and objective diagnostic tests, and the early state of the relevant neurobiology and genetics. Nonetheless, progress in understanding pathophysiology and in treatment development would benefit greatly from improved animal models. Here we review the current state of animal models of mental illness, with a focus on schizophrenia, depression and bipolar disorder. We argue for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders, and for explicit guidelines when animal models are reported.
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              Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

              Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. Shank3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for development of 22q13 deletion syndrome (Phelan-McDermid Syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for Shank3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic like-behaviours in mice.
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                Author and article information

                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                21 March 2014
                2014
                : 5
                : 46
                Affiliations
                [1] 1Peptide Neurobiology Laboratory, Neuropeptides Division, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne VIC, Australia
                [2] 2Florey Department of Neuroscience and Mental Health, The University of Melbourne VIC, Australia
                [3] 3Department of Anatomy and Neuroscience, The University of Melbourne VIC, Australia
                Author notes

                Edited by: Laurence Lanfumey, Institut National de la Santé et de la Recherche Médicale, France

                Reviewed by: Sara Morley-Fletcher, Centre National de la Recherche Scientifique-University Lille, France; Pascal Bonaventure, Janssen Research & Development, LLC, USA

                *Correspondence: Craig M. Smith and Andrew L. Gundlach, Peptide Neurobiology Laboratory, Neuropeptides Division, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC 3052, Australia e-mail: craig.smith@ 123456florey.edu.au ; andrew.gundlach@ 123456florey.edu.au

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology.

                Article
                10.3389/fphar.2014.00046
                3968750
                24711793
                f1c29677-fc8d-40a3-b96c-8928a5413074
                Copyright © 2014 Smith, Walker, Hosken, Chua, Zhang, Haidar and Gundlach.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 28 October 2013
                : 28 February 2014
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 242, Pages: 17, Words: 0
                Categories
                Pharmacology
                Review Article

                Pharmacology & Pharmaceutical medicine
                relaxin-3,rxfp3,neuropeptide,arousal,stress,mood and depression,autism spectrum disorders,eating disorders

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