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      Calbindin Deficits May Underlie Dissociable Effects of 5-HT 6 and mGlu 7 Antagonists on Glutamate and Cognition in a Dual-Hit Neurodevelopmental Model for Schizophrenia

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          Abstract

          Despite several compounds entering clinical trials for the negative and cognitive symptoms of schizophrenia, few have progressed beyond phase III. This is partly attributed to a need for improved preclinical models, to understand disease and enable predictive evaluation of novel therapeutics. To this end, one recent approach incorporates “dual-hit” neurodevelopmental insults like neonatal phencyclidine plus isolation rearing (PCP-Iso). Glutamatergic dysfunction contributes to schizophrenia pathophysiology and may represent a treatment target, so we used enzyme-based microsensors to evaluate basal- and drug-evoked glutamate release in hippocampal slices from rats that received neonatal PCP and/or isolation rearing. 5-HT 6 antagonist-evoked glutamate release (thought to be mediated indirectly via GABAergic disinhibition) was reduced in PCP-Iso, as were cognitive effects of a 5-HT 6 antagonist in a hippocampal glutamate-dependent novel object discrimination task. Yet mGlu 7 antagonist-evoked glutamatergic and cognitive responses were spared. Immunohistochemical analyses suggest these findings (which mirror the apparent lack of clinical response to 5-HT 6 antagonists in schizophrenia) are not due to reduced hippocampal 5-HT input in PCP-Iso, but may be explained by reduced calbindin expression. This calcium-binding protein is present in a subset of GABAergic interneurons receiving preferential 5-HT innervation and expressing 5-HT 6 receptors. Its loss (in schizophrenia and PCP-Iso) would be expected to reduce interneuron firing and potentially prevent further 5-HT 6 antagonist-mediated disinhibition, without impacting on responses of VIP-expressing interneurons to mGlu 7 antagonism. This research highlights the importance of improved understanding for selection of appropriate preclinical models, especially where disease neurobiology impacts on cells mediating the effects of potential therapeutics.

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          The online version of this article (10.1007/s12035-020-01938-x) contains supplementary material, which is available to authorized users.

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          Most cited references 114

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          Interneurons of the hippocampus.

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            Animal models of schizophrenia.

            Developing reliable, predictive animal models for complex psychiatric disorders, such as schizophrenia, is essential to increase our understanding of the neurobiological basis of the disorder and for the development of novel drugs with improved therapeutic efficacy. All available animal models of schizophrenia fit into four different induction categories: developmental, drug-induced, lesion or genetic manipulation, and the best characterized examples of each type are reviewed herein. Most rodent models have behavioural phenotype changes that resemble 'positive-like' symptoms of schizophrenia, probably reflecting altered mesolimbic dopamine function, but fewer models also show altered social interaction, and learning and memory impairment, analogous to negative and cognitive symptoms of schizophrenia respectively. The negative and cognitive impairments in schizophrenia are resistant to treatment with current antipsychotics, even after remission of the psychosis, which limits their therapeutic efficacy. The MATRICS initiative developed a consensus on the core cognitive deficits of schizophrenic patients, and recommended a standardized test battery to evaluate them. More recently, work has begun to identify specific rodent behavioural tasks with translational relevance to specific cognitive domains affected in schizophrenia, and where available this review focuses on reporting the effect of current and potential antipsychotics on these tasks. The review also highlights the need to develop more comprehensive animal models that more adequately replicate deficits in negative and cognitive symptoms. Increasing information on the neurochemical and structural CNS changes accompanying each model will also help assess treatments that prevent the development of schizophrenia rather than treating the symptoms, another pivotal change required to enable new more effective therapeutic strategies to be developed. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
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              Behavioural and neurochemical effects of post-weaning social isolation in rodents-relevance to developmental neuropsychiatric disorders.

              Exposing mammals to early-life adverse events, including maternal separation or social isolation, profoundly affects brain development and adult behaviour and may contribute to the occurrence of psychiatric disorders, such as depression and schizophrenia in genetically predisposed humans. The molecular mechanisms underlying these environmentally induced developmental adaptations are unclear and best evaluated in animal paradigms with translational salience. Rearing rat pups from weaning in isolation, to prevent social contact with conspecifics, produces reproducible, long-term changes including; neophobia, impaired sensorimotor gating, aggression, cognitive rigidity, reduced prefrontal cortical volume and decreased cortical and hippocampal synaptic plasticity. These alterations are associated with hyperfunction of mesolimbic dopaminergic systems, enhanced presynaptic dopamine (DA) and serotonergic (5-HT) function in the nucleus accumbens (NAcc), hypofunction of mesocortical DA and attenuated 5-HT function in the prefrontal cortex and hippocampus. These behavioural, morphological and neurochemical abnormalities, as reviewed herein, strongly resemble core features of schizophrenia. Therefore unravelling the mechanisms that trigger these sequelae will improve our knowledge of the aetiology of neurodevelopmental psychiatric disorders, enable identification of longitudinal biomarkers of dysfunction and permit predictive screening for novel compounds with potential antipsychotic efficacy.
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                Author and article information

                Contributors
                madeleine.king@nottingham.ac.uk
                Journal
                Mol Neurobiol
                Mol. Neurobiol
                Molecular Neurobiology
                Springer US (New York )
                0893-7648
                1559-1182
                12 June 2020
                12 June 2020
                2020
                : 57
                : 8
                : 3439-3457
                Affiliations
                GRID grid.4563.4, ISNI 0000 0004 1936 8868, School of Life Sciences, Medical School, Queen’s Medical Centre, , The University of Nottingham, ; Nottingham, NG7 2UH UK
                Article
                1938
                10.1007/s12035-020-01938-x
                7340678
                32533466
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: University of Nottingham
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                © Springer Science+Business Media, LLC, part of Springer Nature 2020

                Neurosciences

                neonatal pcp, isolation rearing, glutamate, 5-ht6, mglu7, calbindin

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