16p11 Duplication Disrupts Hippocampal-Orbitofrontal-Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for Schizophrenia
Summary: Chromosome 16p11.2 duplications dramatically increase risk for schizophrenia, but the mechanisms remain largely unknown. Here, we show that mice with an equivalent genetic mutation (16p11.2 duplication mice) exhibit impaired hippocampal-orbitofrontal and hippocampal-amygdala functional conn...
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doaj-7728d8dbc8bd473aafcc7b7820bf4f242020-11-25T02:24:43ZengElsevierCell Reports2211-12472020-04-0131316p11 Duplication Disrupts Hippocampal-Orbitofrontal-Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for SchizophreniaGreg C. Bristow0David M. Thomson1Rebecca L. Openshaw2Emma J. Mitchell3Judith A. Pratt4Neil Dawson5Brian J. Morris6Department of Biomedical and Life Sciences, University of Lancaster, Lancaster LA1 4YW, UKStrathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UKInstitute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, West Medical Building, Glasgow G12 8QQ, UKStrathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UKStrathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UKDepartment of Biomedical and Life Sciences, University of Lancaster, Lancaster LA1 4YW, UKInstitute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, West Medical Building, Glasgow G12 8QQ, UK; Corresponding authorSummary: Chromosome 16p11.2 duplications dramatically increase risk for schizophrenia, but the mechanisms remain largely unknown. Here, we show that mice with an equivalent genetic mutation (16p11.2 duplication mice) exhibit impaired hippocampal-orbitofrontal and hippocampal-amygdala functional connectivity. Expression of schizophrenia-relevant GABAergic cell markers (parvalbumin and calbindin) is selectively decreased in orbitofrontal cortex, while somatostatin expression is decreased in lateral amygdala. When 16p11.2 duplication mice are tested in cognitive tasks dependent on hippocampal-orbitofrontal connectivity, performance is impaired in an 8-arm maze “N-back” working memory task and in a touchscreen continuous performance task. Consistent with hippocampal-amygdala dysconnectivity, deficits in ethologically relevant social behaviors are also observed. Overall, the cellular/molecular, brain network, and behavioral alterations markedly mirror those observed in schizophrenia patients. Moreover, the data suggest that 16p11.2 duplications selectively impact hippocampal-amygdaloid-orbitofrontal circuitry, supporting emerging ideas that dysfunction in this network is a core element of schizophrenia and defining a neural circuit endophenotype for the disease. : Chromosome 16p11.2 duplications dramatically increase schizophrenia risk. In this study, Bristow et al. show that the mutation in mice suppresses GABAergic neuron gene expression, disrupts activity in hippocampal-orbitofrontal-amygdaloid circuitry, and compromises sociability and cognitive function. This supports the concept that impairment of this network is a core component of schizophrenia. Keywords: CNVs, prefrontal cortex, functional imaging, cognition, social withdrawal, Taok2, JNKhttp://www.sciencedirect.com/science/article/pii/S2211124720304368 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Greg C. Bristow David M. Thomson Rebecca L. Openshaw Emma J. Mitchell Judith A. Pratt Neil Dawson Brian J. Morris |
spellingShingle |
Greg C. Bristow David M. Thomson Rebecca L. Openshaw Emma J. Mitchell Judith A. Pratt Neil Dawson Brian J. Morris 16p11 Duplication Disrupts Hippocampal-Orbitofrontal-Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for Schizophrenia Cell Reports |
author_facet |
Greg C. Bristow David M. Thomson Rebecca L. Openshaw Emma J. Mitchell Judith A. Pratt Neil Dawson Brian J. Morris |
author_sort |
Greg C. Bristow |
title |
16p11 Duplication Disrupts Hippocampal-Orbitofrontal-Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for Schizophrenia |
title_short |
16p11 Duplication Disrupts Hippocampal-Orbitofrontal-Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for Schizophrenia |
title_full |
16p11 Duplication Disrupts Hippocampal-Orbitofrontal-Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for Schizophrenia |
title_fullStr |
16p11 Duplication Disrupts Hippocampal-Orbitofrontal-Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for Schizophrenia |
title_full_unstemmed |
16p11 Duplication Disrupts Hippocampal-Orbitofrontal-Amygdala Connectivity, Revealing a Neural Circuit Endophenotype for Schizophrenia |
title_sort |
16p11 duplication disrupts hippocampal-orbitofrontal-amygdala connectivity, revealing a neural circuit endophenotype for schizophrenia |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2020-04-01 |
description |
Summary: Chromosome 16p11.2 duplications dramatically increase risk for schizophrenia, but the mechanisms remain largely unknown. Here, we show that mice with an equivalent genetic mutation (16p11.2 duplication mice) exhibit impaired hippocampal-orbitofrontal and hippocampal-amygdala functional connectivity. Expression of schizophrenia-relevant GABAergic cell markers (parvalbumin and calbindin) is selectively decreased in orbitofrontal cortex, while somatostatin expression is decreased in lateral amygdala. When 16p11.2 duplication mice are tested in cognitive tasks dependent on hippocampal-orbitofrontal connectivity, performance is impaired in an 8-arm maze “N-back” working memory task and in a touchscreen continuous performance task. Consistent with hippocampal-amygdala dysconnectivity, deficits in ethologically relevant social behaviors are also observed. Overall, the cellular/molecular, brain network, and behavioral alterations markedly mirror those observed in schizophrenia patients. Moreover, the data suggest that 16p11.2 duplications selectively impact hippocampal-amygdaloid-orbitofrontal circuitry, supporting emerging ideas that dysfunction in this network is a core element of schizophrenia and defining a neural circuit endophenotype for the disease. : Chromosome 16p11.2 duplications dramatically increase schizophrenia risk. In this study, Bristow et al. show that the mutation in mice suppresses GABAergic neuron gene expression, disrupts activity in hippocampal-orbitofrontal-amygdaloid circuitry, and compromises sociability and cognitive function. This supports the concept that impairment of this network is a core component of schizophrenia. Keywords: CNVs, prefrontal cortex, functional imaging, cognition, social withdrawal, Taok2, JNK |
url |
http://www.sciencedirect.com/science/article/pii/S2211124720304368 |
work_keys_str_mv |
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