16p11 Duplication disrupts hippocampal-orbitofrontal-amygdala connectivity, revealing a neural circuit endophenotype for schizophrenia
Open accessAbstract
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.
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In 16p11.2dp/+ mice (Mills), male-specific reductions in locomotion, time in the center of an open field, and ratio of open arm/closed arm time in the elevated plus maze have been reported.
“In 16p11.2dp/+ mice (Mills), male-specific reductions in locomotion, time in the center of an open field, and ratio of open arm/closed arm time in the elevated plus maze have also been reported [73].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [73]
16p11.2dp/+ mice exhibit hypolocomotion, in direct contrast to 16p11.2+/− animals.
“16p11.2dp/+ mice also exhibit hypolocomotion [5, 72, 73], in direct contrast to 16p11.2+/− animals.”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [73]
Two behavioral phenotypes associated with SZ, PPI of startle responses and MK-801-induced hyperlocomotion, were not observed in 16p11.2dp/+ mice, despite a report on female-specific PPI deficits.
“Two behavioral phenotypes associated with SZ, PPI of startle responses and MK-801-induced hyperlocomotion, were not observed in 16p11.2dp/+ mice [72], despite a report on female-specific PPI deficits [73].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [73]
16p11.2dp/+ mice (Mills) exhibit social and cognitive deficits along with increased repetitive self-grooming, with the absence of motor coordination deficits.
“The 16p11.2dp/+ mice (Mills) exhibit social and cognitive deficits [72, 73] along with increased repetitive self-grooming [5, 72], with the absence of motor coordination deficits [72].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [73]
Disrupted connectivity between hippocampal-orbitofrontal and hippocampal-amygdala circuits has been found in 16p11.2dp/+ mice (Mills), as well as reduced expression of several GABAergic markers, including parvalbumin, calbindin and somatostatin in frontal cortex.
“In addition, disrupted connectivity between hippocampal-orbitofrontal and hippocampal-amygdala circuits has been found in 16p11.2dp/+ mice (Mills), as well as reduced expression of several GABAergic markers, including parvalbumin, calbindin and somatostatin in frontal cortex [73].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [73]
Mice with 16p11.2 duplication exhibit impaired social behavior and compromised hippocampal-orbitofrontal cortex-amygdala functional connectivity.
“Mice with 16p11.2duplication exhibit impaired social behavior, as well as compromised hippocampal-orbitofrontal cortex-amygdala functional connectivity, which was assessed using network analysis of 14C-2deoxyglucose imaging data [138].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [138]
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“, 2013), and has been linked to OFC function (Albaugh et al., 2017).”
BackgroundThe median raphe nucleus in anxiety revisited
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Clinical symptom dimensions and deficits on the continuous performance test in schizophrenia
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Self-citationNeuronal MAP kinase p38α inhibits c-Jun N-terminal kinase to modulate anxiety-related behaviour
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Nilsson, S. R. O., Fejgin, K., Gastambide, F., Vogt, M. A., Kent, B. A., Nielsen, V., Nielsen, J., Gass, P., Robbins, T. W., Saksida, L. M., et al. (2016) · Cerebral Cortex · doi:10.1093/cercor/bhw229 · Cited by 31 · see citing works
Filges, I., Sparagana, S., Sargent, M., Selby, K., Schlade‐Bartusiak, K., Lueder, G. T., Robichaux‐Viehoever, A., Schlaggar, B. L., Shimony, J. S., & Shinawi, M. (2014) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.36605 · Cited by 30 · see citing works
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Functional brain connectivity phenotypes for schizophrenia drug discovery
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Deconstructing Schizophrenia: Advances in Preclinical Models for Biomarker Identification
Pratt, J. A., MORRIS, B. J., & Dawson, N. (2018) · Current topics in behavioral neurosciences · doi:10.1007/7854_2018_48 · Cited by 21 · see citing works
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16p11.2 Microduplication and associated symptoms: A case study
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Flagged first, then by citations
Research works printed but not linked: 3
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- Godsil, B.P., Kiss, J.P., Spedding, M., and Jay, T.M. (2013). The hippocampalprefrontal pathway: the weak link in psychiatric disorders? Eur. Neuropsychopharmacol. 23 , 1165-1181. http://refhub.elsevier.com/S2211-1247(2030436-8/sref34)
- Wisden, W., and Morris, B.J. (1994). In Situ Hybridisation Protocols for the Brain (Academic Press). http://refhub.elsevier.com/S2211-1247(2030436-8/sref98)
Cited by
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16p11.2 Copy Number Variations and Neurodevelopmental Disorders
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Neural circuits regulating prosocial behaviors
Walsh, J. J., Christoffel, D. J., & Malenka, R. C. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-022-01348-8 · Cited by 72 · see citing works
Neural Circuits for Social Interactions: From Microcircuits to Input-Output Circuits
Xu, S., Jiang, M., Liu, X., Sun, Y., Yang, L., Yang, Q., & Bai, Z. (2021) · Frontiers in Neural Circuits · doi:10.3389/fncir.2021.768294 · Cited by 47 · see citing works
Brain circuits that regulate social behavior
Li, H., Zhao, Z., Jiang, S., & Wu, H. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03037-6 · Cited by 57 · see citing works
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Increased Prevalence of Rare Copy Number Variants in Treatment-Resistant Psychosis
Farrell, M. S., Dietterich, T. E., Harner, M. K., Bruno, L., Filmyer, D. M., Shaughnessy, R. A., Lichtenstein, M. L., Britt, A. M., Biondi, T. F., Crowley, J. J., et al. (2022) · Schizophrenia Bulletin · doi:10.1093/schbul/sbac175 · Cited by 33 · see citing works
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Self-citationStructural and functional brain alterations revealed by neuroimaging in CNV carriers
Moreau, C. A., Ching, C. R. K., Kumar, K., Jacquemont, S., & Bearden, C. E. (2021) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2021.03.002 · Cited by 25 · see citing works
Recent Developments in Autism Genetic Research: A Scientometric Review from 2018 to 2022
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Panayi, M. C., Boerner, T., Jahans-Price, T., Huber, A., Sprengel, R., Gilmour, G., Sanderson, D. J., Harrison, P. J., Walton, M. E., & Bannerman, D. M. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01861-8 · Cited by 21 · see citing works
Forrest, M. P., Santos, M. D., Piguel, N. H., Wang, Y., Hawkins, N. A., Bagchi, V. A., Dionisio, L. E., Yoon, S., Simkin, D., Martin‐de‐Saavedra, M. D., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36087-x · Cited by 21 · see citing works
Thomson, D. M., Mitchell, E. J., Openshaw, R. L., Pratt, J. A., & MORRIS, B. J. (2021) · Journal of Psychopharmacology · doi:10.1177/02698811211032439 · Cited by 20 · see citing works
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Mitchell, E. J., Thomson, D. M., Openshaw, R. L., Bristow, G. C., Dawson, N., Pratt, J. A., & MORRIS, B. J. (2020) · Scientific Reports · doi:10.1038/s41598-020-69130-8 · Cited by 18 · see citing works
Self-citationThe pleiotropic spectrum of proximal 16p11.2 CNVs
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Openshaw, R. L., Thomson, D. M., Bristow, G. C., Mitchell, E. J., Pratt, J. A., MORRIS, B. J., & Dawson, N. (2023) · Communications Biology · doi:10.1038/s42003-023-04891-2 · Cited by 14 · see citing works
Self-citationClinical and Neurobiological Aspects of TAO Kinase Family in Neurodevelopmental Disorders
Hu, C., Feng, P., Yang, Q., & Xiao, L. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.655037 · Cited by 13 · see citing works
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BLA-involved circuits in neuropsychiatric disorders
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How can we obtain truly translational mouse models to improve clinical outcomes in schizophrenia?
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Muscarinic agonists for schizophrenia: Bridging preclinical evidence and clinical enthusiasm
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Somatostatin: A crossroad between pancreatic and neural pathways
Rahmanian, M., Gharajeh, S. E., Zahedi, A., Gharedaghi, H., Abbasian, H., & Kamali, M. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-30263-3.00022-1
- Authors
- Bristow, G. C., Thomson, D. M., Openshaw, R. L., Mitchell, E. J., Pratt, J. A., Dawson, N., & Morris, B. J.
- Affiliations
- Lancaster University (GB)
- University of Strathclyde (GB)
- University of Glasgow (GB)
- Corresponding author
- Morris, Brian J.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2020-04
- Volume
- 31
- Issue
- 3
- Pages
- 107536
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W3017001597
- Cited by
- 36
- References
- 103
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 7 · 2021: 5 · 2020: 4
- FWCI
- 3.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Strathprints: The University of Strathclyde institutional repository (University of Strathclyde) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Lancaster EPrints (Lancaster University) (submittedVersion)
- Funders
- UK Research and Innovation
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- 16p11.2 duplication, schizophrenia, parvalbumin, calbindin, somatostatin, GABAergic interneurons, working memory, continuous performance test, social behavior deficits, mouse model
- MeSH terms
- Amygdala, Animals, Autistic Disorder, Chromosome Deletion, Chromosomes, Human, Pair 16, Female, Hippocampus, Humans, Male, Intellectual Disability, Schizophrenia, Prefrontal Cortex, Chromosome Disorders, Mice, Endophenotypes
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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