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The Pattern of Cortical Dysfunction in a Mouse Model of a Schizophrenia-Related Microdeletion
Open accessAbstract
We used a mouse model of the schizophrenia-predisposing 22q11.2 microdeletion to evaluate how this genetic lesion affects cortical neural circuits at the synaptic, cellular, and molecular levels. Guided by cognitive deficits, we demonstrated that mutant mice display robust deficits in high-frequency synaptic transmission and short-term plasticity (synaptic depression and potentiation), as well as alterations in long-term plasticity and dendritic spine stability. Apart from previously reported reduction in dendritic complexity of layer 5 pyramidal neurons, altered synaptic plasticity occurs in the context of relatively circumscribed and often subtle cytoarchitectural changes in neuronal density and inhibitory neuron numbers. We confirmed the pronounced DiGeorge critical region 8 (Dgcr8)-dependent deficits in primary micro-RNA processing and identified additional changes in gene expression and RNA splicing that may underlie the effects of this mutation. Reduction in Dgcr8 levels appears to be a major driver of altered short-term synaptic plasticity in prefrontal cortex and working memory but not of long-term plasticity and cytoarchitecture. Our findings inform the cortical synaptic and neuronal mechanisms of working memory impairment in the context of psychiatric disorders. They also provide insight into the link between micro-RNA dysregulation and genetic liability to schizophrenia and cognitive dysfunction.
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“Spine turnover in these animals is higher than in WT, with smaller spine width but comparable spine density and length on apical dendrites [112] and decreased spine density, increased spine width and fewer mushroom spines on the basal dendrites [391].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [112]
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Metadata
- Authors
- Fénelon, K., Xu, B., Lai, C. S., Mukai, J., Markx, S., Stark, K. L., Hsu, P.-K., Gan, W.-B., Fischbach, G. D., MacDermott, A. B., Karayiorgou, M., & Gogos, J. A.
- Affiliations
- Columbia University Irving Medical Center (US)
- New York University (US)
- Columbia University (US)
- Simons Foundation (US)
- New York State Psychiatric Institute (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-09-11
- Volume
- 33
- Issue
- 37
- Pages
- 14825-14839
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3771024
- OpenAlex
- W2048088283
- Cited by
- 116
- References
- 78
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 7 · 2022: 9 · 2021: 13 · 2020: 10 · 2019: 14 · 2018: 6 · 2017: 9 · 2016: 14 · 2015: 12 · 2014: 9 · 2013: 3
- FWCI
- 8.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institute of Mental Health (R01MH067068, R01MH077235, MH 67068, MH077235)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- 22q11.2 microdeletion, schizophrenia, mouse model, cortical dysfunction, synaptic plasticity, short-term plasticity, long-term plasticity, dendritic spines, layer 5 pyramidal neurons, DGCR8, microRNA processing, RNA splicing, working memory, prefrontal cortex, inhibitory interneurons, neuronal density, cognitive impairment
- MeSH terms
- Animals, Cognition Disorders, DiGeorge Syndrome, Disease Models, Animal, Gene Expression Regulation, Male, Mice, Inbred C57BL, Neurons, Phosphopyruvate Hydratase, Proteins, RNA-Binding Proteins, Prefrontal Cortex, Long-Term Potentiation, Recognition, Psychology, Long-Term Synaptic Depression, Dendritic Spines, Mice, Gene Regulatory Networks, Sarcoplasmic Reticulum Calcium-Transporting ATPases, In Vitro Techniques
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.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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