Molecular and genetic evidence for abnormalities in the nodes of Ranvier in schizophrenia
Abstract
CONTEXT: Genetic, neuroimaging, and molecular neurobiological evidence support the hypothesis that the disconnectivity syndrome in schizophrenia (SZ) could arise from failures of saltatory conduction and abnormalities at the nodes of Ranvier (NOR) interface where myelin and axons interact. OBJECTIVE: To identify abnormalities in the expression of oligodendroglial genes and proteins that participate in the formation, maintenance, and integrity of the NOR in SZ. DESIGN: The messenger RNA (mRNA) expression levels of multiple NOR genes were quantified in 2 independent postmortem brain cohorts of individuals with SZ, and generalizability to protein expression was confirmed. The effect of the ANK3 genotype on the mRNA expression level was tested in postmortem human brain. Case-control analysis tested the association of the ANK3 genotype with SZ. The ANK3 genotype's influence on cognitive task performance and functional magnetic resonance imaging activation was tested in 2 independent cohorts of healthy individuals. SETTING: Research hospital. Patients Postmortem samples from patients with SZ and healthy controls were used for the brain expression study (n = 46) and the case-control analysis (n = 272). Healthy white men and women participated in the cognitive (n = 513) and neuroimaging (n = 52) studies. MAIN OUTCOME MEASURES: The mRNA and protein levels in postmortem brain samples, genetic association with schizophrenia, cognitive performance, and blood oxygenation level-dependent functional magnetic resonance imaging. RESULTS: The mRNA expression of multiple NOR genes was decreased in schizophrenia. The ANK3 rs9804190 C allele was associated with lower ANK3 mRNA expression levels, higher risk for SZ in the case-control cohort, and poorer working memory and executive function performance and increased prefrontal activation during a working memory task in healthy individuals. CONCLUSIONS: These results point to abnormalities in the expression of genes and protein associated with the integrity of the NOR and suggest them as substrates for the disconnectivity syndrome in SZ. The association of ANK3 with lower brain mRNA expression levels implicates a molecular mechanism for its genetic, clinical, and cognitive associations with SZ.
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Molecular studies show reduced expression of multiple genes associated with node of Ranvier integrity in schizophrenia.
“molecular studies showing a reduction in expression level of multiple genes associated with the integrity of the node of Ranvier”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Roussos et al., 2012
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- Authors
- Roussos, P.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Roussos, Panos
- ORCID
- Roussos, Panos
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2012-01-01
- Volume
- 69
- Issue
- 1
- Pages
- 7
- ISSN
- 0003-990X (ISSN-L)
- OpenAlex
- W2109874587
- Cited by
- 93
- References
- 35
- Citations by year
- 2026: 1 · 2024: 4 · 2023: 4 · 2022: 1 · 2021: 3 · 2020: 5 · 2019: 2 · 2018: 9 · 2017: 6 · 2016: 6 · 2015: 11 · 2014: 19 · 2013: 12 · 2012: 10
- FWCI
- 8.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- National Institute of Mental Health (P50MH066392, MH066392, R01MH064673, MH-064673)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Social Sciences › Arts and Humanities › Philosophy › Mental Health and Psychiatry
- Keywords
- schizophrenia, nodes of Ranvier, saltatory conduction, ANK3, gene expression, working memory, executive function, prefrontal cortex activation, postmortem brain, genetic association, myelin
- MeSH terms
- Alleles, Animals, Female, Genotype, Haloperidol, Humans, Male, Memory, Short-Term, Polymorphism, Genetic, Ranvier's Nodes, Schizophrenia, Cohort Studies, Case-Control Studies, Rats, Sprague-Dawley, Ankyrins, Rats, Executive Function
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