Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia
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Neuropathological and brain imaging studies suggest that schizophrenia may result from neurodevelopmental defects. Cytoarchitectural studies indicate cellular abnormalities suggestive of a disruption in neuronal connectivity in schizophrenia, particularly in the dorsolateral prefrontal cortex. Yet, the molecular mechanisms underlying these findings remain unclear. To identify molecular substrates associated with schizophrenia, DNA microarray analysis was used to assay gene expression levels in postmortem dorsolateral prefrontal cortex of schizophrenic and control patients. Genes determined to have altered expression levels in schizophrenics relative to controls are involved in a number of biological processes, including synaptic plasticity, neuronal development, neurotransmission, and signal transduction. Most notable was the differential expression of myelination-related genes suggesting a disruption in oligodendrocyte function in schizophrenia.
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Genome-wide analysis reveals differential expression of myelination-related genes in schizophrenia.
“Genome‐wide analysis reveals differential expression of myelination‐related genes in schizophrenia (Hakak et al., 2001 ).”
From Motor learning requires myelination to reduce asynchrony and spontaneity in neural activity (2020) · cites this paper as Hakak et al., 2001
In psychiatric diseases such as schizophrenia, subtle impairment of myelin regulation and thalamocortical dysrhythmia are observed.
“In psychiatric diseases such as schizophrenia, subtle impairment of myelin regulation and thalamocortical dysrhythmia are observed (Hakak et al., 2001 ; Nave & Ehrenreich, 2014 ; Schulman et al., 2011 ).”
From Motor learning requires myelination to reduce asynchrony and spontaneity in neural activity (2020) · cites this paper as Hakak et al., 2001
In patients with chronic schizophrenia, HuD transcript levels are increased in the dorsolateral prefrontal cortex.
“One study employed a DNA microarray on samples from patients with chronic schizophrenia and determined that HuD transcript levels were increased in the dorsolateral prefrontal cortex (Hakak et al. 2001).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Hakak et al. 2001
In the same chronic schizophrenia samples, the abundance of several mRNAs, including those encoding proteins involved in neuronal development, synaptic plasticity, and neurotransmission, is increased.
“The authors also found that there was augmented abundance of several mRNAs including those encoding proteins involved in neuronal development, synaptic plasticity, and neurotransmission.”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Hakak et al. 2001
Consistent findings across schizophrenia transcriptomic studies include dysregulation of GABAergic signalling, downregulation of oligodendrocyte/myelination, mitochondrial/energy metabolism, and synaptic genes, and upregulation of immune/inflammatory genes.
“Despite variable results, consistent findings across studies can be identified, including dysregulation of GABAergic signalling102; downregulation of oligodendrocyte- and myelination-related genes103, mitochondrial function or energy metabolism104, and synaptic genes105; and upregulation of immune and inflammatory genes106.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [103]
Supporting observations for oligodendrocyte impairment in schizophrenia include decreased expression of oligodendrocyte-related genes, impaired oligodendrocyte maturation, reduced number and/or density of oligodendrocytes in gray and white matter, apoptotic oligodendrocytes, and ultrastructural alterations in myelinated fibers.
“The observations supporting this claim include decreased expression of oligodendrocyte-related genes (Hakak et al., 2001; Katsel et al., 2005; Tkachev et al., 2003), impairment of oligodendrocyte maturation (Kerns et al., 2010), reduced number and/or density of oligodendrocytes in gray and white matter (Byne et al., 2008; Hof et al., 2003; Uranova et al., 2004), apoptotic oligodendrocytes and ult”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as Hakak et al., 2001
Frontal fasciculi are among the last fasciculi to structurally mature in the developing human brain, with myelination continuing through adolescence and into early adulthood.
“Second, these frontal fasciculi are among the last fasciculi to structurally mature in the developing human brain, with myelination thought to continue through adolescence and into early adulthood, [40][41][42][43]”
From Schizophrenia, myelination, and delayed corollary discharges: a hypothesis (2012) · cites this paper as [40]
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- Authors
- Hakak, Y., Walker, J. R., Li, C., Wong, W. H., Davis, K. L., Buxbaum, J. D., Haroutunian, V., & Fienberg, A. A.
- Affiliations
- Genomics Institute of the Novartis Research Foundation (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-04-10
- Volume
- 98
- Issue
- 8
- Pages
- 4746-4751
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC31905
- OpenAlex
- W2105097410
- Cited by
- 1,192
- References
- 40
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 15 · 2023: 19 · 2022: 18 · 2021: 31 · 2020: 40 · 2019: 33 · 2018: 22 · 2017: 29 · 2016: 37 · 2015: 52 · 2014: 43 · 2013: 39 · 2012: 68
- FWCI
- 43.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health (5p01mh045212-05)
- U.S. Public Health Service
- National Institute of Mental Health (MH 45212)
- 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, myelination, oligodendrocytes, dorsolateral prefrontal cortex, gene expression, neurodevelopmental defects, neuronal connectivity, synaptic plasticity, postmortem brain, differential gene expression
- MeSH terms
- Chronic Disease, Gene Expression Regulation, Humans, Myelin Sheath, Schizophrenia, Genome, Human, Gene Expression Profiling
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