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Molecular Determinants of Dysregulated GABAergic Gene Expression in the Prefrontal Cortex of Subjects with Schizophrenia
Abstract
Background Prefrontal deficits in gamma-aminobutyric acid (GABA)ergic gene expression, including neuropeptide Y (NPY), somatostatin (SST), and parvalbumin (PV) messenger RNAs (mRNAs), have been reported for multiple schizophrenia cohorts. Preclinical models suggest that a subset of these GABAergic markers (NPY/SST) is regulated by brain-derived neurotrophic factor (BDNF), which in turn is under the inhibitory influence of small noncoding RNAs. However, it remains unclear if these mechanisms are important determinants for dysregulated NPY and SST expression in prefrontal cortex (PFC) of subjects with schizophrenia.Methods Using a postmortem case-control design, the association between BDNF protein, NPY/SST/PV mRNAs, and two BDNF-regulating microRNAs (miR-195 and miR-30a-5p) was determined in samples from the PFC of 20 schizophrenia and 20 control subjects. Complementary studies were conducted in cerebral cortex of mice subjected to antipsychotic treatment or a brain-specific ablation of the Bdnf gene.Results Subjects with schizophrenia showed deficits in NPY and PV mRNAs. Within-pair differences in BDNF protein levels showed strong positive correlations with NPY and SST and a robust inverse association with miR-195 levels, which in turn were not affected by antipsychotic treatment or genetic ablation of Bdnf.Conclusions Taken together, these results suggest that prefrontal deficits in a subset of GABAergic mRNAs, including NPY, are dependent on the regional supply of BDNF, which in turn is fine-tuned through a microRNA (miRNA)-mediated mechanism.
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“It is also of note that common genetic risk for SCZ and BD also indicated shared pathways coalescing onto parvalbumin-positive interneurons, paralleling what has been among the most robust pathologic findings in SCZ and BD63,64.”
From Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders (2021) · cites this paper as [64]
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Metadata
- Authors
- Mellios, N., Huang, H.-S., Baker, S. P., Galdzicka, M., Ginns, E., & Akbarian, S.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Akbarian, Schahram
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2009-06
- Volume
- 65
- Issue
- 12
- Pages
- 1006-1014
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W1979089999
- Cited by
- 266
- References
- 47
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 15 · 2023: 8 · 2022: 13 · 2021: 11 · 2020: 17 · 2019: 17 · 2018: 15 · 2017: 12 · 2016: 18 · 2015: 22 · 2014: 23 · 2013: 22 · 2012: 14
- FWCI
- 12.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- eScholarship@UMassChan (submittedVersion)
- Funders
- National Institute of Mental Health (R01MH081943, MH071476, MH081943, R01MH071476)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- schizophrenia, prefrontal cortex, neuropeptide Y, somatostatin, parvalbumin, brain-derived neurotrophic factor, miR-195, miR-30a-5p, microRNA regulation, antipsychotic drugs, BDNF knockout mice, postmortem brain
- MeSH terms
- Adult, Aged, Aged, 80 and over, Animals, Chromatin, gamma-Aminobutyric Acid, Gene Expression Regulation, Genotype, Humans, Immunoassay, Male, Mice, Inbred C57BL, Middle Aged, Neuropeptide Y, Parvalbumins, RNA, Schizophrenia, Somatostatin, Case-Control Studies, Prefrontal Cortex, Mice, Knockout, Brain-Derived Neurotrophic Factor, MicroRNAs, Immunoprecipitation, Mice, Young Adult
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