Dysregulated ErbB4 Splicing in Schizophrenia: Selective Effects on Parvalbumin Expression
Open accessAbstract
OBJECTIVE: Alternative splicing of ErbB4 transcripts is dysregulated in the dorsolateral prefrontal cortex in schizophrenia. ErbB4 regulates the activity of parvalbumin interneurons, and therefore dysregulated ErbB4 splicing could contribute to lower parvalbumin interneuron activity and consequently lower parvalbumin levels in schizophrenia. However, ErbB4 is also present in calretinin interneurons, which are not affected in schizophrenia. Therefore, the authors hypothesized that dysregulated ErbB4 splicing occurs selectively in parvalbumin interneurons and is associated with lower parvalbumin levels in schizophrenia. METHOD: Tissue samples enriched in calretinin and parvalbumin interneurons were laser microdissected from dorsolateral prefrontal cortex layers 2 and 4, respectively, from matched pairs of schizophrenia and comparison subjects. Transcript levels for pan-ErbB4, four ErbB4 splicing variants (JM-a, JM-b, CYT-1, CYT-2), parvalbumin, and calretinin were quantified by quantitative polymerase chain reaction (qPCR) in each layer. Transcript levels for myocardial infarction associated transcript (MIAT), which regulates ErbB4 splicing, were quantified in gray matter by qPCR and in parvalbumin interneurons by microarray. RESULTS: Calretinin and parvalbumin mRNAs were preferentially expressed in layers 2 and 4, respectively. In schizophrenia subjects, lower parvalbumin levels, higher CYT-1 and JM-a levels, and lower CYT-2 and JM-b levels were detected selectively in layer 4. In layer 4, the JM-a/JM-b ratio was inversely correlated with parvalbumin levels in schizophrenia subjects. MIAT levels were preferentially higher in parvalbumin interneurons in schizophrenia subjects. CONCLUSIONS: These findings suggest that elevated MIAT expression alters ErbB4 splicing selectively in parvalbumin interneurons in schizophrenia. Dysregulated ErbB4 splicing in schizophrenia may contribute to lower activity of parvalbumin interneurons and an activity-dependent down-regulation of parvalbumin expression.
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Reduced numbers of PV-INs have been reported in the hippocampus, entorhinal cortex, and subicular areas in schizophrenia.
“Reductions in the number of PV-INs were reported in the hippocampus, entorhinal cortex, and subicular areas [1,[9][10][11].”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [10]
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Parvalbumin interneuron vulnerability and brain disorders
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BackgroundMethodInfluentialSelf-citationTranscriptome alterations of prefrontal cortical parvalbumin neurons in schizophrenia
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- Authors
- Chung, D. W., Volk, D. W., Arion, D., Zhang, Y., Sampson, A. R., & Lewis, D. A.
- Affiliations
- University of Pittsburgh (US)
- Venue
- American Journal of Psychiatry
- Published
- 2016-01-01
- Volume
- 173
- Issue
- 1
- Pages
- 60-68
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC5242561
- OpenAlex
- W2102125031
- Cited by
- 86
- References
- 40
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 11 · 2023: 7 · 2022: 8 · 2021: 11 · 2020: 7 · 2019: 6 · 2018: 8 · 2017: 11 · 2016: 8
- FWCI
- 7.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH043784, P50MH103204, MH-103204, R37MH043784, MH043784, R01MH100066)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- ErbB4, alternative splicing, schizophrenia, parvalbumin interneurons, calretinin interneurons, dorsolateral prefrontal cortex, MIAT, layer 4
- MeSH terms
- Adult, Female, Humans, Interneurons, Male, Parvalbumins, Schizophrenia, Down-Regulation, Prefrontal Cortex, Alternative Splicing, Receptor, ErbB-4
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