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Published Online: 4 September 2015

Dysregulated ErbB4 Splicing in Schizophrenia: Selective Effects on Parvalbumin Expression

Daniel W. Chung, M.S., David W. Volk, M.D., Ph.D., Dominique Arion, Ph.D., Yun Zhang, M.A., Allan R. Sampson, Ph.D., and David A. Lewis, M.D.Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 173, Number 1
https://doi.org/10.1176/appi.ajp.2015.15020150
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Abstract

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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Supplementary Material

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Volume 173 • Number 1 • January 01, 2016
Pages: 60 - 68
PubMed: 26337038

History

Received: 2 February 2015
Revision received: 27 May 2015
Accepted: 12 June 2015
Published online: 4 September 2015
Published in print: January 01, 2016

Authors

Affiliations

Daniel W. Chung, M.S.
From the Translational Neuroscience Program, Department of Psychiatry, and the Medical Scientist Training Program, University of Pittsburgh School of Medicine; and the Department of Statistics, University of Pittsburgh.
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David W. Volk, M.D., Ph.D.
From the Translational Neuroscience Program, Department of Psychiatry, and the Medical Scientist Training Program, University of Pittsburgh School of Medicine; and the Department of Statistics, University of Pittsburgh.
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Dominique Arion, Ph.D.
From the Translational Neuroscience Program, Department of Psychiatry, and the Medical Scientist Training Program, University of Pittsburgh School of Medicine; and the Department of Statistics, University of Pittsburgh.
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Yun Zhang, M.A.
From the Translational Neuroscience Program, Department of Psychiatry, and the Medical Scientist Training Program, University of Pittsburgh School of Medicine; and the Department of Statistics, University of Pittsburgh.
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Allan R. Sampson, Ph.D.
From the Translational Neuroscience Program, Department of Psychiatry, and the Medical Scientist Training Program, University of Pittsburgh School of Medicine; and the Department of Statistics, University of Pittsburgh.
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David A. Lewis, M.D.
From the Translational Neuroscience Program, Department of Psychiatry, and the Medical Scientist Training Program, University of Pittsburgh School of Medicine; and the Department of Statistics, University of Pittsburgh.
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Notes

Address correspondence to Dr. Lewis ([email protected]).
Presented in part at the 69th annual meeting of the Society of Biological Psychiatry, New York, May 8–10, 2014; the 2014 annual meeting of the Society for Neuroscience, Washington, D.C., Nov. 15–19, 2014; and the 53rd annual meeting of the American College of Neuropsychopharmacology, Phoenix, Dec. 7–11, 2014.

Competing Interests

Dr. Lewis currently receives investigator-initiated research support from Pfizer and in 2012–2014 served as a consultant in the areas of target identification and validation and new compound development to Autifony, Bristol-Myers Squibb, Concert Pharmaceuticals, and Sunovion. Ms. Zhang is currently a part-time employee of Janssen Pharmaceutical Research and Development under the auspices of the University of Pittsburgh’s Curricular Practical Training during her Ph.D. degree program. Dr. Sampson is a statistical consultant to Janssen Pharmaceutical Research and Development. All other authors report no financial relationships with commercial interests.

Funding Information

Supported by NIMH grants MH-043784 to Dr. Lewis and MH-103204 to Dr. Lewis.

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