Dysregulated ErbB4 Splicing in Schizophrenia: Selective Effects on Parvalbumin Expression.
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.


METHODS
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.
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.
Daniel W
DW
Chung
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.
David W
DW
Volk
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.
Dominique
D
Arion
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.
Yun
Y
Zhang
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.
Allan R
AR
Sampson
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.
David A
DA
Lewis
D000328:Adult; D017398:Alternative Splicing; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007395:Interneurons / Q000378:metabolism; D008297:Male; D010320:Parvalbumins / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism*; D066247:Receptor, ErbB-4 / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism
D010320:Parvalbumins; C587689:ERBB4 protein, human; D066247:Receptor, ErbB-4