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Dysregulated ErbB4 Splicing in Schizophrenia: Selective Effects on Parvalbumin Expression
Chung DW, Volk DW, Arion D, Zhang Y, Sampson AR and Lewis DA
American Journal of Psychiatry, Published online September 2015
In a study recently published online in the American Journal of Psychiatry, investigators in the Department of Psychiatry’s Translational Neuroscience Program investigated whether dysregulated ErbB4 splicing occurs selectively in parvalbumin interneurons, and if it is associated with lower parvalbumin levels in schizophrenia. The study was conducted by Daniel Wonjae Chung, MS, currently a student in the MD/PhD program at the University of Pittsburgh School of Medicine, under the mentorship of Dr. David Lewis.
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. 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.
The investigators found that 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.
These findings suggest that elevated MIAT expression alters ErbB4 splicing selectively in parvalbumin interneurons in schizophrenia. Dysregulated ErbB4splicing in schizophrenia may contribute to lower activity of parvalbumin interneurons and an activity-dependent down-regulation of parvalbumin expression.
Daniel W. Chung, MS, David W. Volk, MD, PhD, Dominique Arion, PhD, Yun Zhang, MA, and David A. Lewis, MD (Department of Psychiatry, University of Pittsburgh)
Allan R. Sampson, PhD (Department of Statistics, University of Pittsburgh)