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Dysregulated ErbB4 splicing associated with lower parvalbumin levels in schizophrenia

Elevated myocardial infarction-associated transcript levels alter ErbB4 splicing in parvalbumin interneurons in schizophrenia, which may contribute to lower activity of parvalbumin interneurons and down-regulation of parvalbumin expression.

“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,” Daniel W. Chung, MS, of the University of Pittsburgh School of Medicine, and colleagues wrote.

Researchers analyzed tissues samples enriched in calretinin and parvalbumin interneurons that were laser microdissected from dorsolateral prefrontal cortex layers 2 and 4 from 62 matched pairs of individuals with schizophrenia and comparison patients. Quantitative polymerase chain reaction quantified transcript levels for pan-ErbB4, ErbB4 splicing variants (ie, JM-a, JM-b, CYT-1, CYT-2), parvalbumin and calretinin in each layer and levels for myocardial infarction-associated transcript in gray matter. Microarray was used to quantify transcript levels in parvalbumin interneurons.

Researchers found that calretinin mRNAs were preferentially expressed in dorsolateral prefontal cortex layer 2 and parvalbumin mRNAs were preferentially expressed in layer 4.

Individuals with schizophrenia exhibited lower parvalbumin levels, higher CYT-1 and JM-a levels and lower CYT-2 and JM-b levels selectively in layer 4. The JM-a to JM-b ratio inversely correlated with parvalbumin levels in layer 4 among individuals with schizophrenia.

Myocardial infarction-associated transcript levels were selectively higher in parvalbumin interneurons among individuals with schizophrenia, according to researchers.

“Our study presents novel evidence for alterations in a molecular cascade that may contribute to parvalbumin interneuron dysfunction in schizophrenia. Specifically, higher [myocardial infarction-associated transcript] levels in parvalbumin interneurons may lead to an abnormal shift in ErbB4 splicing from the JM-b to the JM-a variant, which would result in impaired ErbB4 signaling,” Chung and colleagues wrote. “Given the role of ErbB4 signaling in the formation of excitatory inputs, the resulting reduction in excitatory drive to parvalbumin neurons would lead to a corresponding activity-dependent down-regulation of parvalbumin expression in schizophrenia.” – by Amanda Oldt

Disclosure:

Chung reports no relevant financial disclosures. Please see the full study for a list of all authors’ relevant financial disclosures.