Dysregulated ErbB4 Splicing in Schizophrenia: Selective Effects on Parvalbumin Expression

Area of Science:

• Neuroscience
• Molecular Psychiatry
• Genetics

Background:

• Alternative splicing of ErbB4 transcripts is dysregulated in the dorsolateral prefrontal cortex in schizophrenia.
• ErbB4 signaling is crucial for parvalbumin interneuron activity, which is impaired in schizophrenia.
• ErbB4 is also found in calretinin interneurons, unaffected in schizophrenia, suggesting cell-type-specific effects.

Purpose of the Study:

• To investigate whether ErbB4 splicing dysregulation occurs selectively in parvalbumin interneurons in schizophrenia.
• To determine the association between altered ErbB4 splicing and reduced parvalbumin levels in schizophrenia.

Main Methods:

• Laser microdissection of dorsolateral prefrontal cortex layers enriched in calretinin and parvalbumin interneurons from schizophrenia and control subjects.
• Quantitative PCR (qPCR) and microarray to measure transcript levels of ErbB4 variants, parvalbumin, calretinin, and MIAT.
• Analysis of ErbB4 splicing variants (JM-a, JM-b, CYT-1, CYT-2) and their correlation with parvalbumin levels.

Main Results:

• Parvalbumin mRNA was preferentially expressed in layer 4, while calretinin mRNA was in layer 2.
• Schizophrenia subjects showed lower parvalbumin, higher CYT-1 and JM-a, and lower CYT-2 and JM-b levels selectively in layer 4.
• Elevated MIAT levels were found in parvalbumin interneurons of schizophrenia subjects, with an inverse correlation between the JM-a/JM-b ratio and parvalbumin levels.

Conclusions:

• Elevated MIAT expression in parvalbumin interneurons appears to alter ErbB4 splicing in schizophrenia.
• Dysregulated ErbB4 splicing in these interneurons may contribute to reduced parvalbumin interneuron activity and expression in schizophrenia.