Chung Daniel W, Volk David W, Arion Dominique, Zhang Yun, Sampson Allan R, Lewis David 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.
Am J Psychiatry. 2016 Jan;173(1):60-8. doi: 10.1176/appi.ajp.2015.15020150. Epub 2015 Sep 4.
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.
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.
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 ErbB4 splicing in schizophrenia may contribute to lower activity of parvalbumin interneurons and an activity-dependent down-regulation of parvalbumin expression.
精神分裂症患者背外侧前额叶皮质中ErbB4转录本的可变剪接失调。ErbB4调节小白蛋白中间神经元的活性，因此，ErbB4剪接失调可能导致精神分裂症患者小白蛋白中间神经元活性降低，进而导致小白蛋白水平降低。然而，钙视网膜蛋白中间神经元中也存在ErbB4，而精神分裂症患者的钙视网膜蛋白中间神经元未受影响。因此，作者推测，ErbB4剪接失调在小白蛋白中间神经元中选择性发生，且与精神分裂症患者较低的小白蛋白水平相关。
分别从精神分裂症患者与对照受试者的匹配对中，通过激光显微切割从背外侧前额叶皮质第2层和第4层获取富含钙视网膜蛋白和小白蛋白中间神经元的组织样本。通过定量聚合酶链反应（qPCR）对每层中泛ErbB4、四种ErbB4剪接变体（JM-a、JM-b、CYT-1、CYT-2）、小白蛋白和钙视网膜蛋白的转录水平进行定量。通过qPCR对灰质中调节ErbB4剪接的心肌梗死相关转录本（MIAT）的转录水平进行定量，并通过微阵列对小白蛋白中间神经元中的MIAT转录水平进行定量。
钙视网膜蛋白和小白蛋白mRNA分别优先在第2层和第4层表达。在精神分裂症患者中，仅在第4层检测到较低的小白蛋白水平、较高的CYT-1和JM-a水平以及较低的CYT-2和JM-b水平。在第4层，精神分裂症患者中JM-a/JM-b比值与小白蛋白水平呈负相关。精神分裂症患者小白蛋白中间神经元中的MIAT水平优先升高。
这些发现表明，MIAT表达升高在精神分裂症患者的小白蛋白中间神经元中选择性改变了ErbB4剪接。精神分裂症中ErbB4剪接失调可能导致小白蛋白中间神经元活性降低以及小白蛋白表达的活性依赖性下调。
