Working memory requires the activity of parvalbumin (PV) interneurons in the dorsolateral prefrontal cortex (DLPFC). Impaired working memory and lower PV expression in the DLPFC are reported in schizophrenia and to a lesser degree in mood disorders. We previously proposed that activity-dependent PV expression is lower in schizophrenia due to a shift in the splicing of erb-b2 receptor tyrosine kinase 4 (ErbB4) transcripts from major to inactive minor variants that reduces excitatory drive to PV interneurons. Here, we tested the hypothesis that the degree of major-to-minor shift in ErbB4 splicing predicts the level of PV expression across schizophrenia and mood disorders. Levels of ErbB4 splice variants and PV mRNA were quantified by PCR in the DLPFC from 40 matched tetrads (N = 160 subjects) of schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), and unaffected comparison subjects. Relative to unaffected comparison subjects, the magnitude of increases in minor variant levels and decreases in major variant levels was greatest in schizophrenia, intermediate in BD, and least in MDD. The same rank order was present for the magnitude of increases in the composite splicing score, which reflects the degree of major-to-minor shift across all ErbB4 splice loci, and for the magnitude of deficient PV expression. Finally, the composite splicing score negatively predicted PV expression across all subject groups. Together, these findings demonstrate a shared relationship between ErbB4 splicing and PV expression and suggest that scaling of the major-to-minor shift in ErbB4 splicing may influence the severity of deficient PV interneuron activity across diagnoses.

中文翻译：

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精神分裂症和情绪障碍中ErbB4剪接和皮质小白蛋白中间神经元功能改变。

工作记忆需要在背外侧前额叶皮层（DLPFC）中激活小白蛋白（PV）中枢神经。在精神分裂症中报告了DLPFC中的工作记忆受损和PV表达降低，在情绪障碍中报道的程度较小。我们先前提出，由于erb-b2受体酪氨酸激酶4（ErbB4）转录物的剪接从主要变异变为非活性次要变异，从而减少了对PV间神经元的兴奋性驱动，因此精神分裂症的活动依赖性PV表达较低。在这里，我们测试了以下假设，即ErbB4剪接中的主要到次要移位的程度可预测精神分裂症和情绪障碍中PV的表达水平。通过PCR定量分析DLPFC中来自40个匹配的四肢（N = 160位受试者）精神分裂症，双相情感障碍（BD）的ErbB4剪接变体和PV mRNA的水平，重度抑郁症（MDD）和未受影响的比较对象。相对于未受影响的比较对象，精神分裂症患者的次要变异水平升高和主要变异水平降低的幅度最大，BD中等，而MDD最小。对于复合剪接分数的增加幅度（反映了所有ErbB4剪接位点的主要到次要移位的程度）以及PV表达不足的大小，存在相同的等级顺序。最后，复合剪接分数负面预测了所有受试者组的PV表达。总之，这些发现证明了ErbB4剪接与PV表达之间存在共同的关系，并表明ErbB4剪接中主要到次要移位的缩放可能会影响整个诊断过程中PV中间神经元活动不足的严重程度。