Kimoto Sohei, Glausier Jill R, Fish Kenneth N, Volk David W, Bazmi H Holly, Arion Dominique, Datta Dibyadeep, Lewis David A
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA; Department of Psychiatry, Nara Medical University, Nara, Japan;
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA;
Schizophr Bull. 2016 Mar;42(2):396-405. doi: 10.1093/schbul/sbv139. Epub 2015 Sep 30.
N-methyl-d-aspartate receptor (NMDAR) hypofunction in the dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathology of schizophrenia. NMDAR activity is negatively regulated by some G protein-coupled receptors (GPCRs). Signaling through these GPCRs is reduced by Regulator of G protein Signaling 4 (RGS4). Thus, lower levels of RGS4 would enhance GPCR-mediated reductions in NMDAR activity and could contribute to NMDAR hypofunction in schizophrenia. In this study, we quantified RGS4 mRNA and protein levels at several levels of resolution in the DLPFC from subjects with schizophrenia and matched healthy comparison subjects. To investigate molecular mechanisms that could contribute to altered RGS4 levels, we quantified levels of small noncoding RNAs, known as microRNAs (miRs), which regulate RGS4 mRNA integrity after transcription. RGS4 mRNA and protein levels were significantly lower in schizophrenia subjects and were positively correlated across all subjects. The RGS4 mRNA deficit was present in pyramidal neurons of DLPFC layers 3 and 5 of the schizophrenia subjects. In contrast, levels of miR16 were significantly higher in the DLPFC of schizophrenia subjects, and higher miR16 levels predicted lower RGS4 mRNA levels. These findings provide convergent evidence of lower RGS4 mRNA and protein levels in schizophrenia that may result from increased expression of miR16. Given the role of RGS4 in regulating GPCRs, and consequently the strength of NMDAR signaling, these findings could contribute to the molecular substrate for NMDAR hypofunction in DLPFC pyramidal cells in schizophrenia.
背外侧前额叶皮质（DLPFC）中的N-甲基-D-天冬氨酸受体（NMDAR）功能减退与精神分裂症的病理机制有关。NMDAR活性受到一些G蛋白偶联受体（GPCR）的负调控。G蛋白信号调节因子4（RGS4）可降低这些GPCR的信号传导。因此，RGS4水平降低会增强GPCR介导的NMDAR活性降低，并可能导致精神分裂症中NMDAR功能减退。在本研究中，我们在多个分辨率水平上对精神分裂症患者和匹配的健康对照者的DLPFC中的RGS4 mRNA和蛋白水平进行了定量。为了研究可能导致RGS4水平改变的分子机制，我们对小非编码RNA（即微小RNA，miRs）的水平进行了定量，这些微小RNA在转录后调节RGS4 mRNA的完整性。精神分裂症患者的RGS4 mRNA和蛋白水平显著降低，并且在所有受试者中呈正相关。精神分裂症患者DLPFC第3层和第5层的锥体神经元中存在RGS4 mRNA缺陷。相比之下，精神分裂症患者DLPFC中的miR16水平显著更高，并且更高的miR16水平预示着更低的RGS4 mRNA水平。这些发现提供了趋同的证据，表明精神分裂症中RGS4 mRNA和蛋白水平降低可能是由于miR16表达增加所致。鉴于RGS4在调节GPCR中的作用，进而调节NMDAR信号的强度，这些发现可能有助于揭示精神分裂症中DLPFC锥体细胞NMDAR功能减退的分子基础。
