Neurotransmission-related gene expression in the frontal pole is altered in subjects with bipolar disorder and schizophrenia.
Neurotransmission-related gene expression in the frontal pole is altered in subjects with bipolar disorder and schizophrenia.
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DOI：
10.1038/s41398-023-02418-1
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发表时间：
2023-04-08
影响因子：
6.8
通讯作者：
Watson, Stanley J., Jr.
中科院分区：
文献类型：
--
作者：
Medina, Adriana M.;Hagenauer, Megan Hastings;Krolewski, David M.;Hughes, Evan;Forrester, Liam Cannon Thew;Walsh, David M.;Waselus, Maria;Richardson, Evelyn;Turner, Cortney A.;Sequeira, P. Adolfo;Cartagena, Preston M.;Thompson, Robert C.;Vawter, Marquis P.;Bunney, Blynn G.;Myers, Richard M.;Barchas, Jack D.;Lee, Francis S.;Schatzberg, Alan F.;Bunney, William E.;Akil, Huda;Watson, Stanley J., Jr.
额极（Brodmann area 10, BA10）是人类皮层最大的细胞结构区，执行复杂的综合功能。在双相情感障碍（BP）和精神分裂症（SCHIZ）发病年龄之前，BA10经历了密集的青少年灰质修剪，其功能障碍可能是它们共同症状的基础。在本研究中，我们探讨了BA10神经传递相关基因表达在BP和SCHIZ中的作用。我们采用qPCR检测了对照组、BP和SCHIZ死后样本中115个神经传递相关靶点的表达（n = 72）。我们选择这种方法是因为它对低水平表达的检测灵敏度高。然后，我们通过对公开发布的BA10微阵列数据（n = 101）进行荟萃分析，并确定了与qPCR结果趋同的来源，从而加强了我们的发现。为了改进解释，我们利用样本中异常庞大的临床元数据数据库来探索BA10基因表达、治疗方法、滥用物质和症状特征之间的关系，并用公开可用的数据集验证这些发现。利用这些趋同的证据来源，我们确定了20个神经传递相关基因，这些基因在BA10的BP和SCHIZ中差异表达。这些结果包括两个重要的治疗靶点HTR2B和DRD4低水平表达的诊断相关的大幅下降，以及其他与多巴胺能、gaba能和星形细胞功能相关的发现。我们还观察到治疗方法可能产生与诊断效果相反的差异表达。相反，滥用药物对BA10基因表达的影响与BP和SCHIZ相似，可能会放大诊断相关的失调。
The frontal pole (Brodmann area 10, BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning prior to the age of onset for bipolar disorder (BP) and schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ postmortem samples (n = 72). We chose this method for its high sensitivity to detect low-level expression. We then strengthened our findings by performing a meta-analysis of publicly released BA10 microarray data (n = 101) and identified sources of convergence with our qPCR results. To improve interpretation, we leveraged the unusually large database of clinical metadata accompanying our samples to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these findings with publicly available datasets. Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results included a large diagnosis-related decrease in two important therapeutic targets with low levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABAergic and astrocytic function. We also observed that therapeutics may produce a differential expression that opposes diagnosis effects. In contrast, substances of abuse showed similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation.
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