Krolewski David M, Khalil Huzefa, Waselus Maria, Vawter Marquis P, Bunney Blynn G, Myers Richard M, Lee Francis S Y, Schatzberg Alan F, Bunney William E, Akil Huda, Watson Stanley J
Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
University of California-Irvine, Irvine, CA, USA.
Schizophrenia (Heidelb). 2025 Jun 21;11(1):91. doi: 10.1038/s41537-025-00638-6.
Schizophrenia (SZ) and bipolar disorder (BP) patients share overlapping neurocognitive deficits of varied magnitude. Neuroimaging in patients and postmortem gene expression analyses suggest that compromised cingulate gyrus GABA-ergic interneurons may contribute to cognitive impairments in SZ and BP. To address this, we used radioactive in situ hybridization to investigate potential gene expression signatures for SZ and BP using interneuron cell-type specific markers including glutamic acid decarboxylase (GAD67), parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide (VIP) within specific Brodmann's areas (BA) of the cingulate gyrus. We report reduced GAD67 mRNA in anterior midcingulate cortex (aMCC) of BP subjects within BA24c', the most dysregulated subregion across disorders that also demonstrated reduced PV and VIP mRNA in the SZ group. In the retrosplenial (RSC) and ectosplenial (ESC) cortices, decreases in PV expression were shared by both SZ and BP subjects. Our results show unique and shared transcription signatures of two disorders in specific cingulate gyrus regions and cell types. SZ and BP displayed divergent aMCC gene expression reductions suggesting transcriptional changes are associated with disease-specific gene/subregion signatures, potentially underlying differential subregional dysregulation within areas associated with error detection/action monitoring and the salience network. In RSC/ESC, transcriptional changes are associated with more common expression patterns, possibly related to overlapping effects on visuospatial memory processing and allocation of attentional resources involving the default mode network.
精神分裂症（SZ）和双相情感障碍（BP）患者存在程度各异的重叠性神经认知缺陷。对患者的神经影像学研究以及死后基因表达分析表明，扣带回中γ-氨基丁酸能中间神经元受损可能导致SZ和BP患者出现认知障碍。为了探究这一问题，我们使用放射性原位杂交技术，利用中间神经元细胞类型特异性标志物，包括谷氨酸脱羧酶（GAD67）、小白蛋白（PV）、生长抑素（SST）和血管活性肠肽（VIP），在扣带回特定的布罗德曼区域（BA）内研究SZ和BP潜在的基因表达特征。我们报告称，在BA24c'区域的BP受试者前扣带回中部皮质（aMCC）中，GAD67 mRNA水平降低，该区域是所有疾病中失调最严重的亚区域，在SZ组中也显示PV和VIP mRNA水平降低。在压后皮质（RSC）和外侧压后皮质（ESC）中，SZ和BP受试者的PV表达均降低。我们的结果显示了两种疾病在特定扣带回区域和细胞类型中的独特和共同转录特征。SZ和BP在aMCC基因表达降低方面表现出差异，这表明转录变化与疾病特异性基因/亚区域特征相关，可能是与错误检测/动作监测及突显网络相关区域内不同亚区域失调的潜在原因。在RSC/ESC中，转录变化与更常见的表达模式相关，可能与对视觉空间记忆处理以及涉及默认模式网络的注意力资源分配的重叠影响有关。
