Schizophrenia is characterized by substantial alterations in brain function, and previous studies suggest insulin signaling pathways, particularly involving AKT, are implicated in the pathophysiology of the disorder. This study demonstrates elevated mRNA expression of AKT1-3 in neurons from schizophrenia subjects, contrary to unchanged or diminished total AKT protein expression reported in previous postmortem studies, suggesting a potential decoupling of transcript and protein levels. Sex-specific differential AKT activity was observed, indicating divergent roles in males and females with schizophrenia. Alongside AKT, upregulation of PDPK1, a critical component of the insulin signaling pathway, and several protein phosphatases known to regulate AKT were detected. Moreover, enhanced expression of the transcription factor FOXO1, a regulator of glucose metabolism, hints at possible compensatory mechanisms related to insulin signaling dysregulation. Findings were largely independent of antipsychotic medication use, suggesting inherent alterations in schizophrenia. These results highlight the significance of AKT and related signaling pathways in schizophrenia, proposing that these changes might represent a compensatory response to a primary defect of canonical insulin signaling pathways. This research underscores the need for a detailed understanding of these signaling pathways for the development of effective therapeutic strategies.

精神分裂症的特征是大脑功能的重大改变，先前的研究表明胰岛素信号通路，特别是涉及 AKT，与该疾病的病理生理学有关。这项研究表明，精神分裂症受试者神经元中 AKT1-3 的 mRNA 表达升高，与先前尸检研究中报道的 AKT 总蛋白表达不变或减少相反，表明转录本和蛋白质水平可能脱钩。观察到性别特异性差异 AKT 活性，表明男性和女性精神分裂症患者的作用不同。除了 AKT，还检测到胰岛素信号通路的关键成分 PDPK1 的上调，以及几种已知可调节 AKT 的蛋白质磷酸酶。此外，转录因子 FOXO1（葡萄糖代谢调节因子）的表达增强暗示了与胰岛素信号转导失调相关的可能代偿机制。研究结果在很大程度上独立于抗精神病药物的使用，表明精神分裂症的固有改变。这些结果强调了 AKT 和相关信号通路在精神分裂症中的重要性，提出这些变化可能代表对典型胰岛素信号通路原发性缺陷的代偿反应。这项研究强调了详细了解这些信号通路以开发有效治疗策略的必要性。