The cortico-cerebellar-thalamic-cortical circuit has been implicated in the emergence of psychotic symptoms in schizophrenia (SZ). The kynurenine pathway (KP) has been linked to alterations in glutamatergic and monoaminergic neurotransmission and to SZ symptomatology through the production of the metabolites quinolinic acid (QA) and kynurenic acid (KYNA). This work describes alterations in KP in the post-mortem prefrontal cortex (PFC) and cerebellum (CB) of 15 chronic SZ patients and 14 control subjects in PFC and 13 control subjects in CB using immunoblot for protein levels and ELISA for interleukins and QA and KYNA determinations. Monoamine metabolites were analysed by high-performance liquid chromatography and SZ symptomatology was assessed by Positive and Negative Syndrome Scale (PANSS). The association of KP with inflammatory mediators, monoamine metabolism and SZ symptomatology was explored. In the PFC, the presence of the anti-inflammatory cytokine IL-10 together with IDO2 and KATII enzymes decreased in SZ, while TDO and KMO enzyme expression increased. A network interaction analysis showed that in the PFC IL-10 was coupled to the QA branch of the kynurenine pathway (TDO-KMO-QA), whereas IL-10 associated with KMO in CB. KYNA in the CB inversely correlated with negative and general PANSS psychopathology. Although there were no changes in monoamine metabolite content in the PFC in SZ, a network interaction analysis showed associations between dopamine and methoxyhydroxyphenylglycol degradation metabolite. Direct correlations were found between general PANSS psychopathology and the serotonin degradation metabolite, 5-hydroxyindoleacetic acid. Interestingly, KYNA in the CB inversely correlated with 5-hydroxyindoleacetic acid in the PFC. Thus, this work found alterations in KP in two brain areas belonging to the cortico-cerebellar-thalamic-cortical circuit associated with SZ symptomatology, with a possible impact across areas in 5-HT degradation.

中文翻译：

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精神分裂症死后前额叶皮层和小脑的犬尿氨酸通路：与单胺和症状学的关系

皮质-小脑-丘脑-皮质回路与精神分裂症 (SZ) 中精神病症状的出现有关。犬尿氨酸途径 (KP) 通过代谢物喹啉酸 (QA) 和犬尿酸 (KYNA) 的产生与谷氨酸能和单胺能神经传递的改变以及 SZ 症状有关。这项工作描述了 15 名慢性 SZ 患者和 14 名 PFC 对照受试者和 13 名 CB 对照受试者的死后前额叶皮层 (PFC) 和小脑 (CB) 的 KP 变化，使用免疫印迹法检测蛋白质水平，ELISA 检测白细胞介素和 QA 和KYNA 的决定。通过高效液相色谱分析单胺代谢物，并通过阳性和阴性症状量表 (PANSS) 评估 SZ 症状。KP与炎症介质的关联，探讨了单胺代谢和 SZ 症状。在 PFC 中，抗炎细胞因子 IL-10 以及 IDO2 和 KATII 酶的存在在 SZ 中减少，而 TDO 和 KMO 酶表达增加。网络相互作用分析表明，在 PFC 中，IL-10 与犬尿氨酸途径的 QA 分支（TDO-KMO-QA）耦合，而 IL-10 与 CB 中的 KMO 相关。CB 中的 KYNA 与阴性和一般 PANSS 精神病理学呈负相关。尽管 SZ 中 PFC 中的单胺代谢物含量没有变化，但网络相互作用分析显示多巴胺和甲氧基羟基苯二醇降解代谢物之间存在关联。在一般 PANSS 精神病理学和血清素降解代谢物 5-羟基吲哚乙酸之间发现了直接相关性。有趣的是，CB 中的 KYNA 与 PFC 中的 5-羟基吲哚乙酸呈负相关。因此，这项工作发现属于与 SZ 症状相关的皮质-小脑-丘脑-皮质回路的两个大脑区域的 KP 改变，可能影响 5-HT 降解的跨区域。