Background 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). Methods 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. Results 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. Conclusions 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.

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Aim: Several approaches indicate different blood flow disturbances in schizophrenia (Scz). Vascular endothelial growth factor (VEGF) is widely recognized as one of the key molecules implicated in the angiogenesis process through mainly its receptor KDR. The current work was designed to investigate the potential association between three polymorphisms (rs699947; rs833061 and rs3025039) in VEGF gene and two SNPs (rs2305948 and rs1870377) within KDR gene and predisposition to Scz among the Tunisian population. Methods: We carried-out a case-control study composed of 200 schizophrenic patients and 200 healthy subjects using RFLP-PCR. Results: Of all analyzed polymorphisms, only rs3025039, rs833061 and rs1870377 showed a significant risk for Scz. Following the stratified analysis, rs833061 was more prevalent among undifferentiated form. Yet, rs1870377 was especially correlated with paranoid subtype. We found also that rs699947 and rs833061 had an impact on patients' symptomatology. Haplotype analysis unveiled a strong LD between rs833061 and rs3025039 only for undifferentiated patients. Moreover, the -2578/-460/+936 CTT haplotype, with only one mutated allele +936T, conferred a high risk to Scz and, in particular, to undifferentiated and paranoid forms. Among the last-mentioned subgroup, we noticed another overrepresented haplotype (ATT). Furthermore, the +1192/+1719 GT haplotype carrying the minor allele +1719T displayed increased frequencies in schizophrenics as well as in paranoid patients. Conclusion: Our results show that all SNPs associated with the development or the severity of schizophrenia, were subsequently correlated with a decrease in the VEGF levels or influence VEGFR-2 binding affinity. Nevertheless, these data need to be strengthened by further independent analyses.

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