Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology

Amira Ben Afia,Aida Ormazabal,Juan C Leza,Borja Garcia-Bueno,Èlia Vila,Belén Ramos,Karina S Macdowell,Josep M Haro,Rafael Artuch

doi:10.1186/s12974-021-02260-6

Abstract

BackgroundThe 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).MethodsThis 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.ResultsIn 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.ConclusionsThus, 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.

Highlights

The cortico-cerebellar-thalamic-cortical circuit has been implicated in the emergence of psychotic symptoms in schizophrenia (SZ)
We explored the branch of the kynurenine pathway (KP) composed by Indoleamine 2 (IDO)-1 and 2 and kynurenine 3-monooxygenase (KMO) generating quinolinic acid (QA) and the alternative branch composed by TDO and KATII that lead to kynurenic acid (KYNA) production
A tendency to associate is present between KMO and QA (KMO-QA: t test, p value = 0.06) (Figure S1A in Supplementary material). These results indicate that IL-10 is acting upstream of TDO with the coupled TDO-KMO-QA pathway, which was altered in the prefrontal cortex (PFC)

Summary

Introduction

The cortico-cerebellar-thalamic-cortical circuit has been implicated in the emergence of psychotic symptoms in schizophrenia (SZ). The cortico-cerebellar-thalamic-cortical circuit may contribute to negative symptomatology and cognitive deficits in SZ [1, 2]. The cerebellum (CB) sends multiple inputs to the prefrontal cortex (PFC) through the thalamus, as well as dopaminergic inputs through the ventral tegmental area (VTA). The prefrontal cortex is the end route of this circuit responsible for cognitive and negative symptoms in SZ, while the CB is a key area in this circuit integrating and modulating multiple inputs from cortical areas and responsible for sending output signals back to the same cortical region through the thalamus to correct errors in the cortical region. The control of PFC activity through cerebellar circuits improved symptoms, being of particular relevance for the negative ones [4].

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