MacDowell, K. S. | Search bioRxiv

bioRxiv2021

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

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 enzymes 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 metabolites 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.

neuroscience↗

bioRxiv2021

Analysis Of Molecular Networks In The Cerebellum In Chronic Schizophrenia: Modulation By Early Postnatal Life Stressors In Murine Models

Despite the growing importance of the cortico-cerebellar-thalamo-cortical circuit in schizophrenia, limited information is available regarding altered molecular networks in cerebellum. To identify altered protein networks, we conducted proteomic analysis of grey matter of postmortem cerebellar cortex in chronic schizophrenia subjects (n=12) and healthy individuals (n=14) followed by an extensive bioinformatic analysis. Two double-hit postnatal stress murine models for SZ were used to validate the most robust candidates. The models were maternal deprivation combined with an additional stressor: social isolation or chronic restraint stress. We found that the individual proteomic profile allowed the segregation of most schizophrenia cases from healthy individuals. We found 250 proteins with altered levels. This group was enriched in proteins related to mental disorders, mitochondrial disease, stress, and a number of biological functions including energy, immune response, axonal cytoskeletal organization and vesicle-mediated transport. Network analysis identified three modules: energy metabolism, neutrophil degranulation and a mixed module of mainly axonal-related functions. We analysed the most robust candidates in the networks in two double-hit stress murine models. METTL7A from the degranulation pathway was reduced in both models, while NDUFB9 from the energy network and CLASP1 from the axonal module decreased in only one model. This work provides evidence for altered energy, immune and axonal-related networks in the cerebellum in schizophrenia, suggesting that the accumulation of molecular errors, some by an early postnatal stress exposure, could lead to a failure in the normal cerebellar functions, impairing synaptic response and the defence mechanisms of this region against external harmful injuries in schizophrenia.

neuroscience↗