ABSTRACT
BACKGROUND: Transcriptomic studies of the brains of schizophrenia (SZ) patients have produced abundant but largely inconsistent findings about the disorders pathophysiology. These inconsistencies might stem not only from the heterogeneous nature of the disorder, but also from the unbalanced focus on particular cortical regions and protein-coding genes. Compared to protein-coding transcripts, long intergenic non-coding RNA (lincRNA) display substantially greater brain region and disease response specificity, positioning them as prospective indicators of SZ-associated alterations. Further, a growing understanding of the systemic character of the disorder calls for a more systematic screening involving multiple diverse brain regions. AIM: We aimed to identify and interpret alterations of the lincRNA expression profiles in SZ by examining the transcriptomes of 35 brain regions. METHODS: We measured the transcriptome of 35 brain regions dissected from eight adult brain specimens, four SZ patients, and four healthy controls, using high-throughput RNA sequencing. Analysis of these data yielded 861 annotated human lincRNAs passing the detection threshold. RESULTS: Of the 861 detected lincRNA, 135 showed significant region-dependent expression alterations in SZ (two-way ANOVA, BH-adjusted p 0.05) and 37 additionally showed significant differential expression between HC and SZ individuals in at least one region (post hoc Tukey test, p 0.05). For these 37 differentially expressed lincRNAs (DELs), 88% of the differences occurred in a cluster of brain regions containing axon-rich brain regions and cerebellum. Functional annotation of the DEL targets further revealed stark enrichment in neurons and synaptic transmission terms and pathways. CONCLUSION: Our study highlights the utility of a systematic brain transcriptome analysis relying on the expression profiles measured across multiple brain regions and singles out white matter regions as a prospective target for further SZ research.
ABSTRACT
INTRODUCTION: Schizophrenia, although a debilitating mental illness, greatly affects individuals' physical health as well. One of the leading somatic comorbidities associated with schizophrenia is cardiovascular disease, which has been estimated to be one of the leading causes of excess mortality in patients diagnosed with schizophrenia. Although the shared susceptibility to schizophrenia and cardiovascular disease is well established, the mechanisms linking these two disorders are not well understood. Genetic studies have hinted toward shared lipid metabolism abnormalities co-occurring in the two disorders, while lipid compounds have emerged as prognostic markers for cardiovascular disease. In particular, three ceramide species in the blood plasma, Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1), have been robustly linked to the latter disorder. AIM: We aimed to assess the differences in abundances of Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1) in the blood plasma of schizophrenia patients compared to healthy controls. METHODS: We measured the abundances of Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1) in a cohort of 82 patients with schizophrenia and 138 controls without a psychiatric diagnosis and validated the results using an independent cohort of 26 patients with schizophrenia, 55 control individuals, and 19 patients experiencing a first psychotic episode. RESULTS: We found significant alterations for all three ceramide species Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1) and a particularly strong difference in concentrations between psychiatric patients and controls for the ceramide species Cer(d18:1/18:0). CONCLUSIONS: The alteration of Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1) levels in the blood plasma might be a manifestation of metabolic abnormalities common to both schizophrenia and cardiovascular disease.
ABSTRACT
Willner's "chronic mild stress" (CMS) model is a globally recognized and most commonly used depression model. A depression model induced by ultrasonic exposure of variable frequencies has been created in our laboratory. This article compares two models of the depressive-like state according to three validity criteria. Face validity has been demonstrated in sucrose preference test, Porsolt test, social interest, open field and the Morris water maze. Rats after ultrasound impact have more pronounced anhedonia and social isolation. The construct validity has been proven due to increased levels of corticosterone, epinephrine and norepinephrine and reduced levels of dopamine and some of its metabolites in rat plasma after ultrasound exposure. Predictive validity has been described previously, where the therapeutic effects of various classes of antidepressants have been shown. Our study has demonstrated that the ultrasound-induced depression model is suitable, such as the generally accepted CMS protocol, and meets all required validity criteria. The model presented in this article might help to study pathogenetic mechanisms of depressive disorders, as well as to test promising methods of depression treatment.
