Genetic and functional analyses implicate microRNA 499A in bipolar disorder development.

Bipolar disorder (BD) is a complex mood disorder with a strong genetic component. Recent studies suggest that microRNAs contribute to psychiatric disorder development. In BD, specific candidate microRNAs have been implicated, in particular miR-137, miR-499a, miR-708, miR-1908 and miR-2113. The aim of the present study was to determine the contribution of these five microRNAs to BD development. For this purpose, we performed: (i) gene-based tests of the five microRNA coding genes, using data from a large genome-wide association study of BD; (ii) gene-set analyses of predicted, brain-expressed target genes of the five microRNAs; (iii) resequencing of the five microRNA coding genes in 960 BD patients and 960 controls and (iv) in silico and functional studies for selected variants. Gene-based tests revealed a significant association with BD for MIR499A, MIR708, MIR1908 and MIR2113. Gene-set analyses revealed a significant enrichment of BD associations in the brain-expressed target genes of miR-137 and miR-499a-5p. Resequencing identified 32 distinct rare variants (minor allele frequency < 1%), all of which showed a non-significant numerical overrepresentation in BD patients compared to controls (p = 0.214). Seven rare variants were identified in the predicted stem-loop sequences of MIR499A and MIR2113. These included rs142927919 in MIR2113 (pnom = 0.331) and rs140486571 in MIR499A (pnom = 0.297). In silico analyses predicted that rs140486571 might alter the miR-499a secondary structure. Functional analyses showed that rs140486571 significantly affects miR-499a processing and expression. Our results suggest that MIR499A dysregulation might contribute to BD development. Further research is warranted to elucidate the contribution of the MIR499A regulated network to BD susceptibility.

Maternal immune activation leads to atypical turning asymmetry and reduced DRD2 mRNA expression in a rat model of schizophrenia.

Atypical asymmetries have been reported in individuals diagnosed with schizophrenia, linking higher symptom severity to weaker lateralization. Furthermore, both lateralization and schizophrenia are influenced by the dopaminergic system. However, whether a direct link between the etiology of schizophrenia and atypical asymmetries exists is yet to be investigated. In this study, we examined whether maternal immune activation (MIA), a developmental animal model for schizophrenia and known to alter the dopaminergic system, induces atypical lateralization in adolescent and adult offspring. As the dopaminergic system is a key player in both, we analyzed neuronal dopamine D2 receptor (DRD2) mRNA expression. MIA was induced by injecting pregnant rats with 10 mg/kg polyinosinic:polycytidylic (PolyI:C) at gestational day 15. Controls were injected with 0.9 % NaCl. Offspring were tested at adolescence or early adulthood for asymmetry of turning behavior in the open field test. The total number of left and right turns per animal was assessed using DeepLabCut. Strength and preferred side of asymmetry were analyzed by calculating lateralization quotients. Additionally, DRD2 mRNA expression in the prefrontal cortex of offspring at both ages was analyzed using real-time PCR. MIA was associated with a rightward turning behavior in adolescents. In adults, MIA was associated with an absence of turning bias, indicating reduced asymmetry after MIA. The analysis of DRD2 mRNA expression revealed significantly lower mRNA levels after MIA compared to controls in adolescent, but not adult animals. Our results reinforce the association between atypical asymmetries, reduced DRD2 mRNA expression, and schizophrenia. However, more preclinical research is needed.

MORC1 methylation and BDI are associated with microstructural features of the hippocampus and medial prefrontal cortex.

BACKGROUND: Alterations in the hippocampus and prefrontal cortex (PFC) have frequently been reported in depressed patients. These parameters might prove to be a consistent finding in depression. In addition, peripheral DNA methylation of the MORC1 gene promoter showed stable associations with depression across independent samples. However, the question arises whether MORC1, supposedly acting as transcription factor, might also be involved in neurobiological alterations accompanying depression. This study further analyses the role of MORC1 in depression by investigating a potential correlation between peripheral MORC1 DNA methylation and neuronal structural properties previously associated with depression in humans. METHODS: Beck Depression Inventory (BDI) was assessed in 52 healthy participants. DNA was extracted from buccal cells and MORC1 methylation correlated with micro- and macrostructural properties derived from magnetic resonance imaging (MRI) and neurite orientation dispersion and density imaging (NODDI) in the hippocampus and medial prefrontal cortex (mPFC). RESULTS: MORC1 methylation was associated with volume reduction and neurite orientation dispersion and density markers in the hippocampus and mPFC. BDI was positively associated with neurite orientation dispersion and density markers in the hippocampus. LIMITATIONS: The study was conducted in a small sample of healthy participants with subclinical depressive symptoms. Peripheral tissue was analyzed. CONCLUSION: We found significant negative associations between peripheral MORC1 methylation and macro- and microstructural markers in the hippocampus and mPFC. Thus, MORC1 might be involved in neurobiological properties. Studies investigating neuronal methylation patterns of MORC1 are needed to support this hypothesis.