Regulation of Zbp1 by miR-99b-5p in microglia controls the development of schizophrenia-like symptoms in mice

Abstract

Current approaches to the treatment of schizophrenia have mainly focused on the protein-coding part of the genome; in this context, the roles of microRNAs have received less attention. In the present study, we analyze the microRNAome in the blood and postmortem brains of schizophrenia patients, showing that the expression of miR-99b-5p is downregulated in both the prefrontal cortex and blood of patients. Lowering the amount of miR-99b-5p in mice leads to both schizophrenia-like phenotypes and inflammatory processes that are linked to synaptic pruning in microglia. The microglial miR-99b-5p-supressed inflammatory response requires Z-DNA binding protein 1 (Zbp1), which we identify as a novel miR-99b-5p target. Antisense oligonucleotides against Zbp1 ameliorate the pathological effects of miR-99b-5p inhibition. Our findings indicate that a novel miR-99b-5p-Zbp1 pathway in microglia might contribute to the pathogenesis of schizophrenia.

A role for astrocytic miR-129-5p in Frontotemporal Dementia

“…As such, it is interesting that so far there is no report on the deregulation of miR-129-5p in schizophrenia. Even in a large recent study in which 573 blood samples and 30 postmortem brains of schizophrenia patients and controls were analyzed by smallRNAseq, no de-regulation of miR-129 was observed [61]. However, it should be mentioned that recent study reported that miR-129-5p is decreased in exosomes isolated from the postmortem brain of males but not females that suffered from depression [62] Functional data on miR-129-5p is rare.…”

Integrative Analysis of miRNA Expression Profiles Reveals Distinct and Common Molecular Mechanisms Underlying Broad Diagnostic Groups of Severe Mental Disorders

“…Notably, miRNA 584-3p and 99b-5p were downregulated in PSY compared to AFF which was also previously reported as downregulated in the blood for patients with SCZ compared to healthy participants in a previous study 38 . Furthermore, leveraging the same small RNA-sequencing dataset, recent research identi ed miR-99b-5p as a crucial regulator of innate immunity and synaptic plasticity, found to be downregulated in both the blood and brains of patients diagnosed with SCZ 25 (FIGURE 1G, H).…”

“…After quality control and SNPs imputation (see supplementary methods) the dataset contained 1600 individuals and 7,712,287 SNPs. miRNA transcriptome SmallRNAs sequencing and alignment to human genome of the PsyCourse Study has been described previously 25 QC were realized using FastQC v0.12.1 and miRTrace v1.0.0 29 . Samples that generated warnings when analysed by miRTrace were removed from further analysis.…”

“…MiRNAs are small non-coding RNA molecules that post-transcriptionally modulate gene expression, and their dysregulation has been increasingly linked to psychiatric disorders 18,19 . Schizophrenia-spectrum disorders and affective disorders, such as BD and MDD, have been the focus of intensive research efforts to elucidate the role of miRNAs in their pathophysiology and to identify biomarkers which could be predictive of disease state [20][21][22][23][24][25] . It is possible that some of the miRNA expression alterations may be partially mediated by genetic variation i.e.…”