Regulation of Zbp1 by miR-99b-5p in microglia controls the development of schizophrenia-like symptoms in mice
Lalit Kaurani, Rezaul Islam, Urs Heilbronner, D. Krüger, Jiayin Zhou, Aditi Methi, Judith Strauß, Ranjit Pradhan, Sophie Schröder, Susanne Burkhardt, Anna-Lena Schuetz, Tonatiuh Peña, Lena Erlebach, Anika Bühler, Monika Budde, Fanny Senner, Mojtaba Oraki Kohshour, Eva C. Schulte, Max Schmauß, Eva Z. Reininghaus, Georg Juckel, Deborah Kronenberg‐Versteeg, Ivana Delalle, Francesca Odoardi, Alexander Flügel, Thomas G. Schulze, Peter Falkai, Farahnaz Sananbenesi, André Fischer
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.