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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. Synopsis: The involvement of microRNAs in the pathogenesis of schizophrenia is not well-understood. This study shows that miR-99b-5p regulates Z-DNA binding protein 1 (Zbp1) to control inflammatory responses in microglia and the development of schizophrenia-like symptoms in mice. miR-99b-5p is downregulated in the blood and brains of schizophrenia patients. miR-99b-5p inhibition induces schizophrenia-like phenotypes in mice and microglial inflammation. Zbp1 is a novel miR-99b-5p target in microglia. Zbp1 antisense oligos ameliorate the pathological outcomes of decreased miR-99b-5p levels. Dysregulation of a novel miR-99b-5p-Zbp1 (Z-DNA binding protein 1) pathway in microglia induces inflammatory responses and schizophrenia-like phenotypes in mice. [ABSTRACT FROM AUTHOR]

In mammals, histone 3 lysine 4 methylation (H3K4me) is mediated by six different lysine methyltransferases. Among these enzymes, SETD1B (SET domain containing 1b) has been linked to syndromic intellectual disability in human subjects, but its role in the mammalian postnatal brain has not been studied yet. Here, we employ mice deficient for Setd1b in excitatory neurons of the postnatal forebrain, and combine neuron‐specific ChIP‐seq and RNA‐seq approaches to elucidate its role in neuronal gene expression. We observe that Setd1b controls the expression of a set of genes with a broad H3K4me3 peak at their promoters, enriched for neuron‐specific genes linked to learning and memory function. Comparative analyses in mice with conditional deletion of Kmt2a and Kmt2b histone methyltransferases show that SETD1B plays a more pronounced and potent role in regulating such genes. Moreover, postnatal loss of Setd1b leads to severe learning impairment, suggesting that SETD1B‐dependent regulation of H3K4me levels in postnatal neurons is critical for cognitive function. Synopsis: Mammalian histone H3K4 methyltransferases are linked to neurodevelopmental intellectual disability disorders. Conditional postnatal deletion studies reveal a specific role of Setd1b‐controlled gene expression programs, suggesting a potential target for treating cognitive impairment in patients. Postnatal deletion of the H3K4 methyltransferase Setd1b from neurons of the mouse forebrain leads to severe learning impairment.SETD1B in postnatal neurons controls the expression of neuron‐specific genes with a broad H3K4me3 peak, and with roles in learning and memory.Neuronal gene‐expression programs controlled by SETD1B differ substantially from those controlled by the H3K4 methyltransferases KMT2A and KMT2B.Postnatal loss of Setd1b leads to severe learning impairment in mice. [ABSTRACT FROM AUTHOR]