MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-02, Vol.109 (8), p.3125-3130
• Main Authors: Miller, Brooke H., Zeier, Zane, Xi, Li, Lanz, Thomas A., Deng, Shibing, Strathmann, Julia, Willoughby, David, Kenny, Paul J., Elsworth, John D., Lawrence, Matthew S., Roth, Robert H., Edbauer, Dieter, Kleiman, Robin J., Wahlestedt, Claes
• Format: Article
• Language: English
• Subjects: Adolescence; Adult; Animals; Antipsychotic Agents - pharmacology; Antipsychotic Agents - therapeutic use; Biological Sciences; Bipolar Disorder - drug therapy; Bipolar Disorder - genetics; Bipolar Disorder - physiopathology; Brain; Brain - drug effects; Brain - growth & development; Brain - physiopathology; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Cerebral Cortex - physiopathology; Cognitive ability; Cortex (prefrontal); Cyclic AMP; Data processing; Databases, Genetic; Datasets; Demography; Disease Models, Animal; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA microarrays; Down regulation; GATA2 Transcription Factor - metabolism; Gene expression; Gene expression regulation; Gene Expression Regulation - drug effects; Glutamic acid receptors (ionotropic); HEK293 Cells; Humans; Mental disorders; Messenger RNA; Mice; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Muscle Proteins - metabolism; N-Methyl-D-aspartic acid receptors; N-Methylaspartate - metabolism; Neurons; Oligonucleotide Array Sequence Analysis; Open Reading Frames - genetics; Polymerase Chain Reaction; Rats; Receptors, N-Methyl-D-Aspartate - metabolism; Regulatory sequences; Reproducibility of Results; Ribonucleic acid; RNA; Rodents; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - genetics; Schizophrenia - physiopathology; Signal Transduction - drug effects; Untranslated regions; Up regulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1113793109

Schizophrenia is characterized by affective, cognitive, neuromorphological, and molecular abnormalities that may have a neurodevelopmental origin. MicroRNAs (miRNAs) are small noncoding RNA sequences critical to neurodevelopment and adult neuronal processes by coordinating the activity of multiple genes within biological networks. We examined the expression of 854 miRNAs in prefrontal cortical tissue from 100 control, schizophrenic, and bipolar subjects. The cyclic AMP-responsive element binding- and NMDA-regulated microRNA miR-132 was significantly down-regulated in both the schizophrenic discovery cohort and a second, independent set of schizophrenic subjects. Analysis of miR-132 target gene expression in schizophrenia gene-expression microarrays identified 26 genes upregulated in schizophrenia subjects. Consistent with NMDA-mediated hypofunction observed in schizophrenic subjects, administration of an NMDA antagonist to adult mice results in miR-132 down-regulation in the prefrontal cortex. Furthermore, miR-132 expression in the murine prefrontal cortex exhibits significant developmental regulation and overlaps with critical neurodevelopmental processes during adolescence. Adult prefrontal expression of miR-132 can be down-regulated by pharmacologie inhibition of NMDA receptor signaling during a brief postnatal period. Several key genes, including DNMT3A, GATA2, and DPYSL3, are regulated by miR-132 and exhibited altered expression either during normal neurodevelopment or in tissue from adult schizophrenic subjects. Our data suggest miR-132 dysregulation and subsequent abnormal expression of miR-132 target genes contribute to the neurodevelopmental and neuromorphological pathologies present in schizophrenia.