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

Brooke H. Miller, Zane Zeier, Li Xi, Thomas A. Lanz, Shibing Deng, Julia Strathmann, David Willoughby, Paul J. Kenny, John D. Elsworth, Matthew S. Lawrence, Robert H. Roth, Dieter Edbauer, Robin J. Kleiman, Claes Wahlestedt

Research output: Contribution to journalArticle

191 Scopus citations

Abstract

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 geneswithin 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. ConsistentwithNMDA-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 pharmacologic 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 fromadult 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.

Original languageEnglish (US)
Pages (from-to)3125-3130
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number8
DOIs
StatePublished - Feb 21 2012

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Keywords

  • Epigenetics
  • Gene networks
  • Methylation
  • Psychiatric disorders

ASJC Scopus subject areas

  • General

Cite this

Miller, B. H., Zeier, Z., Xi, L., Lanz, T. A., Deng, S., Strathmann, J., Willoughby, D., Kenny, P. J., Elsworth, J. D., Lawrence, M. S., Roth, R. H., Edbauer, D., Kleiman, R. J., & Wahlestedt, C. (2012). MicroRNA-132 dysregulation in schizophrenia has implications for both neurodevelopment and adult brain function. Proceedings of the National Academy of Sciences of the United States of America, 109(8), 3125-3130. https://doi.org/10.1073/pnas.1113793109