MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction

Research output: Contribution to journalJournal articlepeer-review

  • Jannet Kocerha
  • Mohammad Ali Faghihi
  • Miguel A Lopez-Toledano
  • Jia Huang
  • Amy J Ramsey
  • Marc G Caron
  • Nicole Sales
  • David Willoughby
  • Joacim Elmen
  • Henrik F Hansen
  • Henrik Orum
  • Sakari Kauppinen
  • Paul J Kenny
  • Claes Wahlestedt
N-methyl-D-aspartate (NMDA) glutamate receptors are regulators of fast neurotransmission and synaptic plasticity in the brain. Disruption of NMDA-mediated glutamate signaling has been linked to behavioral deficits displayed in psychiatric disorders such as schizophrenia. Recently, noncoding RNA molecules such as microRNAs (miRNAs) have emerged as critical regulators of neuronal functions. Here we show that pharmacological (dizocilpine) or genetic (NR1 hypomorphism) disruption of NMDA receptor signaling reduces levels of a brain-specific miRNA, miR-219, in the prefrontal cortex (PFC) of mice. Consistent with a role for miR-219 in NMDA receptor signaling, we identify calcium/calmodulin-dependent protein kinase II gamma subunit (CaMKIIgamma), a component of the NMDA receptor signaling cascade, as a target of miR-219. In vivo inhibition of miR-219 by specific antimiR in the murine brain significantly modulated behavioral responses associated with disrupted NMDA receptor transmission. Furthermore, pretreatment with the antipsychotic drugs haloperidol and clozapine prevented dizocilpine-induced effects on miR-219. Taken together, these data support an integral role for miR-219 in the expression of behavioral aberrations associated with NMDA receptor hypofunction.
Original languageEnglish
JournalProceedings of the National Academy of Science of the United States of America
Volume106
Issue number9
Pages (from-to)3507-12
Number of pages5
ISSN0027-8424
DOIs
Publication statusPublished - 2009

Bibliographical note

Keywords: Animals; Behavior, Animal; Biological Transport; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Line, Tumor; Dizocilpine Maleate; Gene Expression Regulation; Gene Therapy; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Nervous System Diseases; Protein Subunits; RNA, Messenger; Receptors, N-Methyl-D-Aspartate; Signal Transduction

ID: 20876124