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Evidence for selective microRNAs and their effectors as common long-term targets for the actions of mood stabilizers

Rulun Zhou1, Peixiong Yuan, Yun Wang

  • 1Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
|August 16, 2008
PubMed

Insights

Mood stabilizers like lithium and valproate alter microRNAs (miRNAs) in the brain, affecting genes linked to bipolar disorder. These findings reveal miRNAs as novel targets for psychiatric drug action.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Psychiatry

Background:

  • MicroRNAs (miRNAs) are key regulators of gene expression, influencing central nervous system plasticity.
  • Mood stabilizers, such as lithium and valproate (VPA), are crucial in treating psychiatric disorders.

Purpose of the Study:

  • To investigate the impact of chronic mood stabilizer treatment on hippocampal miRNA levels.
  • To identify specific miRNAs and their downstream targets involved in neuronal function and psychiatric risk.
  • To elucidate the role of miRNAs in the mechanism of action of mood stabilizers.

Main Methods:

  • Chronic treatment of rodents with lithium and VPA.
  • Quantitative PCR to confirm miRNA expression changes.
  • Analysis of predicted miRNA effector genes involved in neuronal pathways.
  • In vitro experiments using primary neuronal cultures to validate miRNA-target interactions.

Main Results:

  • Hippocampal miRNA profiles were altered by chronic lithium and VPA treatment, with several miRNAs (e.g., let-7b, miR-34a) confirmed by qPCR.
  • Predicted targets of these miRNAs are implicated in neurite outgrowth, neurogenesis, and signaling pathways (PTEN, ERK, Wnt/beta-catenin).
  • Mood stabilizer treatment increased expression of genes associated with bipolar disorder risk, including GRM7.
  • Endogenous miR-34a was shown to directly regulate GRM7 levels in neuronal cultures, mediating some effects of lithium and VPA.

Conclusions:

  • Mood stabilizer treatment significantly alters miRNA expression in the hippocampus.
  • MiRNAs and their effector genes, including GRM7, represent novel targets for the therapeutic effects of psychotherapeutic drugs.
  • This study provides the first evidence that miRNAs are direct targets of mood stabilizer action in the brain.

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