Lithium treatment attenuates muscarinic M1 receptor dysfunction

Authors

  • Thomas K Creson,

    1. Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health
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  • Daniel R Austin,

    1. Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health
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  • Galit Shaltiel,

    1. Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health
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  • Joseph McCammon,

    1. Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health
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  • Jürgen Wess,

    1. Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
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  • Husseini K Manji,

    1. Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health
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  • Guang Chen

    1. Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health
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    • Present address: J & J Pharmaceutical Research and Development, L.L.C.
      3210 Merryfield Row
      San Diego, CA 92121, USA
      Fax: 858-784-3085
      E-mail: gchen13@its.jnj.com


  • The authors of this paper report no biomedical financial interests or potential conflicts of interest in connection with this manuscript. HKM and GC are now at Johnson & Johnson Pharmaceutical Research and Development; all of this work was conducted while they were employees of the National Institute of Mental Health.

Corresponding author:
Guang Chen, M.D., Ph.D.
Laboratory of Molecular Pathophysiology and Experimental Therapeutics
NIMH, NIH
Bethesda, MD 20892-3711, USA

Abstract

Creson TK, Austin DR, Shaltiel G, McCammon J, Wess J, Manji HK, Chen G. Lithium treatment attenuates muscarinic M1 receptor dysfunction.
Bipolar Disord 2011: 13: 238–249. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S.

Objective:  Altered muscarinic acetylcholine receptor levels and receptor-coupled signaling processes have been reported in mood disorders. M1, one of five muscarinic receptor subtypes, couples to the phospholipase C/protein kinase C and extracellular signal-regulated kinase (ERK) pathways. Mood stabilizers regulate these pathways. MicroRNAs (miRNAs) are small noncoding RNAs that suppress translation in a sequence-selective manner. Lithium downregulates several miRNAs, including let-7b and let-7c. One predicted target of let-7b and let-7c is the M1 receptor. We hypothesized that miRNAs regulate M1 receptor translation, and that disrupted M1 expression leads to aberrant behaviors and disrupted downstream signaling pathways that are rescued by lithium treatment.

Methods:  The effects of miRNAs and chronic treatment with mood stabilizers on M1 levels were tested in primary cultures and in rat frontal cortex. Effects of M1 ablation and chronic treatment with mood stabilizers on several signaling cascades and M1-modulated behaviors were examined in wild-type and M1 knockout mice.

Results:  Let-7b, but not let-7c, negatively regulated M1 levels. Chronic treatment with lithium, but not valproate, increased M1 levels in the rat cortex. M1 knockout mice exhibit ERK pathway deficits and behavioral hyperactivity; chronic treatment with lithium attenuated these deficits and hyperactivity.

Conclusions:  Lithium treatment can affect M1 receptor function through intracellular signaling enhancement and, in situations without M1 ablation, concomitant receptor upregulation via mechanisms involving miRNAs. Muscarinic dysfunction may contribute to mood disorders, while M1 receptors and the downstream ERK pathway may serve as potential therapeutic targets for alleviating manic symptoms such as psychomotor hyperactivity.

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