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Lithium treatment attenuates muscarinic M 1 receptor dysfunction
Author(s) -
Creson Thomas K,
Austin Daniel R,
Shaltiel Galit,
McCammon Joseph,
Wess Jürgen,
Manji Husseini K,
Chen Guang
Publication year - 2011
Publication title -
bipolar disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.285
H-Index - 129
eISSN - 1399-5618
pISSN - 1398-5647
DOI - 10.1111/j.1399-5618.2011.00915.x
Subject(s) - muscarinic acetylcholine receptor , muscarinic acetylcholine receptor m1 , lithium (medication) , muscarinic acetylcholine receptor m3 , signal transduction , mapk/erk pathway , endocrinology , medicine , receptor , biology , neuroscience , microbiology and biotechnology
Creson TK, Austin DR, Shaltiel G, McCammon J, Wess J, Manji HK, Chen G. Lithium treatment attenuates muscarinic M 1 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. M 1 , 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 M 1 receptor. We hypothesized that miRNAs regulate M 1 receptor translation, and that disrupted M 1 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 M 1 levels were tested in primary cultures and in rat frontal cortex. Effects of M 1 ablation and chronic treatment with mood stabilizers on several signaling cascades and M 1 ‐modulated behaviors were examined in wild‐type and M 1 knockout mice. Results: Let‐7b, but not let‐7c, negatively regulated M 1 levels. Chronic treatment with lithium, but not valproate, increased M 1 levels in the rat cortex. M 1 knockout mice exhibit ERK pathway deficits and behavioral hyperactivity; chronic treatment with lithium attenuated these deficits and hyperactivity. Conclusions: Lithium treatment can affect M 1 receptor function through intracellular signaling enhancement and, in situations without M 1 ablation, concomitant receptor upregulation via mechanisms involving miRNAs. Muscarinic dysfunction may contribute to mood disorders, while M 1 receptors and the downstream ERK pathway may serve as potential therapeutic targets for alleviating manic symptoms such as psychomotor hyperactivity.