Lithium treatment attenuates muscarinic M1 receptor dysfunction

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.