Lithium treatment attenuates muscarinic M₁ receptor dysfunction

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.