title: Lithium treatment attenuates muscarinic M(1) receptor dysfunction.
abstract: 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.
authors.affiliation: Laboratory of Molecular Pathophysiology and Experimental Therapeutics, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Creson
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Austin
authors.forename: Galit
authors.initials: G
authors.lastname: Shaltiel
authors.forename: Joseph
authors.initials: J
authors.lastname: McCammon
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
authors.forename: Husseini K
authors.initials: HK
authors.lastname: Manji
authors.forename: Guang
authors.initials: G
authors.lastname: Chen
mesh_terms: D000661:Amphetamine; D000704:Analysis of Variance; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004347:Drug Interactions; D005106:Exploratory Behavior / Q000187:drug effects; D005625:Frontal Lobe / Q000187:drug effects; D019922:GAP-43 Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy; D007398:Interpersonal Relations; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology*; D018782:Maze Learning / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D043643:Receptor, Muscarinic M1 / Q000172:deficiency / Q000378:metabolism*; D013550:Swimming / Q000523:psychology
chemical_list: D018692:Antimanic Agents; D019922:GAP-43 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D035683:MicroRNAs; D043643:Receptor, Muscarinic M1; C542687:mirnlet7 microRNA, mouse; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D008094:Lithium; D000661:Amphetamine; D048052:Mitogen-Activated Protein Kinase 3