title: β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome.
abstract: Rett syndrome is a severe childhood onset neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein 2 (MECP2), with known disturbances in catecholamine synthesis. Here, we show that treatment with the β2-adrenergic receptor agonist clenbuterol increases survival, rescues abnormalities in respiratory function and social recognition, and improves motor coordination in young male Mecp2-null (Mecp2(-/y)) mice. Importantly, we demonstrate that short-term treatment with clenbuterol in older symptomatic female heterozygous (Mecp2(-/+)) mice rescues respiratory, cognitive, and motor coordination deficits, and induces an anxiolytic effect. In addition, we reveal abnormalities in a microRNA-mediated pathway, downstream of brain-derived neurotrophic factor that affects insulin-like growth factor 1 (IGF1) expression in Mecp2(-/y) mice, and show that treatment with clenbuterol restores the observed molecular alterations. Finally, cotreatment with clenbuterol and recombinant human IGF1 results in additional increases in survival in male null mice. Collectively, our data support a role for IGF1 and other growth factor deficits as an underlying mechanism of Rett syndrome and introduce β2-adrenergic receptor agonists as potential therapeutic agents for the treatment of the disorder.
authors: Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139; and msur@mit.edu nmellios@mit.edu.
authors: Nikolaos
authors: N
authors: Mellios
authors: Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139; and.
authors: Jonathan
authors: J
authors: Woodson
authors: Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139; and.
authors: Rodrigo I
authors: RI
authors: Garcia
authors: Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139; and.
authors: Benjamin
authors: B
authors: Crawford
authors: Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139; and.
authors: Jitendra
authors: J
authors: Sharma
authors: Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139; andCenter for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
authors: Steven D
authors: SD
authors: Sheridan
authors: Center for Human Genetic Research, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
authors: Stephen J
authors: SJ
authors: Haggarty
authors: Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139; and msur@mit.edu nmellios@mit.edu.
authors: Mriganka
authors: M
authors: Sur
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal; D002976:Clenbuterol / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D035683:MicroRNAs / Q000235:genetics; D010641:Phenotype; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects*; D015518:Rett Syndrome / Q000188:drug therapy* / Q000235:genetics
chemical_list: D000319:Adrenergic beta-Antagonists; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D035683:MicroRNAs; D018343:Receptors, Adrenergic, beta-2; D007334:Insulin-Like Growth Factor I; D002976:Clenbuterol
keywords: LIN28A; let-7f