title: Muscleblind1, but not Dmpk or Six5, contributes to a complex phenotype of muscular and motivational deficits in mouse models of myotonic dystrophy.
abstract: Assessment of molecular defects that underlie cognitive deficits observed in mendelian disorders provides a unique opportunity to identify key regulators of human cognition. Congenital Myotonic Dystrophy 1 (cDM1), a multi-system disorder is characterized by both cognitive deficits and a spectrum of behavioral abnormalities, which include visuo-spatial memory deficits, anxiety and apathy. Decreased levels of DMPK (Dystrophia Myotonica-protein kinase), SIX5, a transcription factor or MBNL1 (Muscleblind-like 1), an RNA splice regulator have been demonstrated to contribute to distinct features of cDM1. Mouse strains in which either Dmpk, Six5 or Mbnl1 are inactivated were therefore studied to determine the relative contribution of each gene to these cognitive functions. The open field and elevated plus maze tasks were used to examine anxiety, sucrose consumption was used to assess motivation, whereas the water maze and context fear conditioning were used to examine spatial learning and memory. Cognitive and behavioral abnormalities were observed only in Mbnl1 deficient mice, which demonstrate behavior consistent with motivational deficits in the Morris water maze, a complex visuo-spatial task and in the sucrose consumption test for anhedonia. All three models of cDM1 exhibit normal spatial learning and memory. These data identify MBNL1 as a potential regulator of emotional state with decreased MBNL1 levels underlying the motivational deficits observed in cDM1.
authors.affiliation: Departments of Neurobiology, Psychiatry & Biobehavioral Sciences, Psychology and the Brain Research Institute, Gonda Neuroscience and Genetics Center, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Anna
authors.initials: A
authors.lastname: Matynia
authors.forename: Carina Hoi
authors.initials: CH
authors.lastname: Ng
authors.forename: Warunee
authors.initials: W
authors.lastname: Dansithong
authors.forename: Andy
authors.initials: A
authors.lastname: Chiang
authors.forename: Alcino J
authors.initials: AJ
authors.lastname: Silva
authors.forename: Sita
authors.initials: S
authors.lastname: Reddy
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D003071:Cognition; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005239:Fear; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D009042:Motivation; D009132:Muscles / Q000473:pathology; D009154:Mutation; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000473:pathology; D065636:Myotonin-Protein Kinase; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D013037:Spatial Behavior
chemical_list: C585517:DMPK protein, human; C585516:DMPK protein, mouse; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C479922:Mbnl1 protein, mouse; D016601:RNA-Binding Proteins; C486344:Six5 protein, mouse; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases