title: Seizure-like activity in a juvenile Angelman syndrome mouse model is attenuated by reducing Arc expression.
abstract: Angelman syndrome (AS) is a neurodevelopmental disorder arising from loss-of-function mutations in the maternally inherited copy of the UBE3A gene, and is characterized by an absence of speech, excessive laughter, cognitive delay, motor deficits, and seizures. Despite the fact that the symptoms of AS occur in early childhood, behavioral characterization of AS mouse models has focused primarily on adult phenotypes. In this report we describe juvenile behaviors in AS mice that are strain-independent and clinically relevant. We find that young AS mice, compared with their wild-type littermates, produce an increased number of ultrasonic vocalizations. In addition, young AS mice have defects in motor coordination, as well as abnormal brain activity that results in an enhanced seizure-like response to an audiogenic challenge. The enhanced seizure-like activity, but not the increased ultrasonic vocalizations or motor deficits, is rescued in juvenile AS mice by genetically reducing the expression level of the activity-regulated cytoskeleton-associated protein, Arc. These findings suggest that therapeutic interventions that reduce the level of Arc expression have the potential to reverse the seizures associated with AS. In addition, the identification of aberrant behaviors in young AS mice may provide clues regarding the neural circuit defects that occur in AS and ultimately allow new approaches for treating this disorder.
authors.affiliation: Department of Neurobiology, and.
authors.forename: Caleigh
authors.initials: C
authors.lastname: Mandel-Brehm
authors.affiliation: Department of Neurobiology, and.
authors.forename: John
authors.initials: J
authors.lastname: Salogiannis
authors.affiliation: Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Sameer C
authors.initials: SC
authors.lastname: Dhamne
authors.affiliation: Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rotenberg
authors.affiliation: Department of Neurobiology, and meg@hms.harvard.edu.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Greenberg
mesh_terms: D000161:Acoustic Stimulation; D000200:Action Potentials; D000375:Aging / Q000473:pathology*; D000483:Alleles; D017204:Angelman Syndrome / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004569:Electroencephalography; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006579:Heterozygote; D040582:Inheritance Patterns / Q000235:genetics; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D014465:Ultrasonics; D014828:Vocalization, Animal
chemical_list: D003598:Cytoskeletal Proteins; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C092069:activity regulated cytoskeletal-associated protein; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: ARC; Angelman syndrome; EEG; EPHEXIN5; ultrasonic vocalizations
references.citation: Neurobiol Dis. 2012 Aug;47(2):210-5
references.pmid: 22525571
references.citation: Hum Mol Genet. 2008 Jul 15;17(14):2181-9
references.pmid: 18413322
references.citation: Neural Plast. 2012;2012:710943
references.pmid: 22830052
references.citation: Trends Neurosci. 2011 Jun;34(6):293-303
references.pmid: 21592595
references.citation: J Hered. 1967 May-Jun;58(3):135-40
references.pmid: 6055327
references.citation: Neurobiol Dis. 2005 Nov;20(2):471-8
references.pmid: 15921919
references.citation: Sci Transl Med. 2012 Dec 5;4(163):163ra157
references.pmid: 23220633
references.citation: Behav Brain Res. 2013 Apr 15;243:79-90
references.pmid: 23295389
references.citation: J Neurosci. 2011 Nov 30;31(48):17637-48
references.pmid: 22131424
references.citation: Seizure. 2008 Apr;17(3):211-7
references.pmid: 17904873
references.citation: J Med Genet. 2003 Feb;40(2):87-95
references.pmid: 12566516
references.citation: Brain Dev. 2013 Mar;35(3):245-51
references.pmid: 22704603
references.citation: Behav Genet. 1998 Jul;28(4):315-25
references.pmid: 9803024
references.citation: Neurosci Biobehav Rev. 2013 Sep;37(8):1893-916
references.pmid: 23518269
references.citation: Methods Mol Biol. 2011;768:343-63
references.pmid: 21805253
references.citation: Neuron. 1998 Oct;21(4):799-811
references.pmid: 9808466
references.citation: Neurobiol Dis. 2002 Mar;9(2):149-59
references.pmid: 11895368
references.citation: Nature. 2011 Dec 21;481(7380):185-9
references.pmid: 22190039
references.citation: PLoS One. 2010 Aug 20;5(8):e12278
references.pmid: 20808828
references.citation: EMBO J. 1991 Dec;10(13):4129-35
references.pmid: 1661671
references.citation: Nature. 1989 Nov 16;342(6247):281-5
references.pmid: 2812027
references.citation: Nat Genet. 1997 Jan;15(1):70-3
references.pmid: 8988171
references.citation: Pediatr Neurol. 2013 Apr;48(4):271-9
references.pmid: 23498559
references.citation: Epilepsy Behav. 2012 Mar;23(3):261-5
references.pmid: 22341959
references.citation: Nat Neurosci. 2009 Jun;12(6):777-83
references.pmid: 19430469
references.citation: Proc Natl Acad Sci U S A. 2013 May 28;110(22):8888-93
references.pmid: 23671107
references.citation: J Clin Invest. 2012 Dec;122(12):4544-54
references.pmid: 23143301
references.citation: Dev Psychobiol. 1980 Nov;13(6):573-84
references.pmid: 7429018
references.citation: Cell. 2010 Oct 29;143(3):442-55
references.pmid: 21029865
references.citation: PLoS Genet. 2013;9(12):e1004039
references.pmid: 24385930
references.citation: Science. 1999 Jun 4;284(5420):1670-2
references.pmid: 10356397
references.citation: Nat Neurosci. 2011 Mar;14(3):279-84
references.pmid: 21278731
references.citation: Neurosci Biobehav Rev. 2009 Apr;33(4):508-15
references.pmid: 18771687
references.citation: Curr Biol. 2013 May 6;23(9):739-45
references.pmid: 23602481
references.citation: Hum Mol Genet. 2008 Jan 1;17(1):111-8
references.pmid: 17940072
references.citation: Behav Genet. 2005 Jan;35(1):31-52
references.pmid: 15674531
references.citation: Nat Neurosci. 2007 Mar;10(3):280-2
references.pmid: 17259980
references.citation: Dev Med Child Neurol. 2008 Aug;50(8):564
references.pmid: 18754889
references.citation: PLoS Biol. 2013;11(2):e1001478
references.pmid: 23424281
references.citation: Am J Med Genet A. 2011 Jan;155A(1):81-90
references.pmid: 21204213
references.citation: Cell. 2010 Mar 5;140(5):704-16
references.pmid: 20211139
references.citation: PLoS One. 2011;6(12):e27221
references.pmid: 22174738