Analysis of cerebellar function in Ube3a -deficient mice reveals novel genotype-specific behaviors

Detlef Heck, Yu Zhao, Snigdha Roy, Mark Ledoux, Lawrence Reiter

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Angelman syndrome (AS) is a childhood-onset neurogenetic disorder characterized by functionally severe developmental delay with mental retardation, deficits in expressive language, ataxia, appendicular action tremors and unique behaviors such as inappropriate laughter and stimulus-sensitive hyperexcitibility. Most cases of AS are caused by mutations which disrupt expression of maternal UBE3A. Although some progress has been made in understanding hippocampal-related memory and learning aspects of the disorder using Ube3a deficient mice, the numerous motoric abnormalities associated with AS (ataxia, action tremor, dysarthria, dysphagia, sialorrhea and excessive chewing/mouthing behaviors) have not been fully explored with mouse models. Here we use a novel quantifiable analysis of fluid consumption and licking behavior along with a battery of motor tests to examine cerebellar and other motor system defects in Ube3a deficient mice. Mice with a maternally inherited Ube3a deficiency (Ube3am-/p+) show defects in fluid consumption behavior which are different from Ube3am-/p+ mice. The rhythm of fluid licking and number of licks per visit were significantly different among the three groups (m-/p-, m-/p+, m+/p+) and indicate that not only was fluid consumption dependent on Ube3a expression in the cerebellum, but may also depend on low levels of Ube3a expression in other brain regions. Additional neurological testing revealed defects in both Ube3am-/p+ and Ube3am-/p- mice in rope climbing, grip strength, gait and a raised-beam task. Long-term observation of fluid consumption behavior is the first phenotype reported that differentiates between mice with a maternal loss of function versus complete loss of Ube3a in the brain. The neuronal and molecular mechanisms underlying mouse fluid consumption defects specifically associated with maternally inherited Ube3a deficiency may reveal important new insights into the pathobiology of AS in humans.

Original languageEnglish (US)
Pages (from-to)2181-2189
Number of pages9
JournalHuman molecular genetics
Volume17
Issue number14
DOIs
StatePublished - Jul 1 2008

Fingerprint

Genotype
Angelman Syndrome
Tremor
Ataxia
Mothers
Laughter
Sialorrhea
Dysarthria
Learning Disorders
Mastication
Brain
Hand Strength
Deglutition Disorders
Gait
Intellectual Disability
Cerebellum
Language
Observation
Phenotype
Mutation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Analysis of cerebellar function in Ube3a -deficient mice reveals novel genotype-specific behaviors. / Heck, Detlef; Zhao, Yu; Roy, Snigdha; Ledoux, Mark; Reiter, Lawrence.

In: Human molecular genetics, Vol. 17, No. 14, 01.07.2008, p. 2181-2189.

Research output: Contribution to journalArticle

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