Analysis of Cerebellar Function in Ube3a-deficient Mice Reveals Novel Genotype-specific Behaviors

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2008 Apr 17

PMID 18413322

Citations 71

Authors

Detlef H Heck

Yu Zhao

Snigdha Roy

Mark S Ledoux

Lawrence T Reiter

Affiliations

Soon will be listed here.

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 (Ube3a(m-/p+)) show defects in fluid consumption behavior which are different from Ube3a(m-/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 Ube3a(m-/p+) and Ube3a(m-/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.

Citing Articles

UBE3A: The Role in Autism Spectrum Disorders (ASDs) and a Potential Candidate for Biomarker Studies and Designing Therapeutic Strategies.

Roy B, Amemasor E, Hussain S, Castro K Diseases. 2024; 12(1).

PMID: 38248358 PMC: 10814747. DOI: 10.3390/diseases12010007.

Cerebellar contribution to autism-relevant behaviors in fragile X syndrome models.

Gibson J, Vazquez A, Yamashiro K, Jakkamsetti V, Ren C, Lei K Cell Rep. 2023; 42(12):113533.

PMID: 38048226 PMC: 10831814. DOI: 10.1016/j.celrep.2023.113533.

Altered motor learning and coordination in mouse models of autism spectrum disorder.

Cording K, Bateup H Front Cell Neurosci. 2023; 17:1270489.

PMID: 38026686 PMC: 10663323. DOI: 10.3389/fncel.2023.1270489.

Contextual fear memory impairment in Angelman syndrome model mice is associated with altered transcriptional responses.

Su W, Liu Y, Lam A, Hao X, Baudry M, Bi X Sci Rep. 2023; 13(1):18647.

PMID: 37903805 PMC: 10616231. DOI: 10.1038/s41598-023-45769-x.

Linoleic acid improves PIEZO2 dysfunction in a mouse model of Angelman Syndrome.

Romero L, Caires R, Victor A, Ramirez J, Sierra-Valdez F, Walsh P Nat Commun. 2023; 14(1):1167.

PMID: 36859399 PMC: 9977963. DOI: 10.1038/s41467-023-36818-0.

References

Hayar A, Bryant J, Boughter J, Heck D . A low-cost solution to measure mouse licking in an electrophysiological setup with a standard analog-to-digital converter. J Neurosci Methods. 2005; 153(2):203-7. PMC: 2366209. DOI: 10.1016/j.jneumeth.2005.10.023. View

Crawley J . Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. Brain Res. 1999; 835(1):18-26. DOI: 10.1016/s0006-8993(98)01258-x. View

Dan B, Cheron G . Postural rhythmic muscle bursting activity in Angelman syndrome. Brain Dev. 2004; 26(6):389-93. DOI: 10.1016/j.braindev.2003.12.002. View

Haines D, Dietrichs E, Mihailoff G, McDonald E . The cerebellar-hypothalamic axis: basic circuits and clinical observations. Int Rev Neurobiol. 1997; 41:83-107. DOI: 10.1016/s0074-7742(08)60348-7. View

Horowitz G, Stephan F, Smith J, Whitney G . Genetic and environmental variability in lick rates of mice. Physiol Behav. 1977; 19(4):493-6. DOI: 10.1016/0031-9384(77)90224-4. View

Schmahmann J, Sherman J . Cerebellar cognitive affective syndrome. Int Rev Neurobiol. 1997; 41:433-40. DOI: 10.1016/s0074-7742(08)60363-3. View

Egan G, Silk T, Zamarripa F, Williams J, Federico P, Cunnington R . Neural correlates of the emergence of consciousness of thirst. Proc Natl Acad Sci U S A. 2003; 100(25):15241-6. PMC: 299974. DOI: 10.1073/pnas.2136650100. View

Albrecht U, Sutcliffe J, Cattanach B, Beechey C, Armstrong D, Eichele G . Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nat Genet. 1997; 17(1):75-8. DOI: 10.1038/ng0997-75. View

Moy S, Nadler J . Advances in behavioral genetics: mouse models of autism. Mol Psychiatry. 2007; 13(1):4-26. DOI: 10.1038/sj.mp.4002082. View

10.

Dindot S, Antalffy B, Bhattacharjee M, Beaudet A . The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology. Hum Mol Genet. 2007; 17(1):111-8. DOI: 10.1093/hmg/ddm288. View

11.

Suzuki M, Asada Y, Ito J, Hayashi K, Inoue H, Kitano H . Activation of cerebellum and basal ganglia on volitional swallowing detected by functional magnetic resonance imaging. Dysphagia. 2003; 18(2):71-7. DOI: 10.1007/s00455-002-0088-x. View

12.

Uchida K, Yamada Y, Sato T . The coordination of rhythmical drinking behavior with swallowing in rabbits. Physiol Behav. 1994; 55(5):795-801. DOI: 10.1016/0031-9384(94)90062-0. View

13.

Weijnen J, Wouters J, van Hest J . Interaction between licking and swallowing in the drinking rat. Brain Behav Evol. 1984; 25(2-3):117-27. DOI: 10.1159/000118857. View

14.

Jiang Y, Armstrong D, Albrecht U, Atkins C, Noebels J, Eichele G . Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron. 1998; 21(4):799-811. DOI: 10.1016/s0896-6273(00)80596-6. View

15.

Miura K, Kishino T, Li E, Webber H, Dikkes P, Holmes G . Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice. Neurobiol Dis. 2002; 9(2):149-59. DOI: 10.1006/nbdi.2001.0463. View

16.

Zhu J, Li H, Ding Y, Wang J . Cerebellar modulation of feeding-related neurons in rat dorsomedial hypothalamic nucleus. J Neurosci Res. 2006; 84(7):1597-609. DOI: 10.1002/jnr.21059. View

17.

Matsuura T, Sutcliffe J, Fang P, Galjaard R, Jiang Y, Benton C . De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat Genet. 1997; 15(1):74-7. DOI: 10.1038/ng0197-74. View

18.

Reiter L, Seagroves T, Bowers M, Bier E . Expression of the Rho-GEF Pbl/ECT2 is regulated by the UBE3A E3 ubiquitin ligase. Hum Mol Genet. 2006; 15(18):2825-35. PMC: 3742451. DOI: 10.1093/hmg/ddl225. View

19.

Rougeulle C, Glatt H, Lalande M . The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nat Genet. 1997; 17(1):14-5. DOI: 10.1038/ng0997-14. View

20.

Cheron G, Servais L, Wagstaff J, Dan B . Fast cerebellar oscillation associated with ataxia in a mouse model of Angelman syndrome. Neuroscience. 2004; 130(3):631-7. DOI: 10.1016/j.neuroscience.2004.09.013. View