Cellular neuropathology associated with cognitive and behavioural dysfunction in a mouse model of Williams-Beuren syndrome
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1
University of New South Wales, School of Medical Sciences, Australia
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2
Univeristy of New South Wales, School of Medical Sciences, Australia
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3
University of New South Wales, Translational Neuroscience Facility, Australia
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4
The Florey Institute of Neuroscience and Mental Health, Neural Plasticity , Australia
Williams-Beuren Syndrome (WBS) is a neurodevelopmental genetic disorder caused by the hemizygous deletion of 28 genes on chromosome 7q11.23. Genotype/phenotype correlations in patients with atypical deletions suggest that one of these genes, GTF2IRD1, discovered in our laboratory plays a major role in the neurological characteristics of WBS. Affected individuals show mental retardation and a unique cognitive and behavioural profile. We have generated targeted Gtf2ird1 knockout (KO) mice and they show a series of neurological and physical phenotypes that parallel some of the WBS features including facial dysmorphology, growth retardation, altered vocalization and anxiety responses, exploratory activity changes and motor coordination deficits. GTF2IRD1 is strongly expressed in the Purkinje neurons of the cerebellum and functional defects of these cells could explain the impaired motor coordination. As a means to understand the cellular defects that underpin the cognitive and behavioural changes in our mice, we chose to begin by examining the Purkinje neurons in detail. We have used calbindin immunofluorescence to study Purkinje neuron morphology and no major defects were identified. The Golgi silver impregnation technique was used to study Purkinje cell microanatomy in greater detail and we are in the process of quantifying the extent of dendritic branching and spine formation. We also use primary cell culture of isolated Purkinje neurons to study early neurite branching and we will test the function of KO Purkinje neurons using patch-clamp electrophysiology in live slice samples. High-resolution MRI analysis will also be employed to examine the overall anatomy, volumes and layers of the KO brains. These data, along with analysis of other Gtf2ird1-expressing cell types, will address the cellular basis of the cognitive and behavioural dysfunction in Gtf2ird1 KO mice and provide important clues regarding the role of GTF2IRD1 in WBS.
Keywords:
Ataxia,
Williams-Beuren syndrome,
mouse knockout,
Purkinje neurons,
GTF2IRD1
Conference:
XII International Conference on Cognitive Neuroscience (ICON-XII), Brisbane, Queensland, Australia, 27 Jul - 31 Jul, 2014.
Presentation Type:
Poster
Topic:
Motor Behaviour
Citation:
Chang
C,
Canales
C,
Power
J,
Hannan
A,
Hardeman
E and
Palmer
S
(2015). Cellular neuropathology associated with cognitive and behavioural dysfunction in a mouse model of Williams-Beuren syndrome.
Conference Abstract:
XII International Conference on Cognitive Neuroscience (ICON-XII).
doi: 10.3389/conf.fnhum.2015.217.00040
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Received:
19 Feb 2015;
Published Online:
24 Apr 2015.
*
Correspondence:
Ms. Cecilia Chin Roei Chang, University of New South Wales, School of Medical Sciences, Sydney, Australia, cecilia.c.chang@student.unsw.edu.au
Mr. Cesar Canales, Univeristy of New South Wales, School of Medical Sciences, Sydney, Australia, c.canalesmartinez@unsw.edu.au
Dr. John Power, University of New South Wales, Translational Neuroscience Facility, Sydney, Australia, john.power@unsw.edu.au
Prof. Anthony Hannan, The Florey Institute of Neuroscience and Mental Health, Neural Plasticity, Melbourne, Australia, anthony.hannan@florey.edu.au
Prof. Edna Hardeman, Univeristy of New South Wales, School of Medical Sciences, Sydney, Australia, e.hardeman@unsw.edu.au
Dr. Stephen Palmer, University of New South Wales, School of Medical Sciences, Sydney, Australia, s.palmer@unsw.edu.au