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dc.contributor.supervisor Anderson, Judith (Biological Sciences) Jakobson, Lorna (Psychology) en_US
dc.contributor.author Snow, Wanda Mae
dc.date.accessioned 2012-11-13T17:29:14Z
dc.date.available 2012-11-13T17:29:14Z
dc.date.issued 2012-11-13
dc.identifier.uri http://hdl.handle.net/1993/11296
dc.description.abstract This series of experiments investigated dystrophin localization in the normal cerebellum and examined Purkinje neuron function in normal and dystrophin-deficient mice to better understand the physiological basis for cognitive deficits associated with Duchenne muscular dystrophy (DMD), a common genetic disorder among children. Cognitive impairments are consistently reported in DMD, yet precise mechanisms for their occurrence are unknown. Dystrophin protein, which is absent in DMD, is normally localized to muscles and specific neurons in the brain. Purkinje neurons are rich in dystrophin, specifically in somatic and dendritic membranes. Studies demonstrate perturbed cerebellar function in the absence of dystrophin, suggesting that DMD should be regarded as a cerebellar disorder in addition to being considered a neuromuscular disorder. However, theory and evidence are not generated from overlapping information: research investigating cerebellar involvement in DMD has focused on the vermal region, associated with motor function. The lateral region, implicated in cognition, has not been explicitly examined in DMD. The first experiment revisited the issue of dystrophin distribution in the mouse cerebellum using immunohistochemistry to investigate qualitative and quantitative differences between cerebellar regions. Both regions showed dystrophin localized to Purkinje neuron somatic and dendritic membranes, but dystrophin density was 30% greater in the lateral than the vermal region. The second experiment examined intrinsic electrophysiological properties of vermal and lateral Purkinje neurons from wild-type (WT) mice and from the mdx mouse model of DMD which lack dystrophin. Significant differences in action potential firing frequency, regularity, and shape were found between cerebellar regions. Purkinje neurons from mdx mouse cerebellum exhibited membrane hyperpolarization and irregular action potential firing, regardless of region. Spontaneous action potential firing frequency was reduced in Purkinje neurons from lateral cerebellum in mdx mice relative to controls, demonstrating that a loss of dystrophin causes a potent dysregulation of Purkinje neuron function in the region associated with cognition. This research extends our understanding of cerebellar pathology in DMD and its potential relevance to cognitive deficits in the disorder. Moreover, this research further supports the role of the cerebellum as a structure important for cognition and contributes to our understanding of dystrophin’s role in the brain. en_US
dc.subject mdx mice en_US
dc.subject Purkinje neurons en_US
dc.subject dystrophin en_US
dc.subject quantification en_US
dc.subject dendrites en_US
dc.subject morphometry en_US
dc.subject immunohistochemistry en_US
dc.subject somata en_US
dc.subject whole cell en_US
dc.subject patch clamp en_US
dc.title Cerebellar pathophysiology in a mouse model of Duchenne muscular dystrophy en_US
dc.degree.discipline Psychology en_US
dc.contributor.examiningcommittee Mondor, Todd (Psychology) Fry, Mark (Psychology) Hare, James (Biological Sciences) Turner, Ray (University of Calgary) en_US
dc.degree.level Doctor of Philosophy (Ph.D.) en_US
dc.description.note February 2013 en_US


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