Do cognitive problems start before motor dysfunction in animal models for Huntington Disease
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Other Titles: | Gehen kognitive Defizite motorischen Dysfunktionen in Tiermodellen für Chorea Huntington voraus. | Authors: | Abada, Komla Yah-se ![]() |
Supervisor: | Koch, Michael ![]() |
1. Expert: | Koch, Michael ![]() |
Experts: | Ellenbroek, Bart | Abstract: | Huntington s disease (HD) is a devastating neurodegenerative disorder caused by a genetic mutation that produces an expansion of C-A-G repeats in the huntingtin (HTT) gene. This expansion results in a selective neuronal degeneration in striatal and cortical brain regions. Although HD is best known for chorea, the disease is actually a triad of progressive cognitive, psychiatric and motor symptoms and patients usually die within 15 to 20 years of onset. Cognitive impairments seem to occur decades prior to the onset of motor symptoms. This potentially offers a long time window for treatments to delay or halt disease progression. Development of such treatments requires the generation of transgenic animal models for HD. Such models are now available and have already greatly enhanced our understanding of the pathogenesis of HD. But unsolved questions such as: "Do cognitive manifestations precede motor deficits in transgenic mouse and rat models for HD?" µremain. We address this question in 3 studies that examine the development of motor, cognitive and psychiatric symptoms in BACHD mice and rats, two recently generated models for HD. Unlike other genetic models, BACHD mice and rats express the full length of the human mutant HTT (97 polyglutamine repeats) and present neuropathology similarities to that of patients. We found progressive motor, cognitive and psychiatric deficits in transgenics BACHD mice and rats compared to their wild type littermate controls, on different tasks such as catwalk, rotarod, open field, zero-maze, cross-maze, prepulse inhibition and fear conditioning. The findings indicate that progressive cognitive deficits can be reliably detected with methodologically rigorous protocols. However some phenotypic variability (body weight and emotional-like behavior, for example) was found and might involve species differences and ectopic expression of the human mutant HTT gene. Finally, the time course for the emergence of the various symptoms indicates that motor abnormalities might be the first to occur in transgenic BACHD mice and rats. In conclusion: we have identified robust cognitive and motor phenotypes for BACHD mice and rats that can be used to test novel compounds from HD drug discovery programs. Certain tests like fear conditioning, lend themselves for translational approaches and characterization of HD patients in such tests would be a logical next step. Confirmation of a fear conditioning phenotype in HD patients would offer an additional functional read-out for drug testing and decrease program risk by bridging the gap between rodent and human testing. |
Keywords: | Anxiety; Fear conditioning; Gait analysis; Memory; Motor deficits; Huntington Disease; Object recognition; Prepulse inhibition; Spatial learning; Strategy shifting; Transgenic mice and rats. | Issue Date: | 14-Nov-2013 | Type: | Dissertation | Secondary publication: | no | URN: | urn:nbn:de:gbv:46-00103750-11 | Institution: | Universität Bremen | Faculty: | Fachbereich 02: Biologie/Chemie (FB 02) |
Appears in Collections: | Dissertationen |
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