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The Journal of Neuroscience, December 1, 2001, 21(23):9112-9123
Changes in Cortical and Striatal Neurons Predict Behavioral and Electrophysiological Abnormalities in a Transgenic Murine Model of Huntington's Disease
Genevieve A. Laforet1, Ellen Sapp3, Kathryn Chase2, Charmian McIntyre3, Frederick M. Boyce3, Mary Campbell2, Beth A. Cadigan2, Lori Warzecki2, Danilo A. Tagle4, P. Hemachandra Reddy4, Carlos Cepeda5, Christopher R. Calvert5, Eve S. Jokel5, Gloria J. Klapstein5, Marjorie A. Ariano6, Michael S. Levine5, Marian DiFiglia3, and Neil Aronin2 Departments of 1 Psychiatry and 2 Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655, 3 Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, 4 Genetics and Molecular Biology Branch, National Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, 5 Mental Retardation Research Center, University of California at Los Angeles, Los Angeles, California 90095, and 6 Department of Neuroscience, Chicago Medical School, North Chicago, Illinois 60064
Neurons in Huntington's disease exhibit selective morphological and subcellular alterations in the striatum and cortex. The link between these neuronal changes and behavioral abnormalities is unclear. We investigated relationships between essential neuronal changes that predict motor impairment and possible involvement of the corticostriatal pathway in developing behavioral phenotypes. We therefore generated heterozygote mice expressing the N-terminal one-third of huntingtin with normal (CT18) or expanded (HD46, HD100) glutamine repeats. The HD mice exhibited motor deficits between 3 and 10 months. The age of onset depended on an expanded polyglutamine length; phenotype severity correlated with increasing age. Neuronal changes in the striatum (nuclear inclusions) preceded the onset of phenotype, whereas cortical changes, especially the accumulation of huntingtin in the nucleus and cytoplasm and the appearance of dysmorphic dendrites, predicted the onset and severity of behavioral deficits. Striatal neurons in the HD mice displayed altered responses to cortical stimulation and to activation by the excitotoxic agent NMDA. Application of NMDA increased intracellular Ca2+ levels in HD100 neurons compared with wild-type neurons. Results suggest that motor deficits in Huntington's disease arise from cumulative morphological and physiological changes in neurons that impair corticostriatal circuitry.
Key words: cortex; Huntington's disease; NMDA; neuronal morphology; striatum; transgenic mice
Copyright © 2001 Society for Neuroscience 0270-6474/01/21239112-12$05.00/0
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