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Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington's disease.

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 Ca(2+) 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.

Pubmed ID: 11717344 RIS Download

Mesh terms: Age of Onset | Animals | Behavior, Animal | Calcium | Cell Nucleus | Cerebral Cortex | Corpus Callosum | Corpus Striatum | Dendrites | Disease Models, Animal | Disease Progression | Electrophysiology | Excitatory Amino Acid Agonists | Heterozygote | Huntington Disease | In Vitro Techniques | Mice | Mice, Transgenic | Nerve Tissue Proteins | Neurons | Nuclear Proteins | Phenotype | Receptors, N-Methyl-D-Aspartate | Trinucleotide Repeat Expansion

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Associated grants

  • Agency: NIDDK NIH HHS, Id: DK32520
  • Agency: NINDS NIH HHS, Id: NS 16367
  • Agency: NINDS NIH HHS, Id: NS 35711
  • Agency: NINDS NIH HHS, Id: NS 38194

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