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 subcell ular alterations in the striatum and cortex. The link between these neurona l changes and behavioral abnormalities is unclear. We investigated relation ships between essential neuronal changes that predict motor impairment and possible involvement of the corticostriatal pathway in developing behaviora l phenotypes. We therefore generated heterozygote mice expressing the N-ter minal one-third of huntingtin with normal (CT18) or expanded (HD46, HD100) glutamine repeats. The HD mice exhibited motor deficits between 3 and 10 mo nths. The age of onset depended on an expanded polyglutamine length; phenot ype severity correlated with increasing age. Neuronal changes in the striat um (nuclear inclusions) preceded the onset of phenotype, whereas cortical c hanges, especially the accumulation of huntingtin in the nucleus and cytopl asm and the appearance of dysmorphic dendrites, predicted the onset and sev erity of behavioral deficits. Striatal neurons in the HD mice displayed alt ered responses to cortical stimulation and to activation by the excitotoxic agent NMDA. Application of NMDA increased intracellular Ca2+ levels in HD1 00 neurons compared with wild-type neurons. Results suggest that motor defi cits in Huntington's disease arise from cumulative morphological and physio logical changes in neurons that impair corticostriatal circuitry.