Brain neurotransmitter deficits in mice transgenic for the Huntington's disease mutation

Huntington's disease (HD) is associated with an expansion in the CAG repeat sequence of a gene on chromosome 4, resulting in a neurodegenerative proce ss particularly affecting the striatum and with profound but selective chan ges in content of various neurotransmitters. Recently, transgenic mice expr essing a fragment of the human HD gene containing a large CAG expansion hav e been generated; these mice exhibit a progressive neurological phenotype t hat includes motor disturbances, as well as neuronal deficits. To investiga te their underlying neurotransmitter pathology, we have determined concentr ations of GABA, glutamate, and the monoamine neurotransmitters in several b rain regions in these mice and control animals at times before and after th e emergence of the behavioural phenotype. in contrast to the findings in HD , striatal GABA was unaffected, although a deficit was observed in the cere bellum, consistent with a dysfunction of Purkinje cells. Losses of the mono amine transmitters were observed, some of which are not seen in HD. Thus, 5 -hydroxytryptamine and, to a greater extent, 5-hydroxyindoleacetic acid lev els were diminished in all brain regions studied, and noradrenaline was par ticularly affected in the hippocampus. Dopamine was decreased in the striat um in older animals, parallelling evidence for diminished dopaminergic acti vity in HD.