Altered neurotransmitter receptor expression in transgenic mouse models ofHuntington's disease

Alterations in neurotransmitter receptors are a pathological hallmark of th e neurodegeneration seen in Huntington's disease (HD). However, the signifi cance of these alterations has been uncertain, possibly reflecting simply t he loss of brain cells. It is not known for certain whether the alteration of neurotransmitter receptors occurs before the onset of symptoms in human HD. Recently we developed transgenic mice that contain a portion of a human HD gene and develop a progressive abnormal neurological phenotype. Neurotr ansmitter receptors that are altered in HD (receptors for glutamate, dopami ne, acetylcholine and adenosine) are decreased in the brain of transgenic m ice, in some cases before the onset of behavioural or motor symptoms. In tr ansgenic mice, neurotransmitter receptor alterations occur before neuronal death. Further, receptor alterations are selective in that certain receptor s, namely N-methyl-D-aspartate and gamma-aminobutyric acid receptors! are u naltered. Finally, receptor decreases are preceded by selective decreases i n the corresponding mRNA species, suggesting the altered transcription of s pecific genes. These results suggest that (i) receptor decreases precede, a nd therefore might contribute to the development of clinical symptoms, and (ii) altered transcription of specific genes might be a key pathological me chanism in HD.