ALTERED BRAIN NEUROTRANSMITTER RECEPTORS IN TRANSGENIC MICE EXPRESSING A PORTION OF AN ABNORMAL HUMAN HUNTINGTON-DISEASE GENE

Loss of neurotransmitter receptors, especially glutamate and dopamine receptors, is one of the pathologic hallmarks of brains of patients wi th Huntington disease (HD). Transgenic mice that express exon 1 of an abnormal human HD gene (line R6/2) develop neurologic symptoms at 9-11 weeks of age through an unknown mechanism. Analysis of glutamate rece ptors (GluRs) in symptomatic 12-week-old R6/2 mice revealed decreases compared with age-matched littermate controls in the type 1 metabotrop ic GluR (mGluR1), mGluR2, mGluR3, but not the mGluR5 subtype of G prot ein-linked mGluR, as determined by [H-3]glutamate receptor binding, pr otein immunoblotting, and in situ hybridization. Ionotropic lpha-amino -3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors we re also decreased, while N-methyl-D-aspartic acid receptors were not d ifferent compared with controls. Other neurotransmitter receptors know n to be affected in HD were also decreased in R6/2 mice, including dop amine and muscarinic cholinergic, but not gamma-aminobutyric acid rece ptors. D-1-like and D-2-like dopamine receptor binding was drastically reduced to one-third of control in the brains of 8- and 12-week-old R 6/2 mice. In situ hybridization indicated that mGluR and D-1 dopamine receptor mRNA were altered as early as 4 weeks of age, long prior to t he onset of clinical symptoms. Thus, altered expression of neurotransm itter receptors precedes clinical symptoms in R6/2 mice and may contri bute to subsequent pathology.