Regional and subtype selective changes of neurotransmitter receptor density in a rat transgenic for the Huntington's disease mutation.
Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disorder caused by a CAG/polyglutamine repeat expansion in the gene encoding the huntingtin protein. We have recently generated a rat model transgenic for HD, which displays a slowly progressive phenotype resembling the human adult-onset type of disease. In this study we systematically assessed the distribution and density of 17 transmitter receptors in the brains of 2-year-old rats using quantitative multi-tracer autoradiography and high-resolution positron emission tomography. Heterozygous animals expressed increased densities of M(2) acetylcholine (increase of 148 +/- 16% of controls; p > 0.001; n = 7), nicotine (increase of 149 +/- 16% of controls; p > 0.01; n = 6), and alpha(2) noradrenergic receptors (increase of 141 +/- 15% of controls; p > 0.001; n = 6), respectively. Densities of these receptors were decreased in homozygous animals. Decreases of receptor density in both hetero- and homozygous animals were found for M1 acetylcholine, 5-HT 2A serotonin, A 2A adenosine, D1 and D2 dopamine, and GABA(A) receptors, respectively. Other investigated receptor systems showed small changes or were not affected. The present data suggest that the moderate increase of CAG/polyglutamine repeat expansions in the present rat model of Huntington's disease is characterized by subtype-selective and region-specific changes of neuroreceptor densities. In particular, there is evidence for a contribution of predominantly presynaptically localized cholinergic and noradrenergic receptors in the response to Huntington's disease pathology.
Bauer
Andreas
A
Institute of Medicine, Research Center Jülich, Jülich, Germany. an.bauer@fz-juelich.de
Zilles
Karl
K
Matusch
Andreas
A
Holzmann
Carsten
C
Riess
Olaf
O
von Hörsten
Stephan
S
D000818:Animals; D030801:Animals, Genetically Modified; D001345:Autoradiography / Q000379:methods; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000378:metabolism*; D001931:Brain Mapping; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000235:genetics*; D007091:Image Processing, Computer-Assisted / Q000379:methods; D009154:Mutation; D049268:Positron-Emission Tomography / Q000379:methods; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000145:classification / Q000378:metabolism*; D013997:Time Factors; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
D017981:Receptors, Neurotransmitter