Alterations in dopamine and benzodiazepine receptor binding precede overt neuronal pathology in mice modelling early Huntington disease pathogenesis.
Huntington disease (HD) is an inherited, late onset, progressive neurodegenerative disorder. Primary degeneration appears to selectively occur in striatal medium spiny neurones but this is most likely preceded by a period of neuronal dysfunction. Altered levels of neurotransmitter receptors may disrupt neuronal function and contribute to a toxic environment within the brain. In the present study, a knock-in HD mouse modelling early stages of the disease was used to determine whether alterations in neurotransmitter receptor densities occurred before overt neuronal loss. Receptor autoradiography demonstrated reduced dopamine D2 and increased benzodiazepine receptor binding in the striatum of HD animals compared to wild-type littermates. The density of benzodiazepine receptor binding was also increased in the cerebral cortex of the HD mice. Changes in opioid and dopamine D1 receptor densities were more subtle and influenced by the genetic background of the mice. Our findings are consistent with the hypothesis that alterations in neurotransmitter receptor density precede cell loss and may be an active cellular response to the initial stages of HD pathogenesis.
Kennedy
Laura
L
Division of Molecular Genetics, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow, G11 6NU, UK.
Shelbourne
Peggy F
PF
Dewar
Deborah
D
D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009474:Neurons / Q000473:pathology*; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D011957:Receptors, Opioid / Q000378:metabolism
D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; D011957:Receptors, Opioid