Decrease in striatal enkephalin mRNA in mouse models of Huntington's disease

Huntington's disease is a devastating progressive neurodegenerative illness characterized by massive neuronal loss in the striatum, It is caused by th e presence of an expanded CAG repeat in the gene encoding huntingtin, a pro tein of unknown function. We have examined the expression of neurotransmitt ers and other antigens present in striatal neurons with immunohistochemistr y, and the level of expression of mRNAs encoding enkephalin, substance P, a nd glutamic acid decarboxylases with quantitative in situ hybridization his tochemistry, in the striatum of two mouse models of Huntington's disease: t ransgenic animals expressing exon 1 of the human huntingtin gene with 144 C AG repeats and " knock-in" mice containing a chimeric mouse/human exon 1 wi th 71 or 94 GAG; repeats inserted by homologous targeting. Although the tra nsgenic (but not the knock-in) mice were previously shown to display promin ent huntingtin- and ubiquitin-containing nuclear inclusions in striatal neu rons, in situ nick translation followed by emulsion autoradiography did not reveal any DNA damage in striatum or cortex in these mice. Immunolabeling for calbindin D 289, enkephalin, substance P, glutamic acid decarboxylases (M-r 65,000 or 67,000, GAD65 and GAD67), somatostatin, choline acetyltransf erase, parvalbumin, and glial fibrillary acidic protein were remarkably sim ilar in transgenic, knock-in, and wildtype mice. Both transgenic and knock- in mice, however, showed a marked decrease in the level of expression of en kephalin mRNA in striatal neurons without significant decreases in mRNAs en coding substance P, GAD65, or GAD67, The data indicate that decreased expre ssion of enkephalin mRNA may be an early sign of neuronal dysfunction due t o the Huntington's disease mutation. (C) 2000 Academic Press.