Cellular localization of huntingtin in striatal and cortical neurons in rats: Lack of correlation with neuronal vulnerability in Huntington's disease

Immunohistochemistry and single-cell RT-PCR were used to characterize the l ocalization of huntingtin and/or its mRNA in the major types of striatal ne urons and in corticostriatal projection neurons in rats. Single-label immun ohistochemical studies revealed that striatum contains scattered large neur ons rich in huntingtin and more numerous medium-sized neurons moderate in h untingtin. Double-label immunohistochemical studies showed that the large h untingtin-rich striatal neurons include nearly all cholinergic interneurons and some parvalbuminergic interneurons. Somatostatinergic striatal interne urons, which are medium in size, rarely contained huntingtin. Calbindin imm unolabeling showed that the vast majority of the medium-sized striatal neur ons that contain huntingtin are projection neurons, but only similar to 65% of calbindin-labeled projection neurons (localized to the matrix compartme nt of striatum) were labeled for huntingtin. Calbindin-containing projectio n neurons of the matrix compartment and calbindin-negative projection neuro ns of the striatal patch compartment contained huntingtin with comparable f requency. Single-cell RT-PCR confirmed that striatal cholinergic interneuro ns contain huntingtin, but only similar to 65% of projection neurons contai ned detectable huntingtin message. The finding that huntingtin is not consi stently found in striatal projection neurons [which die in Huntington's dis ease (HD)] but is abundant in striatal cholinergic interneurons (which surv ive in Huntington's disease) suggests that the mutation in huntingtin that causes HD may not directly kill neurons. In contrast to the heterogeneous e xpression of huntingtin in the different striatal neuron types, we found al l corticostriatal neurons to be rich in huntingtin protein and mRNA. One po ssibility raised by our findings is that the HD mutation may render cortico striatal neurons destructive rather than render striatal neurons vulnerable .