SPARING OF THE DOPAMINERGIC-NEURONS CONTAINING CALBINDIN-D-28K AND OF THE DOPAMINERGIC MESOCORTICAL PROJECTIONS IN WEAVER MUTANT MICE

In mice carrying the weaver mutation there is a spontaneous degeneration of dopaminergic neurons that is heterogeneous among cell groups: nigrostriatal neurons are more affected than mesolimbic neurons, while involvement of the mesocortical system is controversial. We questioned whether the pattern of cell loss in mesencephalon and fiber depletion in telencephalon could be related to the differential content of Calbindin-D-28k in dopaminergic cells. The mesencephalon of seven-month-old mutants was serially sectioned and alternate series were immunostained with tyrosine hydroxylase and Calbindin-D-28k. Cell counts indicated a 40% loss for the ensemble of dopamine mesencephalic neurons. However, double-immunostained preparations revealed that this cell loss was restricted to the neurons that lacked Calbindin-D-28k, which were reduced by 72%, while the dopaminergic neurons containing Calbindin-D-28k were completely spared. Calbindin-D-28k was present in both the cytoplasm and nucleus of the dopaminergic cells. This nuclear localization was confirmed at the ultrastructural level. In the telencephalon of weaver mutants, areas receiving projections from the Calbindin-D-28k-positive dopaminergic neurons, such as the cerebral cortex, contained normal densities of fibers, while areas harboring projections from the non-Calbindin-D-28k dopaminergic neurons, such as the dorsal striatum, had reduced amounts of fibers. The vulnerability pattern in the mesencephalon of weaver mutants bears similarities to that described in idiopathic Parkinson's disease or in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism: Calbindin-D-28k may thus delimit a group of dopaminergic neurons resistant to cell death in different conditions. On the other hand, the vulnerability pattern of dopaminergic fibers in weaver differs from that of Parkinson's disease, since there is a complete sparing of the dopaminergic mesocortical projection in weaver, contrasting with the damage of these projections in Parkinson's disease.