Gaspar P, Ben Jelloun N, Febvret A
INSERM U 106, Batiment de Pédiatrie, Hôpital Salpêtrière, Paris, France.
Neuroscience. 1994 Jul;61(2):293-305. doi: 10.1016/0306-4522(94)90232-1.
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-D28k in dopaminergic cells. The mesencephalon of seven-month-old mutants was serially sectioned and alternate series were immunostained with tyrosine hydroxylase and Calbindin-D28k. 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-D28k, which were reduced by 72%, while the dopaminergic neurons containing Calbindin-D28k were completely spared. Calbindin-D28k 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-D28k-positive dopaminergic neurons, such as the cerebral cortex, contained normal densities of fibers, while areas harboring projections from the non-Calbindin-D28k 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-D28k 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.
在携带韦弗突变的小鼠中，多巴胺能神经元会自发退化，且在不同细胞群中存在异质性：黑质纹状体神经元比中脑边缘神经元受影响更严重，而中脑皮质系统是否受累存在争议。我们质疑中脑的细胞丢失模式和端脑的纤维缺失是否与多巴胺能细胞中钙结合蛋白-D28k的含量差异有关。对7月龄突变体的中脑进行连续切片，交替系列切片分别用酪氨酸羟化酶和钙结合蛋白-D28k进行免疫染色。细胞计数表明，中脑多巴胺能神经元整体损失了40%。然而，双重免疫染色标本显示，这种细胞损失仅限于缺乏钙结合蛋白-D28k的神经元，这些神经元减少了72%，而含有钙结合蛋白-D28k的多巴胺能神经元则完全未受影响。钙结合蛋白-D28k存在于多巴胺能细胞的细胞质和细胞核中。这种核定位在超微结构水平上得到了证实。在韦弗突变体的端脑中，接受来自钙结合蛋白-D28k阳性多巴胺能神经元投射的区域，如大脑皮层，纤维密度正常，而接受来自非钙结合蛋白-D28k多巴胺能神经元投射的区域，如背侧纹状体，纤维数量减少。韦弗突变体中脑的易损模式与特发性帕金森病或N-甲基-4-苯基-1,2,3,6-四氢吡啶诱导的帕金森综合征中描述的相似：因此，钙结合蛋白-D28k可能界定了一组在不同条件下对细胞死亡有抗性的多巴胺能神经元。另一方面，韦弗突变体中多巴胺能纤维的易损模式与帕金森病不同，因为韦弗突变体中多巴胺能中脑皮质投射完全未受影响，这与帕金森病中这些投射受损形成对比。
