Abstract
Calbindin (CB) is a calcium binding protein reported to protect dopaminergic neurons from degeneration. Although a direct link between CB content and differential vulnerability of dopaminergic neurons has long been accepted, factors other than CB have also been suggested, particularly those related to the dopamine transporter. Indeed, several studies have reported that CB levels are not causally related to the differential vulnerability of dopaminergic neurons against neurotoxins. Here we have used dual stains for tyrosine hydroxylase (TH) and CB in 3 control and 3 MPTP-treated monkeys to visualize dopaminergic neurons in the ventral tegmental area (VTA) and in the dorsal and ventral tiers of the substantia nigra pars compacta (SNcd and SNcv) co-expressing TH and CB. In control animals, the highest percentages of co-localization were found in VTA (58.2%), followed by neurons located in the SNcd (34.7%). As expected, SNcv neurons lacked CB expression. In MPTP-treated animals, the percentage of CB-ir/TH-ir neurons in the VTA was similar to control monkeys (62.1%), whereas most of the few surviving neurons in the SNcd were CB-ir/TH-ir (88.6%). Next, we have elucidated the presence of CB within identified nigrostriatal and nigroextrastriatal midbrain dopaminergic projection neurons. For this purpose, two control monkeys received one injection of Fluoro-Gold into the caudate nucleus and one injection of cholera toxin (CTB) into the postcommissural putamen, whereas two more monkeys were injected with CTB into the internal division of the globus pallidus (GPi). As expected, all the nigrocaudate- and nigroputamen-projecting neurons were TH-ir, although surprisingly, all of these nigrostriatal-projecting neurons were negative for CB. Furthermore, all the nigropallidal-projecting neurons co-expressed both TH and CB. In summary, although CB-ir dopaminergic neurons seem to be less prone to MPTP-induced degeneration, our data clearly demonstrated that these neurons are not giving rise to nigrostriatal projections and indeed CB-ir/TH-ir neurons only originate nigroextrastriatal projections.
Highlights
Parkinson’s disease (PD) is characterized by a progressive and selective loss of midbrain dopaminergic (DA) neurons
Systemic administration of MPTP to non-human primates induces a selective nigrostriatal degeneration mimicking the pattern of differential vulnerability of DA neurons observed in PD patients; the greatest loss being found in ventrolateral territories of the SNc (Schneider et al, 1987; Schneider and Dacko, 1991; Varastet et al, 1994)
MPTP treatment induced a severe loss of dopaminergic neurons, few tyrosine hydroxylase (TH)-ir cells within the dorsal and ventral tiers of the SNc were still visible. (Figures 1J–L)
Summary
Parkinson’s disease (PD) is characterized by a progressive and selective loss of midbrain dopaminergic (DA) neurons. This cell loss follows a heterogeneous pattern as described in PD patients. Animal models for PD showed a similar pattern of midbrain DA neurons loss (German et al, 1988, 1996; Varastet et al, 1994; Liang et al, 1996; Oiwa et al, 2003; Fitzpatrick et al, 2005). Systemic administration of MPTP to non-human primates induces a selective nigrostriatal degeneration mimicking the pattern of differential vulnerability of DA neurons observed in PD patients; the greatest loss being found in ventrolateral territories of the SNc (Schneider et al, 1987; Schneider and Dacko, 1991; Varastet et al, 1994)
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