Neurotoxicity of MPTP to migrating neuroblasts: studies in acute and subacute mouse models of Parkinson's disease

Abstract

The acute or subacute administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been widely used in C57BL/6 mice to develop models of Parkinson's disease (PD). The loss of dopaminergic neurons is suggested to be mediated by a mechanism of nonapoptotic cell death or by apoptosis. In recent years, the notion that the neurotoxicity of MPTP is restricted to dopaminergic neurons in the substantia nigra (SN) has been challenged. Here, we provide evidence of rapid cell death in the subventricular zone (SVZ) and rostral migratory stream (RMS) in the adult C57BL/6 mouse brain in response to acute or subacute treatment with MPTP. Significant terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) of fragmented DNA was observed at 24 h (or 1 day) after the last injection in the acute model or after the first injection in the subacute model. Ultrastructural analysis confirmed that dying cells displayed an apoptotic morphology. Using a double labeling method, we demonstrated that the phenotype of the cells undergoing apoptosis is that of migrating neuroblasts. This is further supported by evidence of a subsequent loss of migrating neuroblasts. The results raise the possibility that migrating neuroblasts in the SVZ and RMS may be more vulnerable to MPTP than nigrostriatal dopaminergic neurons in the SN, and the death of migrating neuroblasts may be a primary event in the mouse model of PD. Furthermore, our data suggests that the death and subsequent loss of migrating neuroblasts in the acute or subacute model probably lead to a decreased potential for neurogenesis to some extent.