Injury and strain-dependent dopaminergic neuronal degeneration in the substantia nigra of mice after axotomy or MPTP

Abstract

We studied the effects of axotomy or neurotoxin on the survival of substantia nigra pars compacta (SNpc) neurons in two strains of mice, FVB/N or C57BL/6. Fluoro gold (FG) was injected into both striata of the mice to retrogradely label the nigrostriatal neuronal population. Ten days later, these neurons were axotomized in the medial forebrain bundle (MFB) unilaterally or N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was administered intraperitonealy for 2 days to produce bilateral degeneration. MFB transection or MPTP administration produced a progressive loss of FG-labeled and tyrosine hydroxylase immunolabeled (TH+) neurons in both strains. Relative to control, 72% of SNpc neurons died 4 weeks after axotomy in C57BL/6 mice and 50% died after axotomy in FVB/N mice. MPTP resulted in death of 80% of SNpc neurons in C57BL/6 mice but only 40% in the FVB strain 4 weeks after MPTP administration. In this more sensitive strain, MPTP cell death was associated with positive staining for terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and nuclear condensation. In contrast, no TUNEL staining was detected in SNpc after MPTP in FVB/N mice. Further, while similar kinetics and extent of cell death accompanied axotomy, axotomy-induced cell death was TUNEL negative in both FVB/N and C57BL/6 mice. Double staining for TUNEL and microtubule associated protein 2 confirmed that the majority of the TUNEL positive cells were neurons. These data indicate that genetic factors and the type of lesion play an important role in determining death of dopaminergic neurons after injury.