Time course of dopamine neuron loss and glial response in the 6-OHDA striatal mouse model of Parkinson's disease.

Abstract

The 6-hydroxydopamine (6-OHDA) neurotoxic lesion of the midbrain dopamine (DA) system is one of the most widely used techniques for modelling Parkinson's disease in rodents. The majority of studies using this approach, however, largely limit their analysis to lesioning acutely, and looking at behavioural deficits and the number of surviving tyrosine hydroxylase (TH)-stained cells in the midbrain. Here we have analysed additional characteristics that occur following intrastriatal delivery of 6-OHDA, providing better understanding of the neurodegenerative process. Female C57/Black mice were given lesions at 10 weeks old, and killed at several different time points postoperatively (3 and 6 h, 1, 3, 6, 9 and 12 days). While the detrimental effect of the toxin on the TH+ fibres in the striatum was immediate, we found that the loss of TH+ dendritic fibres, reduction in cell size and intensity of TH expression, and eventual reduction in the number of TH+ neurons in the substantia nigra was delayed for several days post-surgery. We also investigated the expression of various transcription factors and proteins expressed by midbrain DA neurons following lesioning, and observed changes in the expression of Aldh1a1 (aldehyde dehydrogenase 1 family, member A1) as the neurodegenerative process evolved. Extracellularly, we looked at microglia and astrocytes in reaction to the 6-OHDA striatal lesion, and found a delay in their response and proliferation in the substantia nigra. In summary, this work highlights aspects of the neurodegenerative process in the 6-OHDA mouse model that can be applied to future studies looking at therapeutic interventions.