In Parkinson's disease (PD), the progressive degeneration of the nigrostriatal dopamine (DA) pathway leads to loss of striatal DA content, dysregulation of the basal ganglia motor circuit, and inhibition of movement. Various pathogenic pathways drive DA neuron death in PD, including oxidative stress, mitochondrial dysfunction, neuroinflammation, glutamate excitotoxicity, and failure of protein degradation pathways. The aim of the current study was to evaluate glutamatergic and behavioural abnormalities in a mouse model of PD, based on the intranigral infusion of proteasome inhibitor lactacystin (LAC). C57BL6/J mice, 12 weeks of age, were stereotaxically injected with 1.5uL LAC 2ug/uL in saline (n=8, LAC group) or 1.5uL saline (n=8, SHAM group) in the left substantia nigra pars compacta. One week following surgery, mice were tested in various behavioural paradigms (rotarod, open field, tail suspension, Y maze), and brain tissue further processed for cresyl violet staining, VGLUT2 immunohistochemistry, and glutamate immunogold electron microscopy. Our findings demonstrate that LAC-treated mice show loss of nigral neurons and behavioural deficits, including impaired motor coordination and balance, motor asymmetry, hyperactivity, and response perseveration. Furthermore, LAC infusion led to an increase in VGLUT2 immunoreactivity in the ipsilateral substantia nigra pars compacta. Our findings at a behavioural and molecular level indicate a possible compensatory mechanism by which the surviving DA neurons at the site of the lesion become hyperactive, as recently observed in mice lesioned with proteasome inhibitor epoxomicin (Subramaniam et al. 2014 Eur J Neurosci). In conclusion, we report that mice treated with proteasome inhibitor LAC develop parkinsonian behavioural features, and glutamatergic dysfunction that could be linked with increased activity of the subthalamic nucleus. In the future we aim at performing ultrastructural analysis of excitatory synapses, as well as evaluating expression of glutamate transporters, levels of extracellular glutamate, and the activity of the STN after LAC lesion.
|VUB DS-LSM PhD Day Research Unlimited, 31 March 2015, Brussels, Belgium.
|Published - 31 mrt 2015
|VUB DS-LSM PhD day Research Unlimited - Brussel, Belgium
Duur: 31 mrt 2015 → 31 mrt 2015
|VUB DS-LSM PhD day Research Unlimited
|31/03/15 → 31/03/15