The impact of tyrosine hydroxylase loss on dopamine signaling during nigrostriatal neuron loss in a rat Parkinson’s disease model

Purpose: Parkinson’s disease (PD) is a neurological disorder resulting from the degeneration of nigrostriatal dopamine (DA) neurons. DA plays a major role in the control of movement initiation via the nigrostriatal pathway. The relationship between DA tissue levels and synaptic levels is poorly understood, and the impact of tyrosine hydroxylase (TH) loss upon synaptic DA levels is not well defined either. As the rate limiting enzyme of DA synthesis, tyrosine hydroxylase (TH) protein was evaluated against these indices of DA function. Since PD involves progressive loss of the nigrostriatal neurons and TH protein, understanding how synaptic DA levels may change against this decrease will shed light on whether compensatory processes are engaged to maintain synaptic DA levels, and can outline possible limits of such processes and their influence upon the timing of onset of hypokinesia, a major PD symptom.

Methods: We used the established rat neurotoxin model 6-hydroxydopamine (6-OHDA) utilizing stereotactic surgery to lesion the nigrostriatal pathway and emulate the pathological course of human PD, which features DA and TH loss in the Str proceeding at a faster rate than in the SN. Following microdialysis, brain tissue punches from the SN and Str regions of both lesioned and control rats were harvested at 7 and 28 days, and then analyzed by high-performance liquid chromatography to quantify both synaptic and tissue DA. We followed with TH protein analyses to statistically quantify the relationships between TH protein, DA tissue, and synaptic DA.

Results: Our results show that TH protein levels had a highly significant correlation against DA tissue levels in the lesioned Str and SN; however, only synaptic DA release levels in the Str following depolarizing stimulation had a significant correlation with TH protein. Additionally, only 15% of the variance in lesioned Str synaptic DA levels can be explained by tissue DA and TH concentrations when using a multivariate linear regression model. These results show that compensatory processes are engaged during nigrostriatal lesion to maintain synaptic levels, but these mechanisms are inadequate to offset major TH protein loss in the Str.

Conclusions: The particular significance of this study lies in its focus on extracellular neurotransmitter analysis – something that has not been extensively explored. Our findings will provide novel insight into how synaptic DA levels are affected by expected decreases in tissue content, thus deepening the current understanding on transmission within the basal ganglia and generating areas for further research.