Alterations in the motor cortical and striatal glutamatergic system and d-serine levels in the bilateral 6-hydroxydopamine rat model for Parkinson's disease

Abstract

Parkinson's disease (PD) is hallmarked by progressive degeneration of the substantia nigra pars compacta (SNc) neurons and is associated with aberrant glutamatergic activity. However, studies on the glutamatergic system in the motor cortex and striatum, two motor loop-related areas, are lacking in the clinically relevant bilateral SNc 6-hydroxydopamine (6-OHDA) rat model, and therefore led to the rationale behind the present investigations. Using Western blotting, the expression levels of the glial glutamate transporters, GLT-1 and GLAST, as well as xCT, the specific subunit of system xc−, and the vesicular glutamate transporters, VGLUT1 and 2 were investigated at two different time points (1 week and 2 weeks) post-lesion. In addition, the total content of glutamate was measured. Moreover, the total d-serine levels were, to the best of our knowledge, studied for the first time in these two PD-related areas in the bilateral 6-OHDA rat model. In the motor cortex, no significant changes were observed in the different glutamate transporter expression levels in the bilaterally-lesioned rats. In the striatum, GLAST expression was significantly decreased at both time points whereas VGLUT1 and 2 expressions were significantly decreased 2 weeks after bilateral 6-OHDA lesion. Interestingly, bilateral 6-OHDA SNc lesion resulted in an enhancement of the total d-serine content in both motor cortex and striatum at 1 week post-lesion suggesting its possible involvement in the pathophysiology of PD. In conclusion, this study demonstrates disturbed glutamate and d-serine regulation in the bilateral SNc-lesioned brain which could contribute to the behavioral impairments in PD.