Glutamate transporters in the rat basal ganglia: Localization and modulations in normal and Parkinsonian rats

Parkinson's disease (PD) is a serious motor disorder in human and it is caused by a degeneration of dopaminergic neurons in the basal ganglia. One damaging effect after dopamine denervation is an overactivity of glutamate pathways in the brain and this is related to the onset of symptoms of Parkinson's disease. Glutamate transmission is regulated by vesicular glutamate transporters (VGLUT1-T3) and excitatory amino acid transporters (EAATs: GLT1, GLAST and EAAC1). In normal rats, double labeling experiments revealed that pattern of distribution of VGLUT1 and VGLUT2 immunoreactivities was found to be primarily segregated in the neuropilar elements, whereas VGLUT3 immunoreactivity was found in the perikarya of different subpopulations of neurons in the basal ganglia. The present results indicate that VGLUT1 and T2 proteins are likely to be expressed by sub-groups of glutamatergic terminals that differ in origin. VGLUT3 is only found in subpopulations of neurons in the basal ganglia suggests possible roles of glutamate in these neurons. In 6-hydroxydopamine (6-OHDA)-lesioned rats, an animal model of Parkinson's disease, immunoreactivity for GLT1 and GLAST was found to be decreased in the striatum of the lesioned side. Prominent decreases in GLT1 and GLAST protein expressions were also found. These findings indicate that excessive levels of extracellular glutamate after the onset of Parkinson's disease may at least be due to a depletion of glial glutamate transporters, i.e., a deficit in re-cycling of glutamate as a neurotransmitter. In addition, immunoreactivity for EAAC1 and VGLUT3 was differentially modulated in the basal ganglia after 6-OHDA lesion. These results indicate that the expression of EAAC1 and VGLUT3 are related to change of activities of neurons in the basal ganglia after dopamine denervation. These findings may have important implications in the treatment of Parkinson's disease. Last but not the least, GLT1 expression was found to be increased after the administration of an antibiotic ceftriaxone in normal and 6-OHDA lesioned rats. Immunoreactivity for GLT1 was found to be increased in the lesioned striatum compared to the non-lesioned side of the ceftriaxone-treated rats. Although, no amelioration in motor behavior was found, these results provide evidence that ceftriaxone is potent positive regulator for GLT1 expression. These findings may have potential clinical application in the treatment of Parkinson's disease.