Nigrostriatal denervation does not affect glutamate transporter mRNA expression but subsequent levodopa treatment selectively increases GLT1 mRNA and protein expression in the rat striatum

Abstract

There is growing evidence that the loss of the nigrostriatal dopaminergic neurones induces an overactivity of the corticostriatal glutamatergic pathway which seems to be central to the physiopathology of parkinsonism. Moreover, glutamatergic mechanisms involving NMDA receptors have been shown to interfere with the therapeutical action of levodopa. Given the key role played by uptake processes in glutamate neurotransmission, this study examined the effects of nigrostriatal deafferentation and of levodopa treatment on the striatal expression of the glutamate transporters GLT1, GLAST and EAAC1 in the rat. No signi®cant changes in striatal mRNA levels of these transporters were detected after either levodopa treatment (100 mg/kg; i.p., twice a day for 21 days) or unilateral lesion of the nigrostriatal pathway by intranigral 6-hydroxydopamine injection. In contrast, animals with the lesion subsequently treated with levodopa showed a selective increase (36%) in GLT1 mRNA levels in the denervated striatum versus controls. These animals also showed increased GLT1 protein expression, as assessed by immunostaining and western blotting. These data provide the ®rst evidence that levodopa therapy may interfere with striatal glutamate transmission through change in expression of the primarily glial glutamate transporter GLT1. We further suggest that levodopa-induced GLT1 overexpression may represent a compensatory mechanism preventing neurotoxic accumulation of endogenous glutamate.

Downregulation of glial glutamate transporters after dopamine denervation in the striatum of 6‐hydroxydopamine‐lesioned rats

“…Previous reports have shown that there is no change in GLT1 mRNA after dopamine denervation (Lievens et al, 2001;Robelet et al, 2004). Lievens et al (2001) also reported that the GLT1 protein level was modulated after 6-OHDA lesion using Western blot analysis.…”

“…Previous studies have indicated that there is a downregulation of GLT1 in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice (Dervan et al, 2004) but no modulation in GLT1 mRNA is found in 6-hydroxydopamine (6-OHDA)-lesioned rats (Lievens et al, 2001;Robelet et al, 2004). Despite these observations, the modulation of another important glial glutamate transporter, GLAST, after dopamine denervation, and importantly the status of the neuronal glutamate transporter EAAC1, is not clear.…”

Glutamate and GABA receptors and transporters in the basal ganglia: What does their subsynaptic localization reveal about their function?

“…The available information regarding the distribution of EAATs in the basal ganglia derives mostly from in situ hybridization (Torp et al, 1994;Velaz-Faircloth et al, 1996;Lievens et al, 2001) and light microscopic immunohistochemical studies (Rothstein et al, 1994;Lehre et al, 1995); except for EM data from our group on the ultrastructural localization of GLT1, GLAST and EAAC1 in monkey (Charara et al, 2002).…”

“…Interestingly, the density of GLT1 in striatal astrocytes is decreased in a rodent model of PD (Dervan et al, 2004). This deficiency suggests a compromised ability of glial cells to regulate glutamate and its associated synaptic functions in parkinsonism, which appears to be reversed after levodopa treatment (Lievens et al, 2001). …”

High-Frequency Stimulation of the Subthalamic Nucleus Potentiates l-DOPA-Induced Neurochemical Changes in the Striatum in a Rat Model of Parkinson's Disease

“…The major molecular changes associated with LIDs in animal models and PD patients are the increase in preprodynorphin (PPDyn) mRNA levels in striatonigral neurons and the additional increase, above lesion-induced levels, in preproenkephalin (PPE) mRNA in striatopallidal neurons (Cenci et al, 1998;Henry et al, 1999Henry et al, , 2003Calon et al, 2000Calon et al, , 2002Zeng et al, 2000;Tel et al, 2002). The role of glutamatemediated mechanisms in these changes is supported by the experimental data showing that L-DOPA-induced overexpression of PPE is reduced by a glutamate antagonist (Perier et al, 2002) and is topographically superimposed to the increased expression of the glial glutamate transporter GLT1 (Lievens et al, 2001). Among the signal transduction pathways underlying the development of LIDs, striatal induction of the transcription factor ⌬FosB is suggested to play a major role and to positively modulate PPDyn (Andersson et al, 1999).…”