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

Abstract

Overactivity of glutamatergic neurotransmission in the basal ganglia is known to be closely related to the onset and pathogenesis of Parkinson's disease. Glutamate homeostasis around glutamatergic synapses is tightly regulated by two groups of glutamate transporters: glial glutamate transporters GLT1 (EAAT2) and GLAST (EAAT1), and neuronal glutamate transporter EAAC1. In order to investigate the changes of glutamate transporters after the onset of Parkinson's disease, unilateral 6-hydroxydopamine-lesioned rat, an animal model of Parkinson's disease, was employed. By immunofluorescence and Western blot analyses, GLT1 and GLAST proteins were significantly reduced in the striatum with lesion. No change in GLT1 and GLAST protein was found in the substantia nigra. The reduction of GLT1 protein in the striatum was more prominent than that of GLAST protein (approximately 40% vs. 20%). In addition, EAAC1 protein was found to be increased in the substantia nigra pars reticulata of the lesioned rats but not in the striatum. The present results indicate that reductions of GLT1 and GLAST may impair glutamate homeostasis around glutamatergic synapses in the striatum and contribute to over-spills of glutamate in the system. An increase in the EAAC1 level in the substantia nigra pars reticulata may increase GABA synthesis and enhance GABAergic neurotransmission. These results indicate that there are differential and distinct modulations of glutamate transporters after dopamine denervation in the 6-hydroxydopamine-lesioned rat.

Effect of 6-hydroxydopamine (6-OHDA) on proliferation of glial cells in the rat cortex and striatum: evidence for de-differentiation of resident astrocytes

“…A similar upregulation of GFAP has been shown in 6-OHDA-or MPTP-lesion models in which the neurotoxins are injected directly into the striatum (Chadi and Gomide 2004;Gomide et al 2005;Henning et al 2008;Yoo et al 2005), the median forebrain bundle (Henning et al 2008;Stromberg et al 1986), or the substantia nigra (Chung et al 2008;Sheng et al 1993). Similar to our findings, the activation of astrocytes in these studies is not restricted to the direct sites of 6-OHDA or MPTP injection but comprise various brain regions (Chadi and Gomide 2004;Gomide et al 2005) that represent target areas of dopaminergic projections.…”

“…The injection of the neurotoxin 6-OHDA into the nigrostriatal system can be used to study the effect of dopaminergic depletion not only on neurons or neuronal precursors (Aponso et al 2008;Chung et al 2008;Hoglinger et al 2004;Hu et al 1990;Rodriguez et al 2001), but also on astrocytes (Gordon et al 1997;Henning et al 2008;Sheng et al 1993;Stromberg et al 1986;Yoo et al 2005). We have investigated the effect of 6-OHDA on astrocytes in the striatum and cortex in the adult rat brain, in a model in which the neurotoxin is not injected into the nigro-striatal system but into the lateral ventricles.…”

Reverse microdialysis of a 5-HT2A receptor antagonist alters extracellular glutamate levels in the striatum of the MPTP mouse model of Parkinson’s disease

“…There is the possibility that the increased extracellular levels of glutamate associated with loss of DA could result from downregulation of striatal GLT-1. Whereas some groups have reported downregulation of GLT-1 following dopaminergic lesioning (Holmer et al, 2005; Chung et al, 2008), others have observed an upregulation of striatal GLT-1 (Massie et al, 2010). We and others did not detect changes in striatal GLT-1 expression (Lievens et al, 2001).…”

Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease

“…Recently, several studies demonstrated that EAAT2 expression is involved in PD. Decreased EAAT2 expression has been reported in animal models of PD, including the 6-hydroxydopaminelesioned PD model and the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated mouse model [145,146]. Recently, growing evidence shows ceftriaxone has beneficial effects in PD animal model, including the prevention of motor dysfunction, neuronal death, and PD related memory deficits [147][148][149][150][151][152].…”