Expression of glutamate receptors in the human and rat basal ganglia: effect of the dopaminergic denervation on AMPA receptor gene expression in the striatopallidal complex in Parkinson's disease and rat with 6-OHDA lesion.
The overactivity of subthalamopallidal and corticostriatal glutamatergic neurons observed in Parkinson's disease (PD) suggests that antagonists of glutamate receptor could be used to alleviate the motor symptoms of the disease. In this study, we analysed two features of the striatopallidal complex: (1) the distribution of alpha-amino-3 hydroxy-5-methyl-4-isoxasol-propionate (AMPA) and kainate receptors and their corresponding mRNA by immunohistochemistry and in situ hybridisation and (2) the effect of dopaminergic denervation on AMPA receptor gene expression in PD patients and rats with 6-hydroxydopamine (6-OHDA)-induced degeneration of the nigrostriatal dopaminergic system. All AMPA receptor mRNAs and proteins (GluR1-4) were detected in the internal segment of the globus pallidus (GPi). Among kainate receptors, only KA1 and KA2 were detectable and only at a low level. Only GluR4 protein was detected in the neuropil of the GPi. In the striatum, GluR1, GluR2, and GluR3 were detected in about 70% of medium-sized and large neurons. By contrast, GluR4 mRNA was detected in only a small number of large and medium-sized neurons. Among kainate receptors, GluR6, GluR7, and KA2 were detected in about 50-60% of medium-sized neurons, whereas GluR5 and KA1 were restricted to 1-2% and 20-30% of these neurons, respectively. These results suggest that antagonists of AMPA and kainate receptors could be effective in alleviating motor symptoms in Parkinson's disease by blocking the overstimulation of pallidal and striatal neurons by glutamate. A significant decrease in GluR1 gene expression (-33%) was observed in the neurons of the GPi in PD patients and in rat entopeduncular nucleus ipsilateral to the 6-OHDA lesion (-20%). GluR2, GluR3, and GluR4 mRNA levels in the GPi and GluR1-4 levels in the striatum were unchanged in PD patients and 6-OHDA-lesioned rats compared with their respective controls. These data suggest that dopamine positively regulates only GluR1 gene expression in the GPi.
Bernard
V
V
INSERM U289, Hôpital de la Salpêtrière, Paris.
Gardiol
A
A
Faucheux
B
B
Bloch
B
B
Agid
Y
Y
Hirsch
E C
EC
D000818:Animals; D001479:Basal Ganglia / Q000737:chemistry*; D016022:Case-Control Studies; D003342:Corpus Striatum / Q000378:metabolism*; D003714:Denervation; D004298:Dopamine / Q000502:physiology*; D015870:Gene Expression; D005917:Globus Pallidus / Q000378:metabolism; D006801:Humans; D008297:Male; D016627:Oxidopamine; D010300:Parkinson Disease / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics*; D017470:Receptors, Glutamate / Q000235:genetics*; D018092:Kainic Acid Receptors / Q000235:genetics
D004298:Dopamine; D016627:Oxidopamine; D012333:RNA, Messenger; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors