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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online January 8, 2004 as doi:10.1096/fj.03-0576fje. |
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* Basal Gang, Laboratoire de physiologie et physiopathologie de la signalization cellulaire, CNRS UMR 5543, Université Victor Segalen, Bordeaux, France;
Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; and
Department of Neurology, Charité Campus Virchow, Humboldt-University Berlin, Germany
2Correspondence: Basal Gang, CNRS UMR 5543, Université Victor Segalen, 146, Rue Léo-Saignat, 33076 Bordeaux Cedex, France. E-mail: Abdelhamid.Benazzouz{at}umr5543.u-bordeaux2.fr
SPECIFIC AIMS
High-frequency stimulation (HFS) of the subthalamic nucleus (STN) dramatically alleviates motor symptoms in Parkinson’s disease. Though the preferred site of stimulation is in the antero-dorsal part of the STN, it has been suggested that zona incerta (ZI) stimulation might be as beneficial to the patients. Although benefits afforded by STN/ZI HFS are empirically acknowledged, the contribution of the STN or ZI to the clinical improvement remains to be experimentally studied. The present study investigates metabolic changes induced in basal ganglia nuclei during HFS of the STN or the ZI in normal rats and in rats with a 6-hydroydopamine (6-OHDA) lesion. The expression of cytochrome oxidase subunit I (CoI) mRNA, a metabolic marker of global changes in neuronal activity, was measured in the STN, the globus pallidus (GP), and the SNr.
PRINCIPAL FINDINGS
1. Effects of electrical stimulation of the STN
In normal rats, HFS (130 Hz) of the STN induced a significant reduction in the level of CoI mRNA expression in the STN (Fig. 1
A) and SNr (Fig. 1B
) of the stimulated side compared with the intact side. In the GP, a significant increase in CoI mRNA expression was observed in normal rats with 130 Hz stimulation of the STN (Fig. 1C
). In contrast, low-frequency stimulation (LFS=20 Hz) of the STN did not affect the level of CoI mRNA expression in these three structures of the basal ganglia (Fig. 1A-C
). In 6-OHDA lesioned rats, the level of CoI mRNA expression was significantly higher in both the STN (Fig. 1A
) and the SNr (Fig. 1B
) than usually observed in normal control rats. In comparison to control rats, a significant decrease in CoI mRNA expression was observed in the GP ipsilateral to the 6-OHDA injection (Fig. 1C
). In 6-OHDA lesioned rats, HFS of the STN induced a normalization of CoI mRNA levels in the STN (Fig. 1A
) and GP (Fig. 1C
) compared with 6-OHDA lesioned rats without STN stimulation. In the SNr, HFS of the STN not only reversed changes in the expression of CoI mRNA but decreased it to a level significantly lower than that of normal animals (Fig. 1B
). LFS (20 Hz) of the STN in 6-OHDA lesioned rats did not induce any significant change in the level of CoI mRNA expression in the STN (Fig. 1A
) and SNr (Fig. 1B
). However, a normalization of the expression was observed in the GP (Fig. 1C
).
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2. Effects of electrical stimulation of the ZI
In normal rats, HFS of the ZI induced a significant decrease in the level of CoI mRNA expression in the SNr (Fig. 2
B) of the stimulated side. A strong trend toward a decrease in CoI mRNA level was observed in the STN (Fig. 2A
). In the GP, a significant increase in the level of CoI mRNA expression was observed in normal rats with HFS of the ZI (Fig. 2C
). LFS of the ZI did not affect the level of CoI mRNA expression in the three studied structures of the basal ganglia in normal rats (Fig. 2A-C
). In 6-OHDA lesioned rats, HFS of the ZI showed a trend toward normalization of the level of CoI mRNA expression in the STN (Fig. 2A
). In the SNr, HFS of the ZI not only reversed changes in the expression of CoI mRNA but decreased the expression to a level that is significantly lower than that of normal animals (Fig. 2B
). In the GP, HFS of the ZI normalized the level of CoI mRNA expression in 6-OHDA lesioned rats (Fig. 2C
). LFS (20 Hz) of the ZI in 6-OHDA lesioned rats induced a normalization of the level of CoI mRNA expression in the SNr (Fig. 2B
). However, it did not induce any significant change in the STN (Fig. 2A
) and GP (Fig. 2C
).
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CONCLUSIONS
This study shows that HFS of the STN reverses the pathological changes in metabolic activity in STN, GP and SNr and that HFS of the ZI reverses changes in SNr and GP in an experimental rodent model of Parkinson’s disease. In normal rats, HFS of the STN induced a decrease in the level of CoI mRNA expression in the STN and SNr suggesting a reduction in the global metabolic activity of these two nuclei. From these results we can postulate that HFS of the STN inhibits the stimulated site resulting in a reduction of the activity of its efferent structure, the SNr, considered the principal output structure of the basal ganglia in the rat. These results agree with our previous electrophysiological data. In 6-OHDA lesioned rats, HFS of the STN reverses dopamine denervation-induced changes in the expression of CoI mRNA in the STN, SNr, and GP. As in normal rats, HFS of the STN decreased the metabolic activity of STN and SNr in 6-OHDA lesioned rats. These results are consistent with the hypothesis that HFS of the STN alleviates parkinsonian motor symptoms by decreasing STN neuronal activity, resulting in a reduction of glutamatergic tone from the STN to the output structures of the basal ganglia. Our evidence supports the assumption that HFS of the STN mimics the effects of STN lesion by reducing, possibly abolishing, neuronal activity in the STN and the output structures of basal ganglia. The mechanism by which HFS decreases the activity of STN and SNr neurons is not clearly determined. Recent in vitro studies have reported that HFS exercises a direct effect on the membrane of STN neurons mediated by a blockade of Na+ and Ca2+ voltage-gated currents. The inhibitory effect observed in the SNr could be due at least in part to the alleviation of excitatory glutamatergic afferents from the STN. Moreover, as HFS of the STN not only reversed changes in the expression of CoI mRNA in the SNr but decreased the expression to a level lower than that of controls, it is possible that the decrease of glutamatergic transmission is reinforced by the activation of GABAergic pallidonigral projections. The pronounced decrease in the level of CoI mRNA in SNr combined with the normalization of the level in STN may be needed for the improvement of motor symptoms.
HFS of the ZI reversed dopamine denervation-induced metabolic changes in SNr and GP. These improvements were similar to those induced by HFS of the STN. Thus, the present results suggest that the ZI may directly or indirectly control basal ganglia activity and therefore could be implicated in the pathophysiology of Parkinson’s disease. In the absence of a significant effect on STN metabolic activity, we suggest that HFS of the ZI has a direct action on SNr neurons without implying the STN. We can postulate that the prominent effect of ZI HFS on SNr metabolic activity may be due to the activation of GABAergic pallidonigral and/or striatonigral bundles resulting in the depression of neuronal activity in the SNr. Our metabolic data suggest that ZI might be a good target for deep brain stimulation in Parkinson’s disease. However, further studies are needed to understand the implication of ZI in the regulation of motricity.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-0576fje; 
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