Phenotype of Striatofugal Medium Spiny Neurons in Parkinsonian and Dyskinetic Nonhuman Primates: A Call for a Reappraisal of the Functional Organization of the Basal Ganglia

Abstract

The classic view of anatomofunctional organization of the basal ganglia is that striatopallidal neurons of the "indirect" pathway express D 2 dopamine receptors and corelease enkephalin with GABA, whereas striatopallidal neurons of the "direct" pathway bear D 1 dopamine receptors and corelease dynorphin and substance P with GABA. Although many studies have investigated the pathophysiology of the basal ganglia after dopamine denervation and subsequent chronic levodopa (L-dopa) treatment, none has ever considered the possibility of plastic changes leading to profound reorganization and/or biochemical phenotype modifications of medium spiny neurons. Therefore, we studied the phenotype of striatal neurons in four groups of nonhuman primates, including the following: normal, parkinsonian, parkinsonian chronically treated with L-dopa without exhibiting dyskinesia, and parkinsonian chronically treated with L-dopa exhibiting overt dyskinesia. To identify striatal cells projecting to external (indirect) or internal (direct) segments of the globus pallidus, the retrograde tracer cholera toxin subunit B (CTb) was injected stereotaxically into the terminal areas. Using immunohistochemistry techniques, brain sections were double labeled for CTb and dopamine receptors, opioid peptides, or the substance P receptor (NK1). We also used HPLC-RIA to assess opioid levels throughout structures of the basal ganglia. Our results suggest that medium spiny neurons retain their phenotype because no variations were observed in any experimental condition. Therefore, it appears unlikely that dyskinesia is related to a phenotype modification of the striatal neurons. However, this study supports the concept of axonal collateralization of striatofugal cells that project to both globus pallidus pars externa and globus pallidus pars interna. Striatofugal pathways are not as segregated in the primate as previously considered.

RGS9–2 Negatively Modulates l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia in Experimental Parkinson's Disease

“…The question remains as to the identity of the MSNs and of the other cell types that can be transfected by the HSV virus. We showed previously in the primate (1) that striatofugal pathways are not as segregated (Nadjar et al, 2006) as previously thought (Gerfen et al, 1990) and (2) that a significant proproportion of MSNs should coexpress D1R and D2R (Aizman et al, 2000;Nadjar et al, 2006). This raises the possibility that, even if HSV-mediated RGS9 -2 expression was truly preferentially modulating D2R, HSV-mediated RGS9 -2 expression (1) affects both striatofugal pathways anyway and (2) modulates the activity of the MSNs coexpressing D1R and D2R.…”

“…The right hemisphere was immediately frozen by immersion in isopentane and then stored at Ϫ80°C. The left hemisphere was dissected for isolating the striatum (combining caudate nucleus, putamen and nucleus accumbens, across the rostrocaudal extent) that was then frozen in isopentane and stored at -80°C (Nadjar et al, 2006).…”

“…The G-protein-coupled DA receptors (DAR) are expressed by striatal medium spiny neurons (MSNs) connecting the striatum to the basal ganglia output nuclei through the so-called "direct" and "indirect" pathways (Alexander and Crutcher, 1990) (but see Nadjar et al, 2006). The GABAergic direct pathway projects directly to the internal segment of the globus pallidus (GPi) and expresses the D1 DA receptor (D1R), whereas the GABAergic indirect pathway, directed at the external pallidal segment (GPe), expresses the D2 DA receptor (D2R).…”

Dopamine-Deprived Striatal GABAergic Interneurons Burst and Generate Repetitive Gigantic IPSCs in Medium Spiny Neurons

“…1, available at www.jneurosci.org as supplemental material). (Nadjar et al, 2006), we reasoned that the two types of GABA A sPSCs patterns recorded could correspond to these two types of MSNs. To test this hypothesis, we performed immunocytochemical labeling of intracellularly injected biocytin with D 1 dopamine receptor antibodies (see Materials and Methods).…”

Statistical Properties of Pauses of the High-Frequency Discharge Neurons in the External Segment of the Globus Pallidus

“…Traditional models of the basal ganglia networks emphasized their role in the control of motor activity (DeLong, 1971;Mink and Thach, 1987;Turner and Anderson, 1997) and considered the GPe to be a relay station along the indirect pathway connecting input and output structures of the basal ganglia (Albin et al, 1989). More recent studies have shown that the basal ganglia are involved in limbic and associative processes as well as in motor computation and view the GPe as a central component of this neural network (Bolam et al, 2000;Arkadir et al, 2004;Levesque and Parent, 2005;Turner and Anderson, 2005;Nadjar et al, 2006). …”