Dopaminergic Neurons Intrinsic to the Primate Striatum

Abstract

Intrinsic, striatal tyrosine hydroxylase-immunoreactive (TH-i) cells have received little consideration. In this study we have characterized these neurons and their regulatory response to nigrostriatal dopaminergic deafferentation. TH-i cells were observed in the striatum of both control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys; TH-i cell counts, however, were 3.5-fold higher in the striatum of MPTPlesioned monkeys. To establish the dopaminergic nature of the TH-i cells, sections were double-labeled with antibodies to dopamine transporter (DAT). Immunofluorescence studies demonstrated that nearly all TH-i cells were double-labeled with DAT, suggesting that they contain the machinery to be functional dopaminergic neurons. Two types of TH-i cells were identified in the striatum: small, aspiny, bipolar cells with varicose dendrites and larger spiny, multipolar cells. The aspiny cells, which were more prevalent, corresponded morphologically to the GABAergic interneurons of the striatum. Doublelabel immunofluorescence studies using antibodies to TH and glutamate decarboxylase (GAD 67 ), the synthetic enzyme for GABA, showed that 99% of the TH-i cells were GAD 67 -positive. Very few (Ͻ1%) of the TH-i cells, however, were immunoreactive for the calcium-binding proteins calbindin and parvalbumin. In summary, these results demonstrate that the dopaminergic cell population of the striatum responds to dopamine denervation by increasing in number, apparently to compensate for loss of extrinsic dopaminergic innervation. Moreover, this population of cells corresponds largely with the intrinsic GABAergic cells of the striatum. This study also suggests that the adult primate striatum does retain some intrinsic capacity to compensate for dopaminergic cell loss.

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“…In putamen, neuromelanin is likely synthesized within a particular type of neurons expressing tyrosine hydroxylase, the key enzyme for DOPA synthesis. These neurons are present in human and non-human primates and contain a high amount of DOPA; here, the precursor of neuromelanin synthesis is indeed Cys-DOPA (20,21). In brain cortex, the presence of neurons containing tyrosine hydroxylase able to synthesize DOPA was also reported, and this is in agreement with our finding that DOPA is the precursor of neuromelanin identified in this region (22).…”

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“…Although absence of TH expression clearly excludes DA identity, its presence alone is not sufficient to determine a DA neuron phenotype. For example, noradrenergic (NA) neurons rely on TH expression [35], and the enzyme has also been found in subpopulations of GABAergic neurons of the striatum, olfactory bulb and cortex [36][37][38][39].…”

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“…The reason why these neurons have not received much attention may be related to their paucity in rats and to the widespread belief that dopaminergic innervation of the striatum is exclusively extrinsinc. This view is challenged by recent studies in monkeys showing changes in number and\or morphology of striatal TH immunoreactive cells after MPTP treatment suggesting an upregu- lation of dopamine synthesis in these intrinsic striatal neurons (Dubach, 1994 ;Betarbet et al, 1997). This upregulation lasted at least for 2 y after the treatment (Betarbet et al 1997), but it is unknown whether -DOPA treatment has an effect on it.…”

“…This view is challenged by recent studies in monkeys showing changes in number and\or morphology of striatal TH immunoreactive cells after MPTP treatment suggesting an upregu- lation of dopamine synthesis in these intrinsic striatal neurons (Dubach, 1994 ;Betarbet et al, 1997). This upregulation lasted at least for 2 y after the treatment (Betarbet et al 1997), but it is unknown whether -DOPA treatment has an effect on it. Given that a similar condition may be present in humans, it might be one of the reasons why the first symptoms of Parkinson's disease are recognised only when the majority of the midbrain dopaminergic cells are already lost.…”