Elsevier

Experimental Neurology

Volume 215, Issue 2, February 2009, Pages 220-227
Experimental Neurology

Dopaminergic denervation and spine loss in the striatum of MPTP-treated monkeys

https://doi.org/10.1016/j.expneurol.2008.09.025Get rights and content

Abstract

Striatal spine loss is a key pathological feature of human Parkinson's disease (PD) that can be induced after complete degeneration of the nigrostriatal dopaminergic system in rodent models of parkinsonism. In line with these observations, our findings reveal a significant (30–50%) reduction in spine density in both the caudate nucleus and putamen of severely DA-depleted striata of MPTP-treated monkeys; the sensorimotor post-commissural putamen being the most severely affected region for both dopamine depletion and spine loss. Using MPTP-treated monkeys with complete or partial striatal dopamine (DA) denervation, we also demonstrate that striatal spine loss is an early pathological feature of parkinsonism, which progresses along a positive rostrocaudal and mediolateral gradient in parallel with the extent of striatal dopamine denervation. Quantitative electron microscopy immunocytochemistry for D1 dopamine receptor (D1) in the striatum of control and severely DA-depleted animals revealed that both D1-immunoreactive and immunonegative spines are lost in the putamen of MPTP-treated monkeys.

These data demonstrate that striatal spine loss in MPTP-treated monkeys is an early pathological event of parkinsonism, tightly correlated with the degree of nigrostriatal dopamine denervation that likely affects both direct and indirect striatofugal pathways.

Introduction

Dopamine (DA) plays a critical role in regulating spine density on striatal medium-sized spiny neurons (MSNs) (Arbuthnott et al., 2000, Robinson and Kolb, 1999). A significant reduction in spine density has been demonstrated in postmortem tissue from human parkinsonians (Stephens et al., 2005, Zaja-Milatovic et al., 2005) and in 6-hydroxydopamine (6-OHDA) rodent model of Parkinson's disease (PD) (Ingham et al., 1989, Ingham et al., 1998). The role of DA in modulating striatal spine morphogenesis is also depicted by the significant increase in the number of spines on MSNs in animals treated with psychostimulants (Robinson and Kolb, 1999, Norrholm et al., 2003). Rodent models of PD, characterized by a severe loss of striatal dopamine, show a significant reduction in overall spine density accompanied by a corresponding decrease in the total number of putative glutamatergic terminals forming asymmetric synapses (Ingham et al., 1993, Ingham et al., 1998). Therefore, dopamine is a key transmitter that plays an important role in regulating the growth, maintenance and plasticity of dendritic spines in the striatum. However, because rodent and human data gathered so far have been collected from patients or animal models at the end stage of parkinsonism, it is not clear if striatal spine loss is an early pathological event that progresses with the degeneration of the nigrostriatal system or a late phenomenon that occurs only in severely dopamine-depleted striata.

Although the etiology of the degenerative process that underlies clinical deterioration in PD remains unknown, it is well established that the dopaminergic innervation of specific striatal regions, like the postcommissural sensorimotor putamen, is more sensitive to degeneration than that of other striatal areas in both PD patients and animal models of parkinsonism (Kish et al., 1988, Brooks et al., 1990, Iravani et al., 2005). There is also clear evidence that striatal dopaminergic denervation precedes nigral neuronal loss (Bernheimer et al., 1973, Herkenham et al., 1991, Wu et al., 2003) suggesting that striatal dysfunction in dopamine transmission and, likely, MSNs spine pathology, are early steps towards nigrostriatal dopaminergic degeneration and death of nigral neurons in PD.

In this study, we took advantage of the progressive degenerative process induced by low doses of MPTP to assess the effects of partial or severe dopaminergic depletion on spine loss in MSNs of specific functional striatal sub-regions in monkeys. Furthermore, based on evidence that the striatum comprises two segregated populations of MSNs (Gerfen et al., 1990) that display a different degree of spine loss in rodent models of parkinsonism (Day et al., 2006), we performed a quantitative electron microscopic analysis of the density of striatal D1-immunoreactive and non-immunoreactive spines between normal and MPTP-treated monkeys.

Findings of these studies have been presented in abstract forms (Villalba et al., 2006, Villalba et al., 2007).

Section snippets

Animals and tissue preparation

In total, 6 control (one male and five females) and 6 MPTP-treated (one male and five females) juvenile (3–6 years old) Rhesus monkeys (Macaca mulatta) (Yerkes National Primate Research Center colony) were used in this study. The housing, feeding and experimental conditions used in these studies were in line with those of the National Institutes of Health guidelines and approved by Emory University Institutional Animal Care and use Committee.

Striatal spine loss in severely dopamine-depleted striatum

In a first series of experiments, striatal spine loss was examined in the dorsal striatum of four severely dopamine-depleted monkeys that displayed significant parkinsonian motor signs. The whole extent of the caudate nucleus and putamen of these animals was almost completely devoid of TH innervation (Figs. 1A, A′, B, B′). Only the nucleus accumbens showed significant immunoreactivity (Fig. 1A′). At the midbrain level, the ventral tier SNc was severely damaged, whereas a significant number of

Discussion

The present study provides further evidence for significant striatal spine pathology in parkinsonism. In line with recent human parkinsonian data (Zaja-Milatovic et al., 2005), a regional pattern of spine loss was found in the striatum of MPTP-treated monkeys. Neurons in the postcommissural sensorimotor putamen were significantly more affected than cognitive- and limbic-related striatal cells in the anterior putamen and caudate nucleus. Our findings also demonstrate that striatal spine loss is

Acknowledgments

The authors thank Dr. T. Wichmann for some of the MPTP-treated animals used in this study. This research was supported by NIH grant R01 NS 037948 to Y. Smith and the NIH base grant to the Yerkes National Primate Research Center (RR 00165).

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