Differential synaptic plasticity of the corticostriatal and thalamostriatal systems in an MPTP-treated monkey model of parkinsonism. Eur J Neurosci

Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
European Journal of Neuroscience (Impact Factor: 3.18). 05/2008; 27(7):1647-58. DOI: 10.1111/j.1460-9568.2008.06136.x
Source: PubMed


Two cardinal features of Parkinson's disease (PD) pathophysiology are a loss of glutamatergic synapses paradoxically accompanied by an increased glutamatergic transmission to the striatum. The exact substrate of this increased glutamatergic drive remains unclear. The striatum receives glutamatergic inputs from the thalamus and the cerebral cortex. Using vesicular glutamate transporters (vGluTs) 1 and 2 as markers of the corticostriatal and thalamostriatal afferents, respectively, we examined changes in the synaptology and relative prevalence of striatal glutamatergic inputs in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys using electron microscopic immunoperoxidase and confocal immunofluorescence methods. Our findings demonstrate that the prevalence of vGluT1-containing terminals is significantly increased in the striatum of MPTP-treated monkeys (51.9 +/- 3.5% to 66.5 +/- 3.4% total glutamatergic boutons), without any significant change in the pattern of synaptic connectivity; more than 95% of vGluT1-immunolabeled terminals formed axo-spinous synapses in both conditions. In contrast, the prevalence of vGluT2-immunoreactive terminals did not change after MPTP treatment (21.7 +/- 1.3% vs. 21.6 +/- 1.2% total glutamatergic boutons). However, a substantial increase in the ratio of axo-spinous to axo-dendritic synapses formed by vGluT2-immunoreactive terminals was found in the pre-caudate and post-putamen striatal regions of MPTP-treated monkeys, suggesting a certain degree of synaptic reorganization of the thalamostriatal system in parkinsonism. About 20% of putative glutamatergic terminals did not show immunoreactivity in striatal tissue immunostained for both vGluT1 and vGluT2, suggesting the expression of another vGluT in these boutons. These findings provide striking evidence that suggests a differential degree of plasticity of the corticostriatal and thalamostriatal system in PD.

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Available from: Todd H Ahern
    • "Several studies reported alterations in the different glutamate transporters (vesicular and non-vesicular) in a parkinsonian state (Chung et al., 2008; Favier et al., 2013; Holmer et al., 2005; Kashani et al., 2007; Liévens et al., 2001; Massie et al., 2008, 2010a, 2010b, 2011; Raju et al., 2008; Robelet et al., 2004; Yang et al., 2005). However, the bulk of these studies are performed in the striatum of unilaterallylesioned animals while research in the motor cortex is rare. "
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    ABSTRACT: Parkinson's disease (PD) is hallmarked by progressive degeneration of the substantia nigra pars compacta (SNc) neurons and is associated with aberrant glutamatergic activity. However, studies on the glutamatergic system in the motor cortex and striatum, two motor loop-related areas, are lacking in the clinically relevant bilateral SNc 6-hydroxydopamine (6-OHDA) rat model, and therefore led to the rationale behind the present investigations. Using Western blotting, the expression levels of the glial glutamate transporters, GLT-1 and GLAST, as well as xCT, the specific subunit of system xc(-), and the vesicular glutamate transporters, VGLUT1 and 2 were investigated at two different time points (1 week and 2 weeks) post-lesion. In addition, the total content of glutamate was measured. Moreover, the total D-serine levels were, to the best of our knowledge, studied for the first time in these two PD-related areas in the bilateral 6-OHDA rat model. In the motor cortex, no significant changes were observed in the different glutamate transporter expression levels in the bilaterally-lesioned rats. In the striatum, GLAST expression was significantly decreased at both time points whereas VGLUT1 and 2 expressions were significantly decreased 2 weeks after bilateral 6-OHDA lesion. Interestingly, bilateral 6-OHDA SNc lesion resulted in an enhancement of the total D-serine content in both motor cortex and striatum at 1 week post-lesion suggesting its possible involvement in the pathophysiology of PD. In conclusion, this study demonstrates disturbed glutamate and D-serine regulation in the bilateral SNc-lesioned brain which could contribute to the behavioural impairments in PD. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Jul 2015 · Neurochemistry International
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    • "A striking observation of the study is that asymmetric excitatory cortico-or thalamo-striatal synapses decrease in 6-OHDA rats compared with controls (Figure 4C), a result in agreement with literature in the 6-OHDA rat (Ingham et al., 1989; Day et al., 2006; Scholz et al., 2008; Schuster et al., 2009; Donnelly et al., 2013; Suárez et al., 2014) and in the MPTP-treated macaque monkey (Villalba and Smith, 2011). Further investigations of vGLUT1 and vGLUT2-labeling of asymmetric synapses would help defining if the cortico-striatal or thalamo-striatal pathways, respectively (Raju et al., 2008), are affected comparably or differentially by an increased apposition of GLT1+ astrocyte feets. "
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    ABSTRACT: The current concept of basal ganglia organization and function in physiological and pathophysiological conditions excludes the most numerous cells in the brain, i.e., the astrocytes, present with a ratio of 10:1 neuron. Their role in neurodegenerative condition such as Parkinson's disease (PD) remains to be elucidated. Before embarking into physiological investigations of the yet-to-be-identified "tripartite" synapses in the basal ganglia in general and the striatum in particular, we therefore characterized anatomically the PD-related modifications in astrocytic morphology, the changes in astrocytic network connections and the consequences on the spatial relationship between astrocytic processes and asymmetric synapses in normal and PD-like conditions in experimental and human PD. Our results unravel a dramatic regulation of striatal astrocytosis supporting the hypothesis of a key role in (dys) regulating corticostriatal transmission. Astrocytes and their various properties might thus represent a therapeutic target in PD.
    Full-text · Article · Sep 2014 · Frontiers in Aging Neuroscience
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    • "Growing body of evidence indicates that, in particular for glutamatergic neurotransmission, significant changes occur during the progression of the disease. Changes in the levels of glutamate transporters (Salvatore et al. 2012; Raju et al. 2008), as well as in the subunit composition and phosphorylation pattern of NMDARs (Dunah et al. 2000), were observed in the basal ganglia of different animal models of PD; these changes varied according to the degree of striatal denervation and loss of endogenous dopamine. Both in animal models of PD (Picconi et al. 2012; Gao et al. 2013) and in the brains of PD patients (di Michele et al. 2013), loss of nigral dopaminergic neurons and striatal dopamine depletion locally affect the balance between excitatory and inhibitory neurotransmitters and synaptic plasticity (Fig. 1). "
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    ABSTRACT: Increased levels of extracellular glutamate and hyperactivation of glutamatergic receptors in the basal ganglia trigger a critical cascade of events involving both intracellular pathways and cell-to-cell interactions that affect cell viability and promote neuronal death. The ensemble of these glutamate-triggered events is responsible for excitotoxicity, a phenomenon involved in several pathological conditions affecting the central nervous system, including a neurodegenerative disease such as Parkinson's disease (PD). PD is an age-related disorder caused by the degeneration of dopaminergic neurons within the substantia nigra pars compacta, with a miscellaneous pathogenic background. Glutamate-mediated excitotoxicity may be involved in a lethal vicious cycle, which critically contributes to the exacerbation of nigrostriatal degeneration in PD. Since excitotoxicity is a glutamate-receptor-mediated phenomenon, growing interest and work have been dedicated to the research for modulators of glutamate neurotransmission that might enable new therapeutic interventions to slow down the neurodegenerative process and ameliorate PD motor symptoms.
    Full-text · Article · Aug 2014 · Journal of Neural Transmission
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