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

ABSTRACT 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, Sep 27, 2015
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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.
    Frontiers in Aging Neuroscience 09/2014; 6:258. DOI:10.3389/fnagi.2014.00258 · 4.00 Impact Factor
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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.
    Journal of Neural Transmission 08/2014; 121(8). DOI:10.1007/s00702-013-1149-z · 2.40 Impact Factor
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    • "In rodents, the principal synaptic target of most non-CM/Pf thalamostriatal projections are dendritic spines of striatal medium spiny neurons (MSNs), a pattern of synaptic connectivity similar to the corticostriatal system (Kemp and Powell, 1971; Dube et al., 1988; Xu et al., 1991; Raju et al., 2006; Lacey et al., 2007; Figures 1, 2). In contrast, striatal afferents from CM/Pf (or Pf in rodents) establish asymmetric synapses principally with dendritic shafts of MSNs (Dube et al., 1988; Sadikot et al., 1992b; Smith et al., 1994; Sidibe and Smith, 1996; Raju et al., 2006, 2008; Lacey et al., 2007) and several types of striatal interneurons including cholinergic interneurons (Meredith and Wouterlood, 1990; Lapper and Bolam, 1992; Sidibe and Smith, 1999) and parvalbumin-positive GABA interneurons (Rudkin and Sadikot, 1999; Sidibe and Smith, 1999; Figure 1). Overall, 70–90% of CM/Pf (or Pf) terminals form axo-dendritic synapses in the rat and monkey striatum (Dube et al., 1988; Sadikot et al., 1992b; Raju et al., 2006; Lacey et al., 2007). "
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    ABSTRACT: Because of our limited knowledge of the functional role of the thalamostriatal system, this massive network is often ignored in models of the pathophysiology of brain disorders of basal ganglia origin, such as Parkinson's disease (PD). However, over the past decade, significant advances have led to a deeper understanding of the anatomical, electrophysiological, behavioral and pathological aspects of the thalamostriatal system. The cloning of the vesicular glutamate transporters 1 and 2 (vGluT1 and vGluT2) has provided powerful tools to differentiate thalamostriatal from corticostriatal glutamatergic terminals, allowing us to carry out comparative studies of the synaptology and plasticity of these two systems in normal and pathological conditions. Findings from these studies have led to the recognition of two thalamostriatal systems, based on their differential origin from the caudal intralaminar nuclear group, the center median/parafascicular (CM/Pf) complex, or other thalamic nuclei. The recent use of optogenetic methods supports this model of the organization of the thalamostriatal systems, showing differences in functionality and glutamate receptor localization at thalamostriatal synapses from Pf and other thalamic nuclei. At the functional level, evidence largely gathered from thalamic recordings in awake monkeys strongly suggests that the thalamostriatal system from the CM/Pf is involved in regulating alertness and switching behaviors. Importantly, there is evidence that the caudal intralaminar nuclei and their axonal projections to the striatum partly degenerate in PD and that CM/Pf deep brain stimulation (DBS) may be therapeutically useful in several movement disorders.
    Frontiers in Systems Neuroscience 01/2014; 8:5. DOI:10.3389/fnsys.2014.00005
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