Article

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

Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
European Journal of Neuroscience (Impact Factor: 3.67). 05/2008; 27(7):1647-58. DOI: 10.1111/j.1460-9568.2008.06136.x
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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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    • "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 · 2.87 Impact Factor
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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 · 2.84 Impact Factor
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    • "The real mechanisms underlying this increased excitatory drive remains unknown. Recently, the synaptic changes in both corticostriatal and thalamostriatal afferents have been studied in MPTP-treated monkeys taking as main markers the vesicular glutamate transporters (vGluTs) 1 and 2 (Raju et al. 2008). This study demonstrates the increased presence of vGluT1 in the striatum of MPTP monkeys without any significant change in the pattern of "
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    ABSTRACT: Activity-dependent modifications in synaptic efficacy, such as long-term depression (LTD) and long-term potentiation (LTP), represent key cellular substrates for adaptive motor control and procedural memory. The impairment of these two forms of synaptic plasticity in the nucleus striatum could account for the onset and the progression of motor and cognitive symptoms of Parkinson's disease (PD), characterized by the massive degeneration of dopaminergic neurons. In fact, both LTD and LTP are peculiarly controlled and modulated by dopaminergic transmission coming from nigrostriatal terminals. Changes in corticostriatal and nigrostriatal neuronal excitability may influence profoundly the threshold for the induction of synaptic plasticity, and changes in striatal synaptic transmission efficacy are supposed to play a role in the occurrence of PD symptoms. Understanding of these maladaptive forms of synaptic plasticity has mostly come from the analysis of experimental animal models of PD. A series of cellular and synaptic alterations occur in the striatum of experimental parkinsonism in response to the massive dopaminergic loss. In particular, dysfunctions in trafficking and subunit composition of glutamatergic NMDA receptors on striatal efferent neurons contribute to the clinical features of the experimental parkinsonism. Interestingly, it has become increasingly evident that in striatal spiny neurons, the correct assembly of NMDA receptor complex at the postsynaptic site is a major player in early phases of PD, and it is sensitive to distinct degrees of DA denervation. The molecular defects at the basis of PD progression may be not confined just at the postsynaptic neuron: accumulating evidences have recently shown that the genes linked to PD play a critical role at the presynaptic site. DA release into the synaptic cleft relies on a proper presynaptic vesicular transport; impairment of SV trafficking, modification of DA flow, and altered presynaptic plasticity have been described in several PD animal models. Furthermore, an impaired DA turnover has been described in presymptomatic PD patients. Thus, given the pathological events occurring precociously at the synapses of PD patients, post- and presynaptic sites may represent an adequate target for early therapeutic intervention.
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