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: 3.67). 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, Aug 25, 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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    • "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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    • "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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