Distinct Levels of Dopamine Denervation Differentially Alter Striatal Synaptic Plasticity and NMDA Receptor Subunit Composition

Paillé, Vincent; Picconi, Barbara; Bagetta, Vincenza; Ghiglieri, Veronica; Sgobio, Carmelo; Filippo, Massimiliano Di; Viscomi, Maria Teresa; Giampà, Carmela; Fusco, Francesca R.; Gardoni, Fabrizio; Bernardi, Giorgio; Greengard, Paul; Luca, Monica Di; Calabresi, Paolo

doi:10.1523/jneurosci.2149-10.2010

Cited by 156 publications

(158 citation statements)

References 52 publications

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“…Too early as well as too late interventions might prove detrimental on plasticity: on the one hand, it has been recently shown that inhibition of ␣5-GABA A receptors or very early mobilization therapy, performed within 24 h after stroke, is rather detrimental (Clarkson et al, 2010;Bernhardt et al, 2015). On the other hand, too delayed interventions, such as rehabilitation, is also less effectual in promoting recovery (Paolucci et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

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Neural Stem Cell Transplantation Induces Stroke Recovery by Upregulating Glutamate Transporter GLT-1 in Astrocytes

et al. 2016

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Ischemic stroke is the leading cause of disability, but effective therapies are currently widely lacking. Recovery from stroke is very much dependent on the possibility to develop treatments able to both halt the neurodegenerative process as well as to foster adaptive tissue plasticity. Here we show that ischemic mice treated with neural precursor cell (NPC) transplantation had on neurophysiological analysis, early after treatment, reduced presynaptic release of glutamate within the ipsilesional corticospinal tract (CST), and an enhanced NMDAmediated excitatory transmission in the contralesional CST. Concurrently, NPC-treated mice displayed a reduced CST degeneration, increased axonal rewiring, and augmented dendritic arborization, resulting in long-term functional amelioration persisting up to 60 d after ischemia. The enhanced functional and structural plasticity relied on the capacity of transplanted NPCs to localize in the periischemic and ischemic area, to promote the upregulation of the glial glutamate transporter 1 (GLT-1) on astrocytes and to reduce peri-ischemic extracellular glutamate. The upregulation of GLT-1 induced by transplanted NPCs was found to rely on the secretion of VEGF by NPCs. Blocking VEGF during the first week after stroke reduced GLT-1 upregulation as well as long-term behavioral recovery in NPC-treated mice. Our results show that NPC transplantation, by modulating the excitatory-inhibitory balance and stroke microenvironment, is a promising therapy to ameliorate disability, to promote tissue recovery and plasticity processes after stroke.

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Section: Discussionmentioning

confidence: 99%

“…NMDA EPSC component was identified by using the kinetic method, considering the peak amplitude at 50 ms after the beginning of the event. The NMDAR/AMPAR ratio was calculated by dividing the NMDAR peak by the AMPAR peak (Paillé et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

Neural Stem Cell Transplantation Induces Stroke Recovery by Upregulating Glutamate Transporter GLT-1 in Astrocytes

et al. 2016

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“…In particular, subcellular redistribution of NR2A and NR2B subunits of NMDA receptor, leading to an increased NR2A/NR2B ratio at synaptic sites, is a key element in the complex modifications of glutamatergic synapses which occur both in experimental parkinsonism and in L-DOPA induced dyskinesia (Gardoni et al, 2006;Picconi et al, 2004). Normalization of NR2A subunit localization at synapses in a rat model of early Parkinson's disease is sufficient to improve motor behavior and to rescue corticostriatal synaptic plasticity (Paillé et al, 2010). Here we show that rasagiline can directly modulate NMDA receptor composition at synapse and, consequently, its function, by decreasing NR2A at synaptic sites.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, MAO-B inhibitors have been shown to partially protect neurons against overactivation of NMDA receptors without interfering with their physiological function (Niittykoski et al, 2003). This is intriguing since NMDA receptor is altered in experimental parkinsonism (Dunah and Standaert, 2001;Paillé et al, 2010), during development of L-DOPA induced dyskinesia (Gardoni et al, 2006) and in patients (Calon et al, 2003). In addition, synaptic localization of NMDA receptor subunits, namely NR2A and NR2B, and their functional interactions with scaffolding elements of the PSD-MAGUK protein family have been shown to be crucial to the pathogenesis of Parkinson's disease and to the development of L-DOPA induced dyskinesia (Gardoni et al, 2006;Picconi et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, synaptic localization of NMDA receptor subunits, namely NR2A and NR2B, and their functional interactions with scaffolding elements of the PSD-MAGUK protein family have been shown to be crucial to the pathogenesis of Parkinson's disease and to the development of L-DOPA induced dyskinesia (Gardoni et al, 2006;Picconi et al, 2004). In a rat model of early Parkinson's disease, normalization of the aberrant synaptic localization of NR2A subunits rescued the motor symptoms (Paillé et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Effect of rasagiline on the molecular composition of the excitatory postsynaptic density

Gardoni

Zianni

Eramo

et al. 2011

European Journal of Pharmacology

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In the last decade, several neuroprotective therapies have been proposed for Parkinson's disease and rasagiline was indicated as one of the most promising candidates by preclinical studies. The drug has already been tested in phase III clinical studies (the ADAGIO study). The mechanism underlying rasagiline-dependent neuroprotection is complex and almost unknown. Here, we show that rasagiline is involved in the regulation of the molecular composition of the postsynaptic density of glutamatergic synapses. In hippocampus as well as in striatum, rasagiline induces a significant reduction of synaptic levels of NR2A-containing NMDA receptors and in hippocampal slices it also significantly decreases synaptic levels of GluR1-containing AMPA receptors. This capability of rasagiline to modulate ionotropic glutamate receptors composition at synaptic sites strengthens the rationale for its clinical use to slow the progression of Parkinson's disease.

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Synaptic Changes in Parkinson Disease Assessed with in vivo Imaging

Matuskey

Tinaz

Wilcox

et al. 2020

Annals of Neurology

121

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Objective Parkinson disease is characterized by motor and nonmotor symptoms, reduced striatal dopamine signaling, and loss of dopamine neurons in the substantia nigra. It is now known that the pathological process in Parkinson disease may begin decades before the clinical diagnosis and include a variety of neuronal alterations in addition to the dopamine system. Methods This study examined the density of all synapses with synaptic vesicle glycoprotein 2A (SV2A) in Parkinson disease subjects with mild bilateral disease (n = 12) and matched normal controls (n = 12) using in vivo high‐resolution positron emission tomographic imaging as well as postmortem autoradiography in an independent sample with Parkinson disease (n = 15) and normal controls (n = 13) in the substantia nigra and putamen. Results A group‐by‐brain region interaction effect (F10, 22 = 3.52, p = 0.007) was observed in the primary brain areas with in vivo SV2A binding. Post hoc analyses revealed that the Parkinson disease group exhibited lower SV2A in the substantia nigra (−45%; p < 0.001), red nucleus (−31%; p = 0.03), and locus coeruleus (−17%; p = 0.03). Exploratory analyses also revealed lower SV2A binding in clinically relevant cortical areas. Using autoradiography, we confirmed lower SV2A in the substantia nigra (−17%; p < 0.005) and nonsignificant findings in the putamen (−4%; p = 0.06). Interpretation This work provides the first evidence of synaptic loss in brainstem nuclei involved in the pathogenesis of Parkinson disease in living patients. SV2A imaging holds promise for understanding synaptic changes central to the disease. Ann Neurol 2020;87:329–338

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Distinct Levels of Dopamine Denervation Differentially Alter Striatal Synaptic Plasticity and NMDA Receptor Subunit Composition

Cited by 156 publications

References 52 publications

Neural Stem Cell Transplantation Induces Stroke Recovery by Upregulating Glutamate Transporter GLT-1 in Astrocytes

Neural Stem Cell Transplantation Induces Stroke Recovery by Upregulating Glutamate Transporter GLT-1 in Astrocytes

Effect of rasagiline on the molecular composition of the excitatory postsynaptic density

Synaptic Changes in Parkinson Disease Assessed with in vivo Imaging

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