Rebalance of Striatal NMDA/AMPA Receptor Ratio Underlies the Reduced Emergence of Dyskinesia During D2-Like Dopamine Agonist Treatment in Experimental Parkinson's Disease

Bagetta, Vincenza; Sgobio, Carmelo; Pendolino, Valentina; Papa, Giulia Del; Tozzi, Alessandro; Ghiglieri, Veronica; Giampà, Carmela; Zianni, Elisa; Gardoni, Fabrizio; Calabresi, Paolo; Picconi, Barbara

doi:10.1523/jneurosci.2664-12.2012

Cited by 68 publications

(58 citation statements)

References 62 publications

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“…However, using physiological recordings and dendritic reconstruction techniques, recent studies have revealed that iSPNs undergo profound structural-functional adaptations in LID models (38,45). Moreover, several studies have reported D2 agonist-induced dyskinesias in experimental models of PD (46)(47)(48). These considerations highlight the importance of testing the causality of dSPN and iSPN activity in the genesis of parkinsonian hypokinesia and dyskinesia.…”

Section: Discussionmentioning

confidence: 99%

Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy

Alcacer¹,

Andreoli²,

Sebastianutto³

et al. 2017

Journal of Clinical Investigation

121

115

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Section: Discussionmentioning

confidence: 99%

Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy

Alcacer¹,

Andreoli²,

Sebastianutto³

et al. 2017

Journal of Clinical Investigation

121

115

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“…Furthermore, treatment with L-DOPA did not reduce inwardrectifying AMPAR currents induced by 6-OHDA-lesion. However pramipexole, which was shown to have antiparkinsonian effects and be associated with reduced dyskinesia, could reverse the alteration of glutamatergic transmission as well as restore rectification values to control levels (Bagetta et al, 2012). Controlling the CP-AMPAR content of synapses may therefore be critical to treating striatal motor dysfunctions.…”

Section: Discussionmentioning

confidence: 99%

An Adaptive Role of TNFα in the Regulation of Striatal Synapses

et al. 2014

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Elevation of inflammatory cytokines in the striatum precedes symptoms in a number of motor dysfunctions, but it is unclear whether this is part of the disease process or an adaptive response to the pathology. In pyramidal cells, TNF␣ drives the insertion of AMPA-type glutamate receptors into synapses, and contributes to the homeostatic regulation of circuit activity in the developing neocortex. Here we demonstrate that in the mouse dorsolateral striatum, TNF␣ drives the internalization of AMPARs and reduces corticostriatal synaptic strength, dephosphorylates DARPP-32 and GluA1, and results in a preferential removal of Ca 2ϩ -permeable AMPARs. Striatal TNF␣ signaling appears to be adaptive in nature, as TNF␣ is upregulated in response to the prolonged blockade of D2 dopamine receptors and is necessary to reduce the expression of extrapyramidal symptoms induced by chronic haloperidol treatment. These data indicate that TNF␣ is a regulator of glutamatergic synaptic strength in the adult striatum in a manner distinct from its regulation of synapses on pyramidal cells and mediates an adaptive response during pathological conditions.

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“…Herein, we show that transplanted DA neurons are able to integrate into the host brain microcircuit, restoring corticostriatal synaptic plasticity in a highly reinnervated region. In experimental animal models, PD symptoms are linked to alterations in both LTP and LTD (25,26,35). Thus, the ability to restore corticostriatal synaptic plasticity could help determine the therapeutic potential of novel interventions, including cell transplants.…”

Section: Discussionmentioning

confidence: 99%

Region-specific restoration of striatal synaptic plasticity by dopamine grafts in experimental parkinsonism

Rylander

Bagetta

Pendolino

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Intrastriatal transplantation of dopaminergic neurons can restore striatal dopamine levels and improve parkinsonian deficits, but the mechanisms underlying these effects are poorly understood. Here, we show that transplants of dopamine neurons partially restore activity-dependent synaptic plasticity in the host striatal neurons. We evaluated synaptic plasticity in regions distal or proximal to the transplant (i.e., dorsolateral and ventrolateral striatum) and compared the effects of dopamine-and serotonin-enriched grafts using a rat model of Parkinson disease. Naïve rats showed comparable intrinsic membrane properties in the two subregions but distinct patterns of long-term synaptic plasticity. The ventrolateral striatum showed long-term potentiation using the same protocol that elicited long-term depression in the dorsolateral striatum. The long-term potentiation was linked to higher expression of postsynaptic AMPA and N2B NMDA subunits (GluN2B) and was dependent on the activation of GluN2A and GluN2B subunits and the D1 dopamine receptor. In both regions, the synaptic plasticity was abolished after a severe dopamine depletion and could not be restored by grafted serotonergic neurons. Solely, dopamineenriched grafts could restore the long-term potentiation and partially restore motor deficits in the rats. The restoration could only be seen close to the graft, in the ventrolateral striatum where the graft-derived reinnervation was denser, compared with the distal dorsolateral region. These data provide proof of concept that dopamine-enriched transplants are able to functionally integrate into the host brain and restore deficits in striatal synaptic plasticity after experimental parkinsonism. The region-specific restoration might impose limitations in symptomatic improvement following neural transplantation.onpharmacological dopamine (DA) replacement approaches to the therapy of Parkinson disease (PD) focus on the transplantation of DA-producing neurons into the striatum. Parkinson disease is indeed viewed as the disease of choice to develop intracerebral transplantation therapies, and promising results have been obtained both in experimental models and in some patients using embryonic DA neurons (1, 2). Embryonic DA neurons are able to innervate the host striatum, release DA, and reverse alterations in neuropeptide expression after a parkinsonian lesion (3). There is a continuous debate about whether these effects are sufficient for transplanted neurons to partially restore clinical symptoms or whether other underlying mechanisms also are required. In particular, a functional integration of the graft into the host microcircuits, with bidirectional synaptic contacts between the host and grafted neurons, may give superior therapeutic benefit than a mere neurochemical restoration. Transplanted DA neurons are able to form synapses with the surrounding striatal medium-sized spiny neurons (MSNs) (4) and receive innervation from the host neurons with bidirectional synaptic interactions (5-7). It is, however, unknown wh...

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Rebalance of Striatal NMDA/AMPA Receptor Ratio Underlies the Reduced Emergence of Dyskinesia During D2-Like Dopamine Agonist Treatment in Experimental Parkinson's Disease

Cited by 68 publications

References 62 publications

Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy

Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy

An Adaptive Role of TNFα in the Regulation of Striatal Synapses

Region-specific restoration of striatal synaptic plasticity by dopamine grafts in experimental parkinsonism

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