Rapamycin, by Inhibiting mTORC1 Signaling, Prevents the Loss of Striatal Bidirectional Synaptic Plasticity in a Rat Model of L-DOPA-Induced Dyskinesia.

Valeria Calabrese,Federica Campanelli,Arianna De Rosa,Paolo Calabresi,Luigi Avallone,Giuseppina Natale,Alessandro Usiello,Anna Di Maio,Gioia Marino,Maria Mancini,Antonella Cardinale,Barbara Picconi,Veronica Ghiglieri,Francesco Napolitano

doi:10.3389/fnagi.2020.00230

Abstract

Levodopa (L-DOPA) treatment is the main gold-standard therapy for Parkinson disease (PD). Besides good antiparkinsonian effects, prolonged use of this drug is associated to the development of involuntary movements known as L-DOPA-induced dyskinesia (LID). L-DOPA-induced dyskinesia is linked to a sensitization of dopamine (DA) D1 receptors located on spiny projection neurons (SPNs) of the dorsal striatum. Several evidences have shown that the emergence of LID can be related to striatal D1/cAMP/PKA/DARPP-32 and extracellular signal-regulated kinases (ERK1/2) pathway overactivation associated to aberrant N-methyl-d-aspartate (NMDA) receptor function. In addition, within striatum, ERK1/2 is also able to modulate in a D1 receptor-dependent manner the activity of the mammalian target of rapamycin complex 1 (mTORC1) pathway under DA depletion and L-DOPA therapy. Consistently, increased mTORC1 signaling appears during chronic administration of L-DOPA and shows a high correlation with the severity of dyskinesia. Furthermore, the abnormal activation of the D1/PKA/DARPP-32 cascade is paralleled by increased phosphorylation of the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor at the PKA Ser845 site. The GluA1 promotes excitatory AMPA receptor-mediated transmission and may be implicated in the alterations found at the corticostriatal synapses of dyskinetic animals. In our study, we investigated the role of mTORC1 pathway activation in modulating bidirectional striatal synaptic plasticity in L-DOPA-treated parkinsonian rats. Inhibition of mTORC1 by coadministration of rapamycin to L-DOPA was able to limit the magnitude of LID expression, accounting for a therapeutic effect of this drug. In particular, behavioral data showed that, in L-DOPA-treated rats, rapamycin administration induced a selective decrease of distinct components of abnormal involuntary movements (i.e., axial and orolingual dyskinesia). Furthermore, ex vivo patch clamp and intracellular recordings of SPNs revealed that pharmacological inhibition of mTORC1 also resulted associated with a physiological bidirectional plasticity, when compared to dyskinetic rats treated with L-DOPA alone. This study uncovers the important role of mTORC1 inhibition to prevent the loss of striatal bidirectional plasticity under chronic L-DOPA treatment in rodent models of PD.

Highlights

Parkinson disease (PD) is a progressive neurodegenerative disorder, in which the severe degeneration of substantia nigra pars compacta (SNc) neurons results in the denervation of dopaminergic afferents in the striatum, the main target of nigral fibers (Braak et al, 2003; Wirdefeldt et al, 2011; Postuma et al, 2015)
The 6-OHDA lesions in the MFB region of rat brains led to a complete dopaminergic cell loss in the regions of SNc (>90%) and greater than 70% of TH+ cell loss in ventral tegmental area (VTA) (Figure 1C, left panel) of both treated groups (L-DOPA alone vs. rapamycin + L-DOPA; Figure 1C, right panel)
Here we demonstrated that abnormal striatal mTORC1 pathway activation by chronic L-DOPA is a causal factor to the loss of synaptic depotentiation in spiny projection neurons (SPNs) of parkinsonian rats

Summary

Introduction

Parkinson disease (PD) is a progressive neurodegenerative disorder, in which the severe degeneration of substantia nigra pars compacta (SNc) neurons results in the denervation of dopaminergic afferents in the striatum, the main target of nigral fibers (Braak et al, 2003; Wirdefeldt et al, 2011; Postuma et al, 2015). The synaptic efficiency is expressed by the ability of striatal spiny projection neurons (SPNs) to respond to a given stimulation with a long-term potentiation (LTP) or a long-term depression (Calabresi et al, 1992, 2000a; Malenka and Bear, 2004) Dysfunctions in these two forms of synaptic plasticity or the loss of synaptic downscaling well correlates with impaired control of voluntary movements (Calabresi et al, 2016)

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Results

Conclusion