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

Levodopa (L-DOPA) treatment is the main gold-standard therapy for Parkinson’s 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). LID is linked to a sensitization of dopami...

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Published in:Frontiers in aging neuroscience Vol. 12; p. 230
Main Authors: Calabrese, Valeria, Di Maio, Anna, Marino, Gioia, Cardinale, Antonella, Natale, Giuseppina, De Rosa, Arianna, Campanelli, Federica, Mancini, Maria, Napolitano, Francesco, Avallone, Luigi, Calabresi, Paolo, Usiello, Alessandro, Ghiglieri, Veronica, Picconi, Barbara
Format: Journal Article
Language:English
Published: Lausanne Frontiers Research Foundation 11.08.2020
Frontiers Media S.A
Subjects:
Aging
Animal models
Basal ganglia
Behavior
Behavioral plasticity
Caudate-putamen
Central nervous system diseases
DARPP-32 protein
depotentiation
Dihydroxyphenylalanine
Dopamine D1 receptors
dorsolateral striatum
Dyskinesia
Experiments
Extracellular signal-regulated kinase
functional plasticity
Glutamate receptors
Glutamic acid receptors (ionotropic)
Kinases
Laboratories
Levodopa
levodopa-induced dyskinesia
Movement disorders
N-Methyl-D-aspartic acid receptors
Neostriatum
Neurodegenerative diseases
Neuroscience
Neurosciences
Older people
Parkinson's disease
Phosphorylation
Protein kinase A
Proteins
Rapamycin
Rodents
Signal transduction
Surgery
Synapses
Synaptic plasticity
TOR protein
α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
ISSN:1663-4365, 1663-4365
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Summary:Levodopa (L-DOPA) treatment is the main gold-standard therapy for Parkinson’s 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). LID 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 D1R-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 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 co-administration 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 to 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.
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These authors have contributed equally to this work
Edited by: Nicola Simola, University of Cagliari, Italy
Reviewed by: Denis Hervé, Institut National de la Santé et de la Recherche Médicale (INSERM), France; Karima Chergui, Karolinska Institutet (KI), Sweden; Charles K. Meshul, VA Medical Center/Portland, United States
ISSN:1663-4365
1663-4365
DOI:10.3389/fnagi.2020.00230