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

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

Circuit Mechanisms of L-DOPA-Induced Dyskinesia (LID)

“…In addition, the DAergic denervation in the dorsolateral striatum leads to a supersensitivity of DA receptors in the striatum, which strongly stimulates cAMP signaling pathway ( Park et al, 2014 ; Sancesario et al, 2014 ) and DA- and cAMP-regulated neuronal phosphoprotein (DARPP-32) pathway ( Guan et al, 2007 ; Santini et al, 2007 ). Other signaling cascades are also activated, including ERK kinase ( Fasano et al, 2010 ; Santini et al, 2010 ) and the mammalian target of rapamycin ( Santini et al, 2009 ; Calabrese et al, 2020 ). These pathways regulate gene transcription and protein synthesis, which contribute to LID generation (for review, see Spigolon and Fisone, 2018 ).…”

Experimental Dopamine Reuptake Inhibitors in Parkinson’s Disease: A Review of the Evidence

“…It may also suitable for a better future understanding of l-dopa-induced motor complications, such as dyskinesia. 44–46 MPTP-, α-synuclein- and Parkin animal models recapitulate the progressive loss of dopamine neurons, the involvement of cortical and subcortical regions and other aspects of disease progression, even those involving the mesocorticolimbic system. 47–49 These employed in vitro and in vivo PD models may mirror the slow progression of neuronal dying, which asks for continuous adaptation of dopamine substitution in the clinical practice of the maintenance of PD patients.…”

Current Knowledge on the Background, Pathophysiology, and Treatment of Levodopa-Induced Dyskinesia – Literature Review.

“…Activation of one pathway may affect the activity of other pathways. DARPP-32 signalling modulates ERK and mTORC1 pathways [46,47] Recent studies have closely examined the effect of D1R activation on ERK1/2 through interaction with the tyrosine phosphatase Shp-2. Not only has Shp-2 activation been shown to be a key factor for ERK1/2 and mTOR activation via phosphorylation and consequently for LID expression, but it has also been demonstrated that long-term stimulation with intermittent L-DOPA or D1R agonists leads to Shp-2 phosphorylation.…”

“…This effect can be counteracted by D1R antagonists, consequently influencing the levels of the D1R/Shp-2 pathway end products -p-mTOR and p-ERK1/2 [48]. Rapamycin was shown to selectively affect mTORC1 in the striatum without affecting either PKA/DARPP-32 and ERK pathways or the expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) and NMDA receptor subunits [47].…”