Differential enhancement of ERK, PKA and Ca2+ signaling in direct and indirect striatal neurons of Parkinsonian mice

Mariani, Louise‐Laure; Longueville, Sophie; Girault, Jean‐Antoine; Hervé, Denis; Gervasi, Nicolas

doi:10.1016/j.nbd.2019.104506

Cited by 13 publications

(8 citation statements)

References 84 publications

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“…These disparities on MAPK phosphorylation status might indicate that the R-isomer might partially bind to the dopamine receptors. It has indeed been reported that the activation of dopaminergic receptors leads to the activation of MAPK pathway by especially increasing ERK phosphorylation (Li et al 2006;Cahill et al 2014;Mariani et al 2019;Wang et al 2020) resulting in a subsequent STAT1 phosphorylation (Kim et al 2002;Tichauer et al 2007;Song et al 2017). The differential MAPK and JAK-STAT signaling pathways responses seem then to be independent of the recruitment of the NRF2 transcription factor.…”

Section: Discussionmentioning

confidence: 94%

Apomorphine Reduces A53T α-Synuclein-Induced Microglial Reactivity Through Activation of NRF2 Signalling Pathway

et al. 2021

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The chiral molecule, apomorphine, is currently used for the treatment of Parkinson’s disease (PD). As a potent dopamine receptor agonist, this lipophilic compound is especially effective for treating motor fluctuations in advanced PD patients. In addition to its receptor-mediated actions, apomorphine has also antioxidant and free radical scavenger activities. Neuroinflammation, oxidative stress, and microglia reactivity have emerged as central players in PD. Thus, modulating microglia activation in PD may be a valid therapeutic strategy. We previously reported that murine microglia are strongly activated upon exposure to A53T mutant α-synuclein. The present study was designed to investigate whether apomorphine enantiomers could modulate this A53T-induced microglial activation. Taken together, the results provided evidence that apomorphine enantiomers decrease A53T-induced microgliosis, through the activation of the NRF2 signalling pathway, leading to a lower pro-inflammatory state and restoring the phagocytic activity. Suppressing NRF2 recruitment (trigonelline exposure) or silencing specifically Nfe2l2 gene (siRNA treatment) abolished or strongly decreased the anti-inflammatory activity of apomorphine. In conclusion, apomorphine, which is already used in PD patients to mimic dopamine activity, may also be suitable to decrease α-synuclein-induced microglial reactivity.

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Section: Discussionmentioning

confidence: 94%

Apomorphine Reduces A53T α-Synuclein-Induced Microglial Reactivity Through Activation of NRF2 Signalling Pathway

et al. 2021

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“…A chronic regimen of l-DOPA/benserazide that induced dyskinesia also resulted in attenuation of this enhanced signalling, even though D1R-associated dyskinesia was significantly increased. The occurrence of D1R supersensitivity is well established in 6-OHDA lesioned rats (reviewed in 57,58 ), and a recent study using FRET-based biosensors has demonstrated hyperactivation of PKA and ERK1/2 by D1R agonists in striatal slices taken from 6-OHDA lesioned mice 59 . The present in vivo study extends these findings, by showing that acute D1R-induced PKA and ERK1/2 activation are downregulated by repeated l-DOPA treatment, suggesting that while D1R signalling may be reduced by chronic l-DOPA treatment, the D1R-driven dyskinesia nevertheless increases.…”

Section: Discussionmentioning

confidence: 99%

Dopamine D1 receptor signalling in dyskinetic Parkinsonian rats revealed by fiber photometry using FRET-based biosensors

Jones-Tabah

Mohammad

Hadj-Youssef

et al. 2020

Sci Rep

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As with many G protein-coupled receptors (GPCRs), the signalling pathways regulated by the dopamine D1 receptor (D1R) are dynamic, cell type-specific, and can change in the face of disease or drug exposures. In striatal neurons, the D1R activates cAMP/protein kinase A (PKA) signalling. However, in Parkinson's disease (PD), alterations in this pathway lead to functional upregulation of extracellular regulated kinases 1/2 (ERK1/2), contributing to l-DOPA-induced dyskinesia (LID). In order to detect D1R activation in vivo and to study the progressive dysregulation of D1R signalling in PD and LID, we developed ratiometric fiber-photometry with Förster resonance energy transfer (FRET) biosensors and optically detected PKA and ERK1/2 signalling in freely moving rats. We show that in Parkinsonian animals, D1R signalling through PKA and ERK1/2 is sensitized, but that following chronic treatment with l-DOPA, these pathways become partially desensitized while concurrently D1R activation leads to greater induction of dyskinesia. G protein-coupled receptors (GPCRs) play pivotal roles in mediating neuronal communication in the brain. In fact, 90% of non-olfactory GPCRs are found in the brain 1 , where they regulate neuronal activity by engaging a variety of distal downstream effectors which include second messenger producing enzymes, ion channels, monomeric GTPases and protein kinases. Many GPCRs are pharmacologically targeted in the treatment of neurodegenerative and neuropsychiatric disease. Thus it is critical to understand how these receptors regulate intracellular signalling, and how this in turn regulates circuit function and ultimately, behavior. In cell culture models, these signalling pathways have been dissected extensively, through the use of genetically-encoded fluorescent and bioluminescent biosensors. Some of these biosensors have recently been used in the in vivo context, to link specific signalling patterns with behavioral outcomes 2-6. Many intracellular signalling biosensors utilize changes in Förster resonance energy transfer (FRET) between two fluorescent proteins 7 to report levels or activity of second messengers, protein kinases, GTPases, posttranslational modifications and protein-protein interactions 8-11. These tools have been widely used to dissect signaling pathways in cultured cells and have recently begun to be applied in vivo, aided by recent technological developments in intravital imaging 10,12 , microendoscopy 3 , 2-photon microscopy 13-15 and fluorescence lifetime measurement 16. Here we report a ratiometric fiber-photometry approach for real-time recording of geneticallyencoded FRET biosensors in freely moving rodents. We apply this approach to investigate alterations in striatal GPCR signalling in a rat model of Parkinson's disease and l-DOPA induced dyskinesia. The dopamine D1 receptor (D1R) is a Gα s/olf coupled GPCR expressed throughout the forebrain. As for many GPCRs, several factors can impact D1R signalling, including the properties of specific ligands, the cellular context, interac...

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“…A chronic regimen of L-DOPA/benserazide that induced dyskinesia also resulted in attenuation of this enhanced signalling, even though D1R-associated dyskinesia was significantly increased. The occurrence of D1R supersensitivity is well established in 6-OHDA lesioned rats [reviewed in 50,51 ], and a recent study using FRET-based biosensors has demonstrated hyperactivation of PKA and ERK1/2 by D1R agonists in striatal slices taken from 6-OHDA lesioned mice 52 . The present in vivo study extends these ex vivo findings, by showing that acute D1R-induced PKA and ERK1/2 activation is suppressed by repeated L-DOPA treatment, suggesting that while D1R signalling may be desensitized by chronic L-DOPA treatment, the D1R-driven dyskinesia nevertheless increases.…”

Section: Discussionmentioning

confidence: 99%

Dopamine D1 receptor signalling in dyskinetic Parkinsonian rats revealed by fiber photometry using FRET-based biosensors

Jones-Tabah¹,

Mohammad²,

Hadj-Youssef³

et al. 2020

Preprint

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Like many G protein-coupled receptors (GPCRs), the signalling pathways regulated by the dopamine D1 receptor (D1R) are dynamic, cell-type specific, and can change in response to disease or drug exposures. In striatal neurons, the D1R activates cAMP/protein kinase A (PKA) signalling. However, in Parkinson’s disease (PD), alterations in this pathway lead to activation of extracellular regulated kinases (ERK1/2), contributing to L-DOPA-induced dyskinesia (LID). In order to detect D1R activation in vivo and to study the progressive dysregulation of D1R signalling in PD and LID, we developed ratiometric fiber-photometry with Förster resonance energy transfer (FRET) biosensors and optically detected PKA and ERK1/2 signalling in freely moving rats. We show that in Parkinsonian animals, D1R signalling through PKA and ERK1/2 is sensitized, but that following chronic treatment with L-DOPA, these pathways become partially desensitized while concurrently D1R activation leads to greater induction of dyskinesia.

show abstract

Differential enhancement of ERK, PKA and Ca2+ signaling in direct and indirect striatal neurons of Parkinsonian mice

Cited by 13 publications

References 84 publications

Apomorphine Reduces A53T α-Synuclein-Induced Microglial Reactivity Through Activation of NRF2 Signalling Pathway

Apomorphine Reduces A53T α-Synuclein-Induced Microglial Reactivity Through Activation of NRF2 Signalling Pathway

Dopamine D1 receptor signalling in dyskinetic Parkinsonian rats revealed by fiber photometry using FRET-based biosensors

Dopamine D1 receptor signalling in dyskinetic Parkinsonian rats revealed by fiber photometry using FRET-based biosensors

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