Objective: To identify cell-specific and dynamical modifications of signaling pathways associated with PD and drug-induced modifications

Background: Parkinson’s disease (PD) is characterized by severe locomotor deficits due to the disappearance of dopamine (DA) from the dorsal striatum. Among the mechanisms underlying the development of PD symptoms and treatment-related complications such as dyskinesia, complex alterations in intracellular signaling in both direct and indirect pathway striatal projection neurons (dSPN and iSPN) have been proposed following loss of DA neurons.However the dynamics and cell type specificity of signaling alterations in SPNs resulting from the chronic absence of DA are still poorly characterized, hampering the understanding of their pathophysiological consequences

Method: An experimental model combining the hemiparkinsonian mouse (6-hydroxydopamine (6-OHDA) lesion) model with two-photon fluorescence biosensors imaging (such as EKAR, AKAR and GCaMP6S) in adult corticostriatal slices was used.

Results: We showed that after DA lesion, extracellular signal-regulated kinase (ERK) activation is increased in response to DA D1 receptors (D1R) and/or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) stimulation. We also described that upstream pathway of ERK like cAMP/protein kinase cAMP-dependent (PKA) pathway presented surpersensitive responses to D1R stimulation after 6-OHDA lesion. This cAMP/PKA activation was specific of dSPN and amplified by augmented Gαolf signaling and deficient phosphodiesterase activity. We also described that Ca2+ signaling induced by stimulation of AMPAR was increased specifically in iSPN after DA lesion.

Conclusion: Our work reveals distinct cell type-specific signaling alterations in the striatum after DA denervation. It suggests that over-activation of ERK pathway by DA observed in PD, which is known to be leading to dyskinesia, may be linked to the combined dysregulation of DA and glutamate signaling pathway in the two populations of SPNs. These results suggest that complications in the PD treatments at late stages may be linked to the inability to appropriately regularize both DA and glutamate responses in dSPNs and iSPNs. These findings bring new insights into the implication of these respective neuronal populations in PD and the occurrence of PD treatment complications.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/differential-enhancement-of-erk-pka-and-ca2-signaling-in-direct-and-indirect-striatal-neurons-of-parkinsonian-mice/