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

Parkinson's disease (PD) is characterized by severe locomotor deficits due to the disappearance of dopamine (DA) from the dorsal striatum. The development of PD symptoms and treatment-related complications such as dyskinesia have been proposed to result from complex alterations in intracellular signaling in both direct and indirect pathway striatal projection neurons (dSPNs and iSPNs, respectively) following loss of DA afferents. To identify cell-specific and dynamical modifications of signaling pathways associated with PD, we used a hemiparkinsonian mouse model with 6-hydroxydopamine (6-OHDA) lesion combined with two-photon fluorescence biosensors imaging in adult corticostriatal slices. After DA lesion, extracellular signal-regulated kinase (ERK) activation was increased in response to DA D1 receptor (D1R) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) stimulation. The cAMP-dependent protein kinase (PKA) pathway contributing to ERK activation displayed supersensitive responses to D1R stimulation after 6-OHDA lesion. This cAMP/PKA supersensitivity was specific of D1R-responding SPNs and resulted from Gα_olf upregulation and deficient phosphodiesterase activity. In lesioned striatum, the number of D1R-SPNs with spontaneous Ca²⁺ transients augmented while Ca²⁺ response to AMPA receptor stimulation specifically increased in iSPNs. Our work reveals distinct cell type-specific signaling alterations in the striatum after DA denervation. It suggests that over-activation of ERK pathway, observed in PD striatum, known to contribute to dyskinesia, may be linked to the combined dysregulation of DA and glutamate signaling pathways in the two populations of SPNs. These findings bring new insights into the implication of these respective neuronal populations in PD motor symptoms and the occurrence of PD treatment complications.