D1R-PKA signaling activation in PFC mediated by GDNF facilitates depression remission in Parkinson's disease

Abstract

Abstract Depression is one of the most common non-motor symptoms of Parkinson's disease (PD), which can cause a severe decline in the quality of life of PD patients. Dopamine receptors (DRs) expressed in glutamatergic pyramidal cells in the medial prefrontal cortex (mPFC) shape the local field activity, contributing to behavioral and mood disorders regulation. Studies have demonstrated that the Glial cell-derived neurotrophic factor (GDNF) has a potential antidepressant effect. However, PD has yet to report the anti-depression consequences of GDNF positioning injection into mPFC on DRs. Here, we reported exogenous GDNF injection to mPFC, resulting in up-regulation of D1 dopamine receptor (D1R) protein levels, and found that activating the PKA pathway mediated by D1R produces a long-lasting antidepressant response. In contrast, D2R expression under GDNF stimulation was constant, which indicated D2R signal was ineffective across depression-like measures. Furthermore, we used Golgi staining and western blot to display enhanced synaptic plasticity, such as the increased dendritic branches and dendritic spines, after GDNF treatment in PD models. Therefore, our results identify an exogenous GDNF positive effect on synaptic plasticity mediated by D1R signaling in mPFC to facilitate depression remission in PD.