PET imaging of the influence of physiological and pathological α‐synuclein on dopaminergic and serotonergic neurotransmission in mouse models

摘要

Aims Alpha‐synuclein (α‐syn) aggregation is a neuropathological hallmark of neurodegenerative synucleinopathies. This in vivo study explored glucose metabolism and dopaminergic and serotoninergic neurotransmission in KO α‐syn, wild‐type mice and an accelerated murine model of synucleinopathy (M83). Methods MicroPET acquisitions were performed in all animals aged 5‐6?months using five radiotracers exploring brain glucose metabolism ([sup18/supF]FDG), dopamine neurotransmission ([sup11/supC]raclopride, [sup11/supC]PE2I) and serotonin neurotransmission ([sup18/supF]MPPF, [sup11/supC]DASB). For all radiotracers, except [sup18/supF]FDG, PET data were analyzed with a MRI‐based VOI method and a voxel‐based analysis. Results MicroPET data showed a decrease in [sup11/supC]raclopride uptake in the caudate putamen of KO α‐syn mice, in comparison with M83 and WT mice, reflecting a lower concentration of Dsub2/sub receptors. The increase in [sup18/supF]MPPF uptake in M83 vs WT and KO mice indicates overexpression of 5‐HTsub1A/sub receptors. The lack of change in dopamine and serotonin transporters in all groups suggests unchanged neuronal density. Conclusions This PET study highlights an effect of α‐syn modulation on the expression of the Dsub2/sub receptor, whereas aggregated α‐syn leads to overexpression of 5‐HTsub1A/sub receptor, as a pathophysiological signature.