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

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 ([18 F]FDG), dopamine neurotransmission ([11 C]raclopride, [11 C]PE2I) and serotonin neurotransmission ([18 F]MPPF, [11 C]DASB). For all radiotracers, except [18 F]FDG, PET data were analyzed with a MRI-based VOI method and a voxel-based analysis. RESULTS: MicroPET data showed a decrease in [11 C]raclopride uptake in the caudate putamen of KO α-syn mice, in comparison with M83 and WT mice, reflecting a lower concentration of D2 receptors. The increase in [18 F]MPPF uptake in M83 vs WT and KO mice indicates overexpression of 5-HT1A 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 D2 receptor, whereas aggregated α-syn leads to overexpression of 5-HT1A receptor, as a pathophysiological signature.