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

Abstract

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-HT_1A 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-HT_1A receptor, as a pathophysiological signature.

Keywords: PET; alpha-synuclein; animal model; dopamine; serotonin.