Dopamine D2 receptor upregulation in dorsal striatum in the LRRK2-R1441C rat model of early Parkinson's disease revealed by in vivo PET imaging

Delgado-Goni, T.; Connor-Robson, N.; Cioroch, M.; Paisey, S.; Marshall, C.; Lane, E. L.; Hauton, D.; McCullagh, J.; Magill, P. J.; Cragg, S. J.; Mackay, C. E.; Wade-Martins, R.; Klein, J. C.

doi:10.1101/2023.08.09.550512

bioRxiv · 10.1101/2023.08.09.550512

Dopamine D2 receptor upregulation in dorsal striatum in the LRRK2-R1441C rat model of early Parkinson's disease revealed by in vivo PET imaging

Delgado-Goni, T.·Connor-Robson, N.·Cioroch, M.·Paisey, S.·Marshall, C.·Lane, E. L.·Hauton, D.·McCullagh, J.·Magill, P. J.·Cragg, S. J.·Mackay, C. E.·Wade-Martins, R.·Klein, J. C.

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Abstract

LRRK2 mutations are the most common cause of dominantly inherited Parkinsons disease (PD). Here, we conducted PET imaging in aged transgenic rats carrying human pathogenic LRRK2 R1441C or G2019S mutations with [18F]FDOPA and dopamine D2/3 receptor ligand [18F]fallypride. We interrogate presynaptic integrity and postsynaptic dopamine receptor availability, and compared these to non-transgenic rats. LRRK2 mutant rats displayed similar [18F]FDOPA uptake to non-transgenic animals, consistent with intact dopamine synthesis in striatal axons. However, LRRK2-R1441C rats demonstrated greater binding of [18F]fallypride than LRRK2-G2019S or non-transgenic controls, exhibiting regionally selective binding increase in the dorsal striatum. Immunocytochemical labelling post-mortem confirmed a greater density of D2 receptors in LRRK2-R1441C than other genotypes restricted to the dorsal striatum, consistent with upregulation of D2-receptors as a compensatory response to the greater dopamine release deficit observed in this genotype. These results show that [18F]fallypride PET imaging is sensitive to dysregulation of dopamine signalling in the LRRK2-R1441C rat, detecting upregulation of D2 receptors that parallels observations in early human sporadic PD. Future studies of candidate therapies could exploit this non-invasive approach to assess treatment efficacy.

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Delgado-Goni, T., Connor-Robson, N., Cioroch, M., Paisey, S., Marshall, C., Lane, E. L., Hauton, D., McCullagh, J., Magill, P. J., Cragg, S. J., Mackay, C. E., Wade-Martins, R., Klein, J. C.. 2023-08-13. Dopamine D2 receptor upregulation in dorsal striatum in the LRRK2-R1441C rat model of early Parkinson's disease revealed by in vivo PET imaging. https://doi.org/10.1101/2023.08.09.550512

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