Chronic hyperactivation of midbrain dopamine neurons causes preferential dopamine neuron degeneration

• DOI: 10.7554/elife.98775.2
• Publication Date: 2025-04-23T14:30:42Z
• Authors: Katerina Rademacher; Zak Doric; Dominik Haddad; Aphroditi Mamaligas; Szu-Chi Liao; Rose B Creed; Kohei Kano; Zac Chatterton; YuHong Fu; Joseph H Garcia; Victoria Vance; Yoshitaka Sei; Anatol Kreitzer; Glenda M Halliday; Alexandra B Nelson; Elyssa B Margolis; Ken Nakamura
• Keywords: Hyperactivation; Degeneration (medical)

Parkinson’s disease (PD) is characterized by the death of substantia nigra (SNc) dopamine (DA) neurons, but pathophysiological mechanisms that precede and drive their remain unknown. The activity DA neurons likely altered in PD, we understand little about if or how chronic changes may contribute to degeneration. To address this question, developed a chemogenetic (DREADD) mouse model chronically increase neuron activity, confirmed using ex vivo electrophysiology. Chronic hyperactivation resulted prolonged increases locomotor during light cycle decreases dark cycle, consistent with release circadian disturbances. We also observed early, preferential degeneration SNc projections, recapitulating PD hallmarks selective vulnerability axons comparative resilience ventral tegmental area axons. This was followed eventual loss midbrain neurons. Continuous DREADD activation sustained baseline calcium levels, supporting role for increased neurodegeneration process. Finally, spatial transcriptomics from mice examining striatal targets, cross-validation human patient samples, provided insights into potential hyperactivity-induced toxicity PD. Our results thus reveal neural support driving