Leucine-rich repeat kinase 2 impairs the release sites of Parkinson’s disease vulnerable dopamine axons

Parkinson’s disease (PD) is defined pathologically by loss of dopamine-producing neurons in the substantia nigra pars compacta (SNc). Yet synaptic dysfunction emerges much earlier, making it essential to define the mechanisms that drive early nigrostriatal deregulation. In the SNc, molecularly distinct dopamine neuron subtypes show differential susceptibility to PD. In vivo fiber photometry of striatal dopamine release in awake, head-fixed mice expressing the dopamine sensor GRAB-DA3m. Two intersectional mouse lines targeting distinct dopamine neuron subtypes were studied: Anxa1-iCre mice (Anxa1+, vulnerable subtype) with fiber photometry in the dorsal lateral striatum (DLS), and Calb1-Cre mice (Calb1+, resilient subtype) with fiber photometry in the dorsal medial striatum (DMS). In each session, optogenetic activation of subtype-specific dopamine neuron cell bodies in the substantia nigra pars compacta (SNc) was achieved via Cre-dependent ChRmine expression and red-light (635 nm) stimulation. The experiment compares dopamine release between wild-type (LRRK2-WT) and LRRK2-G2019S knockin mice to investigate how pathogenic LRRK2 kinase activity affects dopamine synaptic function in a subtype-specific manner.