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The nigrostriatal dopamine system in the leucine-rich repeat kinase 2 G2019S knock-in mouse model of Parkinson's disease Paschall, Sarah Afton

Abstract

Mutations on the leucine-rich repeat kinase 2 (LRRK2) gene are the most common variants responsible for idiopathic Parkinson’s disease (PD). Historically, PD is thought of as a late-stage neurodegenerative disease resulting from the loss of dopaminergic neurons in the substantia nigra pars compacta with the presence of Lewy pathology. Current treatments focus on the dopaminergic aspect of this disease, without addressing or successfully halting the underlying causes of this disease. The LRRK2 G2019S mutation is the single most common genetic risk factor for Parkinson’s disease and leads to increased kinase activity with subtle effects on the timing of nigrostriatal dopaminergic transmission. Here, using a genetically faithful G2019S knock-in (GKI) mouse model at multiple age points, although no differences were seen in monoamine, glutamate, or GABA release by in vivo microdialysis of the dorsolateral striatum, more temporally sensitive investigation revealed subtle release augmentation in mutants. Using fast-scan cyclic voltammetry to examine dopamine release and reuptake on a millisecond timescale in acute striatal slices at early (

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Attribution-NonCommercial-NoDerivatives 4.0 International