Open AccessEffects of LRRK2 Inhibitors on Nigrostriatal Dopaminergic Neurotransmission
Author(s) -
Qin Qi,
Zhi LianTeng,
Li XianTing,
Yue ZhenYu,
Li GuoZhong,
Zhang Hui
Publication year - 2017
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12660
Subject(s) - pars compacta , substantia nigra , neurotransmission , dopamine , lrrk2 , pharmacology , dopaminergic , striatum , chemistry , neuroscience , parkinson's disease , medicine , biology , biochemistry , receptor , disease
Summary Introduction Mutations in leucine‐rich repeat kinase 2 ( LRRK 2) are the most prevalent cause of familial and sporadic Parkinson's disease ( PD ). Because most pathogenic LRRK 2 mutations result in enhanced kinase activity, it suggests that LRRK 2 inhibitors may serve as a potential treatment for PD . To evaluate whether LRRK 2 inhibitors are effective therapies for PD , it is crucial to know whether LRRK 2 inhibitors will affect dopaminergic ( DA ergic) neurotransmission. However, to date, there is no study to investigate the impact of LRRK 2 inhibitors on DA ergic neurotransmission. Aims To address this gap in knowledge, we examined the effects of three types of LRRK 2 inhibitors ( LRRK 2‐ IN ‐1, GSK 2578215A, and GNE ‐7915) on dopamine ( DA ) release in the dorsal striatum using fast‐scan cyclic voltammetry and DA neuron firing in the substantia nigra pars compacta ( SN pc) using patch clamp in mouse brain slices. Results We found that LRRK 2‐ IN ‐1 at a concentration higher than 1 μ M causes off‐target effects and decreases DA release, whereas GSK 2578215A and GNE ‐7915 do not. All three inhibitors at 1 μ M have no effect on DA release and DA neuron firing rate. We have further assessed the effects of the inhibitors in two preclinical LRRK 2 mouse models (i.e., BAC transgenic hG 2019S and hR 1441G) and demonstrated that GNE ‐7915 enhances DA release and synaptic vesicle mobilization/recycling. Conclusion GNE ‐7915 can be validated for further therapeutic development for PD .