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However, LRRK<\/jats:styled-content>2 kinase inhibitors may have manifold actions, affecting not only pathological mechanisms in dopaminergic neurons but also physiological functions in nondopaminergic neurons. Therefore, we investigated whether LRRK<\/jats:styled-content>2 kinase inhibitors differentially modulate dopamine and glutamate release from the mouse striatum and cerebral cortex. Spontaneous and KC<\/jats:styled-content>l\u2010evoked [3<\/jats:sup>H]\u2010dopamine and glutamate release from superfused synaptosomes obtained from wild\u2010type and LRRK<\/jats:styled-content>2 knock\u2010out, kinase\u2010dead or G2019S knock\u2010in mice was measured. Two structurally unrelated inhibitors, LRRK<\/jats:styled-content>2\u2010IN<\/jats:styled-content>\u20101 and GSK<\/jats:styled-content>2578215A, were tested. LRRK<\/jats:styled-content>2, phosphoSerine1292 and phosphoSerine935 LRRK<\/jats:styled-content>2 levels were measured in all genotypes, and target engagement was evaluated by monitoring phosphoSerine935 LRRK<\/jats:styled-content>2. LRRK<\/jats:styled-content>2\u2010IN<\/jats:styled-content>\u20101 inhibited striatal glutamate but not dopamine release; GSK<\/jats:styled-content>2578215A inhibited striatal dopamine and cortical glutamate but enhanced striatal glutamate release. LRRK<\/jats:styled-content>2\u2010IN<\/jats:styled-content>\u20101 reduced striatal and cortical phosphoSerine935 levels whereas GSK<\/jats:styled-content>2578215A inhibited only the former. Neither LRRK<\/jats:styled-content>2 inhibitor affected neurotransmitter release in LRRK<\/jats:styled-content>2 knock\u2010out and kinase\u2010dead mice; however, they facilitated dopamine without affecting striatal glutamate in G2019S knock\u2010in mice. GSK<\/jats:styled-content>2578215A inhibited cortical glutamate release in G2019S knock\u2010in mice. We conclude that LRRK<\/jats:styled-content>2\u2010IN<\/jats:styled-content>\u20101 and GSK<\/jats:styled-content>2578215A modulate exocytosis by blocking LRRK<\/jats:styled-content>2 kinase activity, although their effects vary depending on the nerve terminal examined. The G2019S mutation unravels a dopamine\u2010promoting action of LRRK<\/jats:styled-content>2 inhibitors while blunting their effects on glutamate release, which highlights their positive potential for the treatment of PD<\/jats:styled-content>, especially of LRRK<\/jats:styled-content>2 mutation carriers.<\/jats:p>","DOI":"10.1002\/prp2.484","type":"journal-article","created":{"date-parts":[[2019,5,28]],"date-time":"2019-05-28T01:55:23Z","timestamp":1559008523000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Leucine\u2010rich repeat kinase 2 (LRRK<\/scp>2) inhibitors differentially modulate glutamate release and Serine935 LRRK<\/scp>2 phosphorylation in striatal and cerebrocortical synaptosomes"],"prefix":"10.1002","volume":"7","author":[{"given":"Daniela","family":"Mercatelli","sequence":"first","affiliation":[{"name":"Department of Medical Sciences Section of Pharmacology University of Ferrara Ferrara 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