PT - JOURNAL ARTICLE AU - Kamesh, A. AU - Kadgien, C.A. AU - Kuhlmann, N. AU - Coady, S. AU - Hurley, E.P. AU - Barron, J.C. AU - Parsons, M.P. AU - Milnerwood, A.J. TI - Emergent glutamate &amp; dopamine dysfunction in VPS35<sub>(D620N)</sub> knock-in mice and rapid reversal by LRRK2 inhibition AID - 10.1101/2024.09.30.615858 DP - 2024 Jan 01 TA - bioRxiv PG - 2024.09.30.615858 4099 - http://biorxiv.org/content/early/2024/10/01/2024.09.30.615858.short 4100 - http://biorxiv.org/content/early/2024/10/01/2024.09.30.615858.full AB - The D620N variant in Vacuolar Protein Sorting 35 (VPS35) causes autosomal-dominant, late- onset Parkinson’s disease. VPS35 is a core subunit of the retromer complex that canonically recycles transmembrane cargo from sorting endosomes. Although retromer cargoes include many synaptic proteins, VPS35’s neuronal functions are poorly understood. To investigate the consequences of the Parkinson’s mutation, striatal neurotransmission was assessed in 1-, 3- &amp; 6-month-old VPS35 D620N knock-in (VKI) mice. Spontaneous and optogenetically- evoked corticostriatal glutamate transmission was increased in VKI striatal spiny projection neurons by 6 months, when total striatal glutamate release, quantified by iGluSnFR imaging, showed similarities to wild-type. dLight imaging revealed robust increases in VKI striatal dopamine release by 6 months, which were reversed with acute ex vivo leucine-rich repeat kinase 2 (LRRK2) inhibition. We conclude that increased glutamate and dopamine transmission in VKI mice progressively emerges in young-adulthood, and that dopamine dysfunction is likely the result of sustained, rapidly-reversible, LRRK2 hyperactivity.Competing Interest StatementThe authors have declared no competing interest.