Emergent glutamate & dopamine dysfunction in VPS35_(D620N) knock-in mice and rapid reversal by LRRK2 inhibition

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Vacuolar Protein Sorting 35 (VPS35) is crucial for the retromer complex, involved in cargo recycling.
• A specific VPS35 variant (D620N) is linked to autosomal-dominant, late-onset Parkinson's disease.
• Neuronal functions of VPS35, particularly in Parkinson's disease, remain incompletely understood.

Purpose of the Study:

• To investigate the impact of the VPS35 D620N Parkinson's mutation on striatal neurotransmission.
• To explore the role of Leucine-Rich Repeat Kinase 2 (LRRK2) in the observed neurotransmission changes.

Main Methods:

• Utilized VPS35 D620N knock-in (VKI) mouse models.
• Assessed spontaneous and evoked corticostriatal glutamate transmission.
• Employed iGluSnFR and dLight imaging for glutamate and dopamine release analysis.
• Investigated the effects of acute LRRK2 inhibition.

Main Results:

• Increased spontaneous and evoked corticostriatal glutamate transmission in VKI mice by 6 months.
• No significant difference in total striatal glutamate release compared to wild-type.
• Robust increases in striatal dopamine release in VKI mice, reversible with LRRK2 inhibition.
• Glutamate transmission was unaffected by acute LRRK2 inhibition.

Conclusions:

• Progressive emergence of increased striatal neurotransmission in VKI mice during young adulthood.
• Dopamine dysfunction in VKI mice is associated with sustained, reversible LRRK2 hyperactivity.
• LRRK2 hyperactivity is a key factor in the dopamine-related pathology of the VPS35 D620N Parkinson's model.