LRRK2 mediates haloperidol-induced changes in indirect pathway striatal projection neurons

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• Haloperidol manages psychosis by blocking dopamine D2 receptors but causes motor side effects.
• Extrapyramidal symptoms from haloperidol resemble Parkinson's disease motor deficits.
• The molecular basis for these side effects is not well understood.

Purpose of the Study:

• To investigate the role of Leucine-rich repeat kinase 2 (LRRK2) in haloperidol-induced motor side effects.
• To explore the convergent signaling pathways of haloperidol and LRRK2 in the striatum.

Main Methods:

• Utilized pharmacological and genetic inhibition of LRRK2 kinase.
• Employed knock-in mouse models with pathogenic mutant LRRK2.
• Conducted behavioral assays, electrophysiology, anatomical studies, and proteomics.

Main Results:

• LRRK2 kinase inhibition ameliorated haloperidol-induced motor deficits in mice.
• LRRK2 inhibition modulated haloperidol's effects in striatal indirect pathway neurons.
• Haloperidol and increased LRRK2 activity induced similar intracellular signaling patterns.

Conclusions:

• LRRK2 kinase is a key player in the striatal dopamine D2 receptor signaling that causes haloperidol's motor side effects.
• Targeting LRRK2 kinase may offer new therapeutic strategies for psychosis and Parkinson's disease.