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 resembling Parkinson's disease.
• The molecular basis for these extrapyramidal symptoms is not fully understood.
• Leucine-rich repeat kinase 2 (LRRK2) is linked to striatal function and dopamine D2 receptor signaling.

Purpose of the Study:

• To investigate the role of LRRK2 kinase in haloperidol-induced motor side effects.
• To explore the convergent signaling pathways of haloperidol and LRRK2.

Main Methods:

• Pharmacological and genetic inhibition of LRRK2 kinase.
• Use of knock-in mouse models with pathogenic LRRK2 mutations.
• Behavioral assays, electrophysiology, anatomical studies, and proteomics.

Main Results:

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

Conclusions:

• LRRK2 kinase plays a critical role in the motor side effects of haloperidol via striatal dopamine D2 receptor signaling.
• Targeting LRRK2 kinase may offer therapeutic strategies for psychosis and Parkinson's disease.