Description:

Patrick Skelton, Ph.D.
Postdoctoral Fellow in the Laboratory of Loukia Parisiadou, PhD

"Parkinson’s disease-associated LRRK2 mutations impact the physiology of striatal cholinergic interneurons"

Leucine-rich-repeat kinase 2 (LRRK2) mutations represent the most common monogenetic form of Parkinson’s disease (PD). The clinical similarity between LRRK2-linked and idiopathic cases suggests that LRRK2 mutations are a valuable tool for understanding PD in general. LRRK2 is significantly enriched in spiny projection neurons (SPN) in the dorsal striatum, in contrast to the relatively low expression in midbrain dopaminergic neurons that degenerate in PD. Prior to the onset of overt neurodegeneration, LRRK2 mutations reduce evoked dopamine release from midbrain dopamine neurons and disrupt the glutamatergic synaptic inputs onto spiny projection neurons. Meanwhile, data from rodent models suggest that striatal cholinergic interneurons (CIN) are specifically vulnerable to LRRK2 mutation, and clinical evidence indicates cholinergic abnormalities in LRRK2-linked PD. We therefore sought to determine whether LRRK2 mutations influence the physiology of striatal CINs. We generated cholinergic-neuron-specific conditional LRRK2 knockout and LRRK2-R1441C knock-in mouse lines generated by a crossing ChAT-Cre driver line to LRRK2-Floxed and Rosa26 LRRK2-R1441C lines, respectively. Controls were generated by crossing ChAT-Cre mice to wild-type mice. To target CINs for experiments in ex vivo brain slices we used an AAV to express Cre-dependent EGFP. Experiments were performed on adult (8-12 weeks old) mice of both sexes. We found no differences in resting membrane potential, input resistance, action potential waveform, or excitability. However, R1441C knock-in increased the magnitude of the slow afterhyperpolarization. Although the mAHP and Ih­ were not altered, preliminary data suggests that CINs from R1441C knock-in mice have increased spontaneous firing frequency. Ongoing work will investigate evoked acetylcholine release using fluorescent neurotransmitter sensors, and will investigate gene expression changes using TRAP to illuminate the mechanisms underlying the physiological alterations caused by LRRK2 mutation.

Guang Yang, Ph.D.
Postdoctoral Fellow in the Laboratory of Minoli Perera, PharmD, PhD

"Pharmacogenomics of Clopidogrel Response in African Americans"

Clopidogrel is a commonly used antiplatelet agent which works to inhibit blood clots in patients with acute coronary syndrome or those undergoing percutaneous coronary intervention. Studies have shown that loss-of-function coding mutations are significantly associated with clopidogrel resistance. Clopidogrel resistance is highly heritable. Clopidogrel resistance is more common in African ancestry populations compared to European or Asian ancestry populations, begging the question: are population-specific genetic variants contributing to response outside of what has been discovered in European and Asian. Our work will identify genes/pathways unique to clopidogrel response in African ancestry populations leading to improved precision medicine approaches for antiplatelet therapy.