The effect of PD-linked LRRK2 mutations on corticostriatal circuits

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

? DESCRIPTION (provided by applicant): Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common cause of heritable forms of Parkinson's disease (PD), a progressive neurodegenerative disorder for which there is no cure. Though little is known about the normal function of LRRK2, inherited PD progresses identically to idiopathic cases, suggesting the existence of common disease mechanisms and highlighting the need to understand pathogenic mechanisms and circuits through which mutant LRRK2 acts. LRRK2 is enriched in dorsal striatum, the principal target of dopaminergic neurons that degenerate in PD, but paradoxically, its expression peaks developmentally during synaptogenesis. This has presented a conundrum in a field customarily focused on late-stage motor symptoms and underscores the importance of understanding whether PD-related mutations in LRRK2 alter striatal network structure and function early on. Accordingly, my objective is to determine how normal LRRK2 and a PD-related mutant form of LRRK2 control development of excitatory striatal synaptic networks. I will accomplish this using a mouse Lrrk2 knock-in model and with an integrated set of electrophysiological, imaging, anatomical, and pharmacogenetic assays to characterize alterations in neural circuits during development. I hypothesize that a PD-related mutant form of LRRK2 results in abnormal corticostriatal neural network development. My preliminary data strongly support this idea, as mice expressing the most common LRRK2 mutation seen in PD patients exhibit significantly altered striatal synaptic network properties and spine morphology early in life. Furthermore, I hope to identify both the source of this aberrant activity, as I have preliminary data that suggest aberrant striatal inputs arise from cortical sources, as well as how the effects of aberrant striatal inputs may effect downstream basal ganglia circuitry. This project will shed light on early circuit abnormalities that may underlie neurodegeneration in PD later in life.