Striatal Trans-Synaptic Signaling Mechanism in Parkinsonism

Summary: In the United States alone each year an estimated 60,000 individuals are diagnosed with Parkinson's disease (PD) with an economic cost of over fifty billion dollars each year. The individuals with Parkinson's disease show severe hypokinetic motor symptoms as well as anxiety, depression and cognitive decline. There are currently no treatments to prevent the progression of PD. Thus, identifying novel therapeutic targets is essential to address this clinical burden. The primary disease pathology involves degeneration of dopamine-producing neurons in the substantia nigra which triggers maladaptive changes in the striatum that underlie some of the motor and possibly non-motor symptoms in PD. Recent studies have identified an important contribution of the thalamostriatal system to behavioral deficits in PD models. Changes in function of synapses at parafascicular thalamus (Pf) inputs to medium spiny neurons (MSNs) has been observed in mice with 6-OHDA lesion. Importantly, chemogenetic or optogenetic inhibition of Pf neurons or their terminals in the striatum alleviates motor dysfunction in PD models. Therefore, identification of mechanisms underlying this defect has potential to improve motor and non-motor function in PD. Based on our recent studies and preliminary data we hypothesize that glutamate delta 1 receptor (GluD1)-cerebellin 1 (Cbln1) complex and associated synaptic organizers contribute to PD-related changes in thalamostriatal function and therefore can be targeted to mitigate behavioral deficits. Specific Aim1 will examine the effect of dopamine-depletion on GluD1-Cbln1 and associated synaptic organizer expression in an acute neurotoxin as well as a progressive genetic mouse models of PD. Changes in ultrastructure of striatal synapses in PD models will be evaluated using 3D-electron microscopy. Specific Aim 2 will determine the relationship between changes in synaptic organizer levels, synaptic properties and motor and non-motor behaviors. Specific Aim 3 will determine the effect of genetic and pharmacological restoration of normal GluD1-Cbln1 trans- synaptic signaling in rescuing synaptic changes and mitigating behavioral deficits in PD models. To accomplish these aims we will utilize a combination of confocal and electron microscopy (immuno and 3D), brain slice electrophysiology, behavior, optogenetics and genetic approaches to determine the contribution of synaptic organizers in striatal neuroplasticity and behaviors in PD. This project is significant because it would identify therapeutically targetable strategy to alleviate PD motor and non-motor deficits and/or modify disease progression. Scientific rigor of research design is established by the use of multiple methods and approaches, replication of experiments in independent laboratories, use of validated models and reagents, consideration of blinding, biological variables and sex in addition to other aspects of experimental design.