Study Rationale: One pathological hallmark of Parkinson’s disease (PD) is the degeneration of dopamine neurons innervating the striatum. Dopamine loss is associated with several adaptive changes in striatal circuits which are believed to contribute to PD associated symptoms. One of these changes involve acetylcholine signaling by striatal cholinergic interneurons (CINs). Indeed, an early treatment of PD was anticholinergic drugs. Further, acetylcholine and dopamine can also work in concert. Overall, there is there is no consensus explaining how acetylcholine contribute to symptoms and abnormal network dynamic in PD.
Hypothesis: We will investigate the role played by nicotinic receptors (nAChRs) and in particular β2-nAChRs in PD pathophysiology and associated symptoms. Indeed, β2-nAChRs are expressed at strategic locations in the striatum: 1) by dopamine afferents participating in the regulation of dopamine release and 2) by striatal interneurons, controlling striatal projection neurons activity via a feed-forward inhibitory circuit.
Study Design: By selective knock-out of β2-nAChRs we will identify the contribution of the two sources in the feedforward inhibition of striatal projection neurons. Further, we will demonstrate that this circuit is affected in a progressive model of PD. Then, we will show that the selective knock-out of β2-nAChRs can reproduce some specific symptoms observed in PD patients as well as activity changes in striatal projection neurons. Finally, we will test the efficacy of β2-nAChRs agonists to restore striatal physiological activity and for treating specific symptoms of PD.
Impact on Diagnosis/Treatment of Parkinson’s disease: Here, we demonstrate that β2-nAChRs in the striatum are important for cognitive flexibility and we will investigate their role in other aspect such as motivation. Altogether, results from this proposal will demonstrate the importance of striatal β2-nAChRs in the pathophysiology of PD and may provide more targeted therapeutic approaches to alleviate some specific symptoms of PD.
Next Steps for Development: One important goal of this research proposal is to test the therapeutic efficacy of β2-nAChRs agonists in treating some specific symptoms of PD. If successful, it would be essential to test β2-nAChRs agonists as treatment in other animal models as well as in combination with existing therapy such as L-DOPA.