Mechanisms underlying GLP-1 receptor mediated relief of Parkinson’s disease symptoms

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Parkinson’s disease (PD) is a progressive neurodegenerative disease leading to motor impairment due to degeneration of nigrostriatal dopaminergic projections. Currently, L-DOPA therapy effectively relieves the motor symptoms in initial stages of PD, however long term treatment with L-DOPA results in loss of efficacy and the development of dyskinesia. Thus, there is a need for other effective therapies for PD. Dopamine in the striatum plays a critical role in modulation of the direct and indirect motor output pathways by activating D1 and D2 receptors in those pathways, respectively. Under normal conditions, dopamine facilitates movement by increasing activity of the direct pathway and decreasing activity of the indirect pathway. In patients with PD, the loss of dopamine results in decreased activity of the direct pathway and increased activity of the indirect pathway. D1 agonists can relieve PD symptoms by increasing cAMP levels and increasing activity of direct pathway medium spiny neurons (MSNs) that express the D1 dopamine receptors. Exenatide, an FDA approved pharmacotherapy commonly prescribed for the treatment of type 2 diabetes, is a glucagon like peptide-1 receptor (GLP-1R) agonist, and a recent clinical trial reported therapeutic benefits of exenatide for PD symptoms. In preclinical studies, GLP-1R agonist treatment has also been shown to protect dopamine neurons from cell death in PD models, but the acute or chronic effects of these receptors on MSN excitability have not been investigated. Our preliminary data suggest that GLP-1Rs are expressed by direct pathway MSNs, and that activation of these receptors increases the excitability of those neurons. As GLP-1R is positively coupled to adenylyl cyclase activity and cAMP levels, the improved motor control in PD patients receiving the GLP-1R agonist may be related to modulatory effects on striatal circuitry. Experiments outlined in this proposal will use a mouse model of PD to examine two aims: The first is to test whether acute GLP-1R agonist exposure can increase intrinsic excitability and corticostriatal synaptic plasticity in striatal MSNs. The second Aim will explore the effects of chronic GLP-1R agonist treatment on motor performance and corticostriatal plasticity of MSNs. These studies will test the hypothesis that GLP-1R agonists may provide alternate treatment strategies for PD symptoms through their effects on striatal circuitry and synaptic plasticity.