Aberrant, synchronous burst firing in the Globus pallidus externus (GPe) is associated with motor symptoms in Parkinson's disease (PD). Because of its clinical relevance, it is critical that we understand mechanisms that support GPe pacemaking. So far, studies have focused on neuronal mechanisms that regulate GPe pacemaking, such as altered GABAergic from the striatum or glutamatergic input from the subthalamic nucleus. Our previous work showed that DA depletion reduces the intrinsic ionic conductances and activity of GPe neurons. Our working hypothesis is that astrocytes regulate intrinsic and synaptic activity in the GPe. To test this hypothesis, a multi-disciplinary approach will be used. This includes gene expression analysis, ex vivo patch clamp electrophysiological recordings, ex vivo calcium imaging and behavioral analyses.
Two specific aims are proposed in this application.
The first aim focuses on metabolic coupling between neurons and astrocytes. The degree to which metabolic impairments phenocopy the molecular, cellular, and behavioral alterations observed in PD will be assessed using a dopamine depletion mouse model.
The second aim evaluates the degree to which neuronal and synaptic activity in the GPe is regulated by astrocyte-derived signaling molecules. Astrocyte activity, morphology, and neuronal coupling will be compared between naive and dopamine depleted mice to estimate the involvement of astrocytic impairments in PD. As a result of this project we will better understand interactions between neurons and astrocytes - the most abundant cell type in the human brain. More importantly, we will likely have identified new molecular targets for motor function recovery in PD and other neurodegenerative disease.
In Parkinson's disease, motor dysfunction is a consequence of improper neuronal activity in the basal ganglia, a motor switchboard in the brain. The goal of this project is to understand how neuronal activity in the basal ganglia is regulated by non-neuronal cell types in both health and Parkinson's disease. Findings from these studies will benefit our understanding of normal brain function and the importance of non-neuronal cells in health and disease.