The role of intrinsic variability in the synchronization of pallidal neurons

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DESCRIPTION (provided by applicant): GABAergic neurons of the globus pallidus play a significant role in the symptoms of Parkinson's disease. Specifically these neurons fire action potentials in a synchronized fashion in Parkinson's disease, contributing to global oscillations seen in the basal ganglia. Under normal conditions these neurons have an interesting property in that they generate their own action potentials in a reliable and rhythmic fashion, but there is some irregularity in the firing pattern. Pallidal neurons are synaptically coupled with one another and share some GABAergic input from the striatum; activating a shared input briefly synchronizes the activity of neurons until intrinsic variability makes the neurons fire out of phase from one another. Therefore, the mechanisms that control variability in the autonomous firing pattern could influence how these neurons synchronize to a shared input. Ion channels that generate the firing pattern are in a key position to influence the variability or precision of the autonomous tiring pattern. Thus, the goals of the proposed studies are to identity the ion channels that control the precision of firing in pallidal neurons and to determine if their pharmacological blockade can influence the way pallidal neurons synchronize after a common input. Electrophysiological recordings will be made in an in vitro slice preparation which will allow us to identify ion channels using pharmacology and determine key ion channel properties. This data will be used to construct a computer model of a pallidal neuron that replicates the observed variability in a realistic way. Recordings from pairs of neurons and analysis of a network model will be used to further determine how the availability of ion channels affects synchrony. Neurons in the globus pallidus synchronize their electrical activity in Parkinson's disease, but the mechanisms leading to this are not known. These studies will investigate the role of specific ion channels in creating or limiting synchronization. Understanding these ion channel's role could lead to new therapies for the symptoms of Parkinson's disease by identifying potential therapeutic targets.