DYNAMIC PROPERTIES OF ION CHANNELS IN THE SUBTHALAMUS

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The glutamatergic subthalamic nucleus (STN) is a major driving force of neuronal activity in the basal ganglia during normal voluntary movement and in movement disorders e.g. in Parkinson's disease (PD). In idiopathic and experimental models of PD, STN neurons display abnormal patterns of activity, which may arise, in part, from an alteration in their intrinsic membrane properties. Cellular plasticity in the STN may result from the loss of dopaminergic neuromodulation within the STN and/or the altered pattern of synaptic input, which results from the depletion of dopamine in other basal ganglia nuclei. The first specific aim is to determine further the ionic, biophysical and molecular principles that underlie the normal firing properties of STN neurons in vitro i.e., spontaneous oscillation, driven high-frequency activity and rebound burst firing. This will be achieved using current- and voltage-clamp recording of STN neurons in vitro using the perforated, whole-cell and nucleated configurations of the patch clamp technique. The roles of specific ion channels in firing behavior will be adressed by examination of firing and ionic currents in the presence of selective channel blockers, the molecular nature of ion channels in STN neurons will be determined using immunocytochemistry of alpha subunits and messenger RNA expression studies. The second specific aim is to determine how dopamine modulates the firing and ion channel properties of STN neurons. This will be addressed using the combined electrophysiological and molecular approach described above, the neuromodulation of ion channels by dopamine will be determined using selective D1-like and D2-like receptor agonists. The membrane properties of STN neurons in normal and dopamine-depleted animals will then be compared to determine whether cellular plasticity contributes to the abnormal activity of STN neurons in PD.