DYNAMICS OF GABAERGIC INHIBITION IN THE SUBTHALAMUS

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DESCRIPTION:(from applicant's abstract) The excitatory subthalamic nucleus is a major driving force of neuronal activity in the basal ganglia of animals and humans under resting conditions, during voluntary movement and in idiopathic and experimental models of Parkinson's disease. The activity of the subthalamic nucleus is regulated by GABAergic inhibition from the reciprocally connected external globus pallidus. The overall objective of this research is to determine the principles that underlie GABAergic inhibition in the subthalamic nucleus in health and in Parkinson's disease. Perforated patch, whole-cell or extracellular recordings of subthalamic neurons in slices will be used to examine the effects of GABAergic inhibitory postsynaptic potentials/currents (GABA ipsps/ipscs) on spontaneous or driven rhythmic firing. Bursts of GABA ipsps/ipscs will be evoked in subthalamic neurons to determine whether GABA acting at -A and/or -B receptors can produce rebound burst firing in subthalamic neurons. The role of dopamine in the regulation of GABAergic synaptic transmission in the subthalamic nucleus will be examined. Slices containing an intact subthalamic nucleus-external globus pallidus network in the presence of dopamine agonists or antagonists will be studied to determine whether spontaneous or evoked burst firing in subthalamic neurons can trigger low frequency oscillatory activity. Single pallidal neurons will be filled in vivo using juxtacellular labelling and their synaptic boutons in the subthalamic nucleus will be plotted in three dimensions and examined by light and electron microscopy to determine whether neighbouring neurons receive common inputs. The degree of divergence and convergence in the pallidal projection will be determined from stereological estimates of GABAergic terminals in the subthalamic nucleus and the known numbers of neurons in the network.