Gating of Motor Information Flow in Normal and Parkinsonian States by the Interaction between Synaptic Input and Voltage-Gated Channels in the Subthalamus

The subthalamic nucleus (STN) stands out as a pivotal and coalescing point in both the hyperdirect pathway (providing direct excitatory glutamatergic inputs to the STN) and the indirect pathway (providing direct inhibitory GABAergic inputs to the STN) of the basal ganglia network. We have recently established the causal relation between excessive burst discharges in the STN and the motor, and probably also non-motor, symptoms of Parkinson’s disease. However, little is known about the interaction between ionic and synaptic mechanisms underlying the genesis of subthalamic bursts. Subthalamic burst discharges mostly are comprised of repetitive spikes on top of a timely-terminated depolarizing plateau. In theory, the burst plateau would necessitate not only relatively long-lasting depolarizing currents to sustain, but also slowly activating hyperpolarizing currents to be terminated appropriately. In this regard, we have demonstrated that properties and modulation of a slowly-activating (ERG) K+ conductance activated by the plateau depolarization would dramatically affect the length of each burst as well as the timing of bursts in the STN, and consequently locomotor behavior in normal and parkinsonian conditions. In addition, the make of burst discharges also requires a symphony of different conductances, which could be either made available (“deinactivated”) or deactivated by membrane hyperpolarization. Our preliminary studies further show that inhibition of a transient-type K+ conductance made available by membrane hyperpolarization also shapes spontaneous STN bursts. Moreover, not only voltage- but also ligand- or neurotransmitter-activated ion channels are capable of providing membrane depolarizing and hyperpolarizing forces, which may in turn control the voltage-dependent active conductances. We, therefore, reason that the details of the interplay between voltage-gated membrane conductances and synaptic input should be clarified for a better dissection of the mechanisms underlying subthalamic bursts, which may in turn serve as a delicate gate control of motor information flow subject to neuromodulation such as dopamine. We would propose to employ electrical, pharmacological and optogenetical manipulations of ion channels and synaptic transmission in acutely dissociated STN neurons, brain slices that preserve major hyperdirect and indirect circuits, and normal as well as parkinsonian animals to elucidate: (1) the integral roles of the voltage-gated K+ channels and the hyperdirect synaptic transmission in shaping subthalamic bursts, (2) the interplay between the voltage-gated K+ channels and synaptic inputs from both the hyperdirect and indirect pathways in the STN and their contribution to normal and pathological motor processing in multiple temporal and spatial scales, and in vitro as well as in vivo, and (3) the possible modulation of abovementioned attributes by dopamine or other neuromodulators. With the execution of this proposal, we shall gain novel and more in-depth understandings of the correlative roles of neuronal active conductances and synaptic inputs in setting STN neuronal discharge patterns and thus locomotor behaviors. Hopefully we could elucidate more fundamental rationales underlying physiological and pathophysiological motor coding by the basal ganglia pathways centered at the STN, and consequently provide potential bases for the future development of novel therapeutic approaches for relevant movement disorders.

Project ID:PA10708-0788
External Project ID:MOST107-2311-B182-004