Regulation of autonomous pacemaking and high frequency firing in the basal gangliaPublic Deposited
Following dopaminergic denervation in Parkinson's Disease, firing patterns in several basal ganglia neuron populations are pathologically altered. In the globus pallidus (GP), this manifests as a loss of autonomous, rhythmic, high-frequency pacemaking and an appearance of correlated, oscillatory bursting. This oscillatory bursting is best disrupted through high-frequency stimulation of affected nuclei in the basal ganglia. The goal of this research was to understand the intrinsic mechanisms by which the GP and other autonomous pacemakers establish their discharge patterns and how regulation of these mechanisms through electrical, pharmacological and genetic manipulations can alter firing properties. This was accomplished by integrating current-clamp recordings of activity patterns in pacemaking neurons with voltage-clamp recordings isolating important channel types. By direct, high-frequency stimulation of GP neurons, we demonstrate that they are capable of sustaining high frequency firing during stimulation, suggesting that the therapeutic effect of this technique is a disruption of the pathological discharge pattern, not cessation of firing. Analysis of Na+ channel biophysics in these neurons identifies a novel resurgent gating mode present only in channels of pacemaking neurons (GP neurons, striatal cholinergic interneurons and dopaminergic neurons). As a result of the unique properties underlying this gating mode, the Na+ channels in autonomous pacemakers recover more rapidly from the previous spike, increasing availability during the interspike interval and increasing the depolarizing current that drives the membrane towards spike threshold. Without this gating mode, the ability of GP neurons to fire autonomously and at high frequencies is significantly reduced. Activation of D2 receptors also affects channel availability by increasing entry into the slow inactivated state, leading to a reduction in excitability of cholinergic interneurons. Another channel important for autonomous spiking is the HCN channel, which is responsible for keeping the membrane depolarized enough for Na+ channels to drive spiking. Following dopamine depletion, HCN channel density is reduced, leading to silencing of GP activity. This reduction in discharge from the GP can potentially have global effects on network connections throughout the basal ganglia.
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