Phase response curve analysis of a morphologically realistic globus pallidus neuron model reveals a distal dendritic mechanism for synchronization
© Schultheiss et al; licensee BioMed Central Ltd. 2007
Published: 6 July 2007
Phase-locked bursting and oscillations in low frequency bands between the subthalamic nucleus (STN) and the globus pallidus (GP) are key features of the pathophysiology of Parkinson's disease (PD). These dynamics may reflect susceptibility of the basal ganglia (BG) to entrainment with cortical oscillations or could also be a consequence of enhanced reciprocal STN-GP coupling under conditions of dopamine depletion.
Phase response analysis is an efficient method of characterizing the tendency of single neurons to entrain to periodic input, and to predict the tendency of connected networks to synchronize. A phase response curve (PRC) describes the dependency of shifts in spike timing that result from weak inputs on the timing of inputs within the ongoing inter-spike interval (ISI). If, independent of stimulus phase, a depolarizing input causes an advance of the next spike, the PRC will be composed purely of positive values (a Type I PRC). A Type II PRC contains both positive and negative regions, indicating that a depolarizing input can cause either an advance or delay of the next spike depending on when within the ISI it occurs. Type II PRCs favor synchronization in connected neuronal populations.
Methods and results
For distal dendritic sites, larger excitatory stimuli resulted in Type II PRCs. (Fig. 1C.) To uncover the mechanism of this stimulus-amplitude-dependent transition between Type I and Type II PRCs, we analyzed differences in distal dendritic currents between control and stimulated conditions. We found that larger stimuli caused increased outward K+ flow through the Ca++ activated SK channel, and hypothesized that large stimuli delivered to small distal compartments (with high input resistance) activate the high-voltage Ca++ channel (HVA) which in turn activates SK. When we locally up- or down-regulated HVA and SK in tandem, the degree of Type II character was correspondingly increased or decreased, and the complete removal of either HVA or SK from the dendrite yielded identical Type I PRCs. (Fig. 1D.)
Our findings confirm previous work demonstrating PRC attenuation and left-shifting when weak stimuli are applied at increasing distance from the soma. In addition, by using realistic synaptic input, and analyzing evoked active conductances in spatially distinct regions of a realistic model, we characterize a mechanism in distal dendrites for Type II phase response dynamics. As network synchronization is observed in PD but not normal conditions, our findings suggest the hypothesis that GP neurons in PD may receive enhanced distal dendritic excitation and/or show an upregulation of SK conductance.
This article is published under license to BioMed Central Ltd.