Phase Response Curve Analysis of a Full Morphological Globus Pallidus Neuron Model Reveals Distinct Perisomatic and Dendritic Modes of Synaptic Integration

Abstract

Synchronization of globus pallidus (GP) neurons and cortically entrained oscillations between GP and other basal ganglia nuclei are key features of the pathophysiology of Parkinson's disease. Phase response curves (PRCs), which tabulate the effects of phasic inputs within a neuron's spike cycle on output spike timing, are efficient tools for predicting the emergence of synchronization in neuronal networks and entrainment to periodic input. In this study we apply physiologically realistic synaptic conductance inputs to a full morphological GP neuron model to determine the phase response properties of the soma and different regions of the dendritic tree. We find that perisomatic excitatory inputs delivered throughout the interspike interval advance the phase of the spontaneous spike cycle yielding a type I PRC. In contrast, we demonstrate that distal dendritic excitatory inputs can either delay or advance the next spike depending on whether they occur early or late in the spike cycle. We find this latter pattern of responses, summarized by a biphasic (type II) PRC, was a consequence of dendritic activation of the small conductance calcium-activated potassium current, SK. We also evaluate the spike-frequency dependence of somatic and dendritic PRC shapes, and we demonstrate the robustness of our results to variations of conductance densities, distributions, and kinetic parameters. We conclude that the distal dendrite of GP neurons embodies a distinct dynamical subsystem that could promote synchronization of pallidal networks to excitatory inputs. These results highlight the need to consider different effects of perisomatic and dendritic inputs in the control of network behavior.

Phase response curves of subthalamic neurons measured with synaptic input and current injection

“…Furthermore, the iPRC may not accurately describe the response to larger inputs, perhaps not even to inputs as large as a unitary synaptic potential (Acker et al 2003;Netoff et al 2005b). In addition, synaptic potentials are generated by conductance changes, often at electrotonically distant sites on dendrites, whose effects may not be well represented by the effect of current injected at the soma (Goldberg et al 2007;Schultheiss et al 2010). Finally, inputs activating NMDA-type glutamate receptors (NMDARs) can be expected to pose special problems for the iPRC description, because the NMDAR conductance is prolonged and is a nonlinear function of membrane potential.…”

Phase response analysis during in vivo-like high conductance states; dendritic SK determines the mean and variance of responses to dendritic excitation

“…Phase response analysis during in vivo-like high conductance states; dendritic SK determines the mean and variance of responses to dendritic excitation We also demonstrated that synaptic excitation of the distal dendrite can paradoxically delay subsequent spiking when delivered at some phases of the spike cycle (yielding a type II PRC) as a consequence of dendritic activation of the small conductance calcium-activated potassium current, SK 1 . Since during high conductance states spike timing is determined by a balance between intrinsic mechanisms and synaptic input fluctuations, in this study we investigated how somatic and dendritic phase response properties of the GP model are affected by ongoing stochastic synaptic background activity.…”

Do gap junctions regulate synchrony in the Parkinsonian basal ganglia?

“…Related models picked up those ideas and investigated different connectivity changes and their effects on activity (e. g., Kumar et al [2011]). Later, when it became clear how important the intrinsic oscillatory nature of basal ganglia neurons is , models using phase response curves (PRCs) became established (e. g., Schultheiss et al [2010Schultheiss et al [ , 2012, Wilson et al [2011], Holt and Netoff [2014]) which described the reactions of oscillating systems on inputs. Finally, in the last years, models of microcircuitries, for example in striatum [Gittis et al, 2011, Damodaran et al, 2015, have been investigated.…”

“…These channels are assumed to contribute to the firing dynamics in most excitable cells [Bond et al, 1999] and can modulate plasticity [Woodward et al, 2010]. Studies with brain slices of healthy rats [Deister et al, 2009] and computational models of GPe neurons [Deister et al, 2009, Schultheiss et al, 2010 proposed a mechanism of decorrelation via an SK current. Deister et al [2009] showed that rat GP neurons express functional SK channels that contribute to the precision of autonomous firing in GP neurons, and strong SK currents can decrease the sensitivity of GPe neurons to smaller synchronized inputs [Deister et al, 2009].…”

“…Deister et al [2009] showed that rat GP neurons express functional SK channels that contribute to the precision of autonomous firing in GP neurons, and strong SK currents can decrease the sensitivity of GPe neurons to smaller synchronized inputs [Deister et al, 2009]. Phase response curve analysis suggested that dendritic SK channel expression controls synchronization by changing the phase dependence of synaptic effects on spike timing [Schultheiss et al, 2010]. Further, SK channels can indirectly be modulated via dopamine [Ramanathan et al, 2008] and may therefore exhibit altered dynamics in PD.…”