Membrane Channel Interactions Underlying Rat Subthalamic Projection Neuron Rhythmic and Bursting Activity

Abstract

A computational model of the rat subthalamic nucleus projection neuron is constructed using electrophysiological and morphological data and a restricted set of channel specifications. The model cell exhibits a wide range of electrophysiological behaviors characteristic of rat subthalamic neurons. It reveals that a key set of three channels play a primary role in distinguishing behaviors: a high-voltage-activated calcium channel (Cav 1.2.-1.3), a low-voltage-activated calcium channel (Cav 3.-), and a small current calcium-activated potassium channel (KCa 2.1-2.3). Short and long posthyperpolarization rebound responses, low-frequency rhythmic bursting (< 1 Hz), higher-frequency rhythmic bursting (4-7 Hz), and slow action and depolarizing potentials are behaviors all mediated by the interaction of these channels. This interaction can generate a robust calcium-dependent extended depolarization in the dendrites (a depolarizing plateau). The diversity observed in the rat subthalamic physiology (such as short or long rebounds, or the presence of low-frequency rhythmic busting) can arise from alterations in both the density and distributions of these channel types and, consequently, their ability to generate this depolarizing plateau. A number of important predictions arise from the model. For example, blocking or disrupting the low-voltage-activated Cav 3.- calcium current should mute the emergence of rebound responses and rhythmic bursting. Conversely, increasing this channel current via large hyperpolarizing potentials in combination with partial blockade of the high-voltage-activated calcium channels should lead to the more experimentally elusive in vitro high-frequency bursting.

NMDA-induced burst firing in a model subthalamic nucleus neuron

“…Therefore, our model can still reproduce the characteristic firing properties of STN cells shown in the original model (Terman et al 2002), such as the intrinsic spontaneous discharge and postinhibitory rebound bursting (Bevan and Wilson 1999;Bevan et al 2000), which depends on T-type Ca 2ϩ currents. Other currents identified in STN neurons (Atherton et al 2010;Barraza et al 2009;Beurrier et al 1999;Gillies and Willshaw 2006;Hahn and McIntyre 2010;Overton et al 1995;Nakanishi et al 1987) were omitted to maintain a focus on a specific putative burst mechanism, and our results suggest that these additional currents are not necessary for the experimentally observed STN bursting to occur, although they may affect its properties. In particular, we omit HCN currents that have been identified in STN neurons (Atherton et al 2010), since they are activated by synaptic inhibition and act by limiting the availability of low-threshold T-type Ca 2ϩ current, neither of which is an important feature in our study.…”

“…Other currents have been characterized in STN neurons (Atherton et al 2010;Barraza et al 2009;Beurrier et al 1999;Gillies and Willshaw 2006;Hahn and McIntyre 2010;Overton and Greenfield 1995;Nakanishi et al 1987), but since they were found not to be necessary for the reproduction of the experimental results that we studied (Zhu et al 2004(Zhu et al , 2005, they were omitted from the model.…”

Evaluating the impact of the deep brain stimulation induced electric field on subthalamic neurons: A computational modelling study

“…1B) we utilized was previously published by Gillies and Willshaw (2006), and is based on the complex dynamics and morphology of rat STN neurons. The STN morphology consists of a soma and three dendritic trees, as previously reported (Kita et al, 1983;Afsharpour, 1985).…”

“…The NaP current is important in controlling both the frequency and amplitude of the slow ramp depolarization before the action potential. The Kv31 channel played a role in reducing the width of the action potential to match STN neurons as closely as possible (Bevan and Wilson, 1999;Gillies and Willshaw, 2006). KCsa currents and HVA calcium currents are responsible for the emergence of the spontaneous firing properties, intrinsic to STN neurons.…”

“…During movement, they have been found to respond to synaptic input and fired repetitively at much higher frequencies (Wichmann et al, 1994;Beurrier et al, 1999). Based on this wealth of information Gillies and Willshaw (2006) produced and reported a detailed model of STN excitatory neurons which form the basis of the signalling in the STN. Previous work has used this model to look at the effects of applying an electrical field to a single cell placed in the different locations within the brain volume surrounding a DBS electrode (Miocinovic et al, 2006).…”