Silent plateau potentials, rhythmic bursts, and pacemaker firing: Three patterns of activity that coexist in quadristable subthalamic neurons

Abstract

Subthalamic neurons display uncommon intrinsic behaviors that are likely to contribute to the motor and cognitive functions of the basal ganglia and to many of its disorders. Here, we report silent plateau potentials in these cells. These plateau responses start with a transient burst of action potentials that quickly diminish in amplitude because of spike inactivation and current shunt. The resulting interruption of spiking reveals a stable depolarization (up state) that clamps the cell membrane potential near ؊40 mV for several seconds. These plateau potentials coexist in single subthalamic neurons with more familiar patterns of burst and pacemaker firing. Within a narrow range of baseline membrane potentials (؊67 to ؊60 mV), depolarization abruptly switches single cells from bistable to rhythmic bursts or tonic firing modes, thus selecting entirely distinct algorithms for integrating cortical and pallidal synaptic inputs.basal ganglia ͉ bistability ͉ cortex S ubthalamic neurons contribute to the motor (1, 2) and limbic (3, 4) functions of the basal ganglia. Their importance is particularly obvious in Parkinson's disease, in which symptoms improve with high-frequency subthalamic stimulation (5) or subthalamic lesion (6). Thus, there is considerable interest in understanding the synaptic and intrinsic mechanisms that control firing in these cells.At rest, subthalamic neurons display a regular pacemaker activity maintained by sustained (7,8) and resurgent (9) voltagegated Na currents. However, there is little consensus on their firing patterns when they are hyperpolarized.Studies in whole-cell or perforated-patch configurations have reported a quasilinear modulation of cell firing by current injection, excitatory postsynaptic potentials (EPSPs), or inhibitory postsynaptic potentials (IPSPs) (8,(10)(11)(12), with nonlinearities limited to small rebound bursts after IPSPs (13). Consistent with these findings, the in vivo subthalamic responses to cortical stimulation (14-17), their synchronization to cortical slow oscillations (18), and spike-wave discharges (19) are readily explained by the summating contributions of direct cortical inputs and indirect pathways (18,20,21).Studies in whole-cell or cell-attached configurations have revealed more complex bursts of action potentials or spikegenerating plateau potentials that switch to pacemaker firing with membrane depolarization (22-26). These bursts may occur spontaneously (23, 24), generating rhythms strikingly similar to the multisecond-long oscillations reported in subthalamic neurons of locally anesthetized rats (27) and awake monkeys (28).In this study, we investigated the intrinsic behaviors of subthalamic neurons challenged with a wide range of synaptic and current stimuli, during whole-cell, perforated-patch, or cellattached recordings. We found an unexpected homogeneity and complexity in their firing patterns. Independent of the recording conditions, subthalamic neurons display the following four selfsustaining regimes: a resting down state, a quiescent pla...

A Calcium-Activated Nonselective Cation Conductance Underlies the Plateau Potential in Rat Substantia Nigra GABAergic Neurons

“…I CAN and its associated plateau potential is important in controlling the firing pattern of subthalamic nucleus neurons which exhibit tonic, single spike firing, burst firing, as well as a quiescent plateau depolarization under some conditions (Beurrier et al, 1999;Zhu et al, 2004;Kass and Mintz, 2006). Burst firing can be observed in these neurons after release of hyperpolarizing current pulses or application of NMDA, both of which also elicit the plateau potential in subthalamic neurons (Beurrier et al, 1999;Zhu et al, 2004Zhu et al, , 2005.…”

Noradrenergic Modulation of Subthalamic Nucleus Activity: Behavioral and Electrophysiological Evidence in Intact and 6-Hydroxydopamine-Lesioned Rats

“…A larger proportion of STN neurons are nevertheless burst-competent. Burst-competent neurons give specific responses, called plateau potentials, to short depolarizing current pulses given at hyperpolarized levels (Beurrier et al, 1999;Baufreton et al, 2003;Kass and Mintz, 2006). These responses always outlast the stimuli and resemble evoked bursts.…”

Phase relationships support a role for coordinated activity in the indirect pathway in organizing slow oscillations in basal ganglia output after loss of dopamine

“…This process could contribute to the increase in oscillations in the beta frequency (15-30 Hz) range observed in STN after dopamine cell lesion in awake preparations (Baufreton et al, 2005). This appears less suited for shaping slow oscillations, however, as, in the present results, phase relationships show that peak activity in the GP precedes the period of STN bursting by several hundred ms. A recent report by Kass and Mintz (2006), potentially relevant to the firing pattern triggered in the STN by slow antiphase oscillations in cortical and pallidal input, describes three coexisting patterns in STN neurons including pacemaker firing, burst mode, and a bistable state involving a relatively long-lasting silent plateau depolarization that tends to be preceded by a burst discharge. Relatively small changes in baseline membrane potentials, perhaps like those induced by alternating levels of excitatory input from cortex and inhibitory input from the GP, can trigger changes in STN firing between these patterns.…”

“…In vitro studies have made considerable progress in characterizing the neurophysiological properties of the STN neurons and exploring how different patterns of inhibitory and excitatory input might affect STN activity (Mintz et al, 1986;Nakanishi et al, 1987;Beurrier et al, 1999;Bevan and Wilson, 1999;Bevan et al, 2000Bevan et al, , 2002aWigmore and Lacey, 2000;Zhu et al, 2002;Do and Bean, 2003;Hallworth et al, 2003;Wilson et al, 2004a,b;Baufreton et al, 2005;Surmeier et al, 2005;Kass and Mintz, 2006). With respect to the interplay of excitatory and inhibitory input, GABAergic inhibition can increase the efficiency of STN response to excitatory input by promoting recovery of inactivated voltage-dependent Na+ (Na v ) channels (Baufreton et al, 2005).…”