Autonomous pacemakers in the basal ganglia: who needs excitatory synapses anyway?

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Autonomous pacemakers are crucial elements in many neural circuits. This is particularly true for the basal ganglia. This richly interconnected group of nuclei is rife with both fast- and slow-spiking pacemakers. Our understanding of the ionic mechanisms underlying pacemaking in these neurons is rapidly evolving, yielding new insights into the normal functioning of this network and how it goes awry in pathological states such as Parkinson's disease.

Introduction

Autonomous pacemakers — neurons capable of periodic spiking in the absence of synaptic input — are important participants in a wide array of neural circuits in both vertebrates and invertebrates. Several excellent recent reviews provide perspectives on various aspects of this broad topic [1, 2, 3]. However, one area not covered in these reviews is pacemaking in the basal ganglia. Similar to the cerebellum, the basal ganglia are intimately involved in motor control and are rife with fast and slow pacemakers. In the past few years, we’ve made great progress in unraveling the ionic mechanisms underlying this activity. This review briefly summarizes recent advances in our understanding of the ionic mechanisms underlying the two types of pacemaking that are found in the basal ganglia.

The basal ganglia are a group of richly interconnected nuclei that form part of what has traditionally been characterized as the extrapyramidal motor system [4]. The network is unique in the brain, in that it is dominated by sequential tiers of GABAergic neurons. Despite being dominated by inhibitory GABAergic neurons, the output of the basal ganglia is tonically active, exhibiting phasic pauses in association with movement. Initially, it was thought that the glutamatergic subthalamic nucleus (STN) drove this inhibitory network (being the only excitatory element) but we know now that the activity in all of the structures downstream of the striatum — the external and internal segments of the globus pallidus (GP or GPi), the substantia nigra pars reticulata (SNr) and the STN itself — are autonomously active. Because silence carries little information, making the neurons of the output nuclei autonomous pacemakers ensures that signals carried by GABAergic neurons in the striatum and globus pallidus are transmitted to those regions of the brain that the basal ganglia wants to talk to, such as the thalamus and pedunculopontine nucleus.

In addition to the autonomous pacemakers populating the output structures of the basal ganglia, neurons of this type are strategically positioned in two major nuclei processing incoming neural signals. In the striatum, the giant cholinergic interneurons, once thought to be the principal neuron, are autonomous pacemakers. Pauses in their activity are thought to generate a learning signal in the striatum. The pause in cholinergic interneuron activity is generated by synaptically accelerated activity in another basal ganglia pacemaker; the dopaminergic neuron of the substantia nigra pars compacta (SNc) [5].

Basal ganglia pacemakers can be divided into two categories formed upon the basis of the type of pacemaking they exhibit and their intrinsic properties. Principal neurons in the GP, STN and SNr are nominally fast-spiking pacemakers, capable of discharge rates in excess of 200 Hz for sustained periods. By contrast, striatal cholinergic interneurons and dopaminergic neurons are slow-spiking pacemakers, typically spiking at low frequencies (0.2–10 Hz).

Section snippets

Na+ currents drive autonomous pacemaking

Autonomous pacemaking in GP and STN neurons relies upon voltage-dependent Na+ channels [6•, 7, 8••, 9]. That is, Na+ channel blockers (tetrodotoxin [TTX]) abolish autonomous activity and subthreshold oscillations in membrane potential. In this respect, these basal ganglia neurons resemble cerebellar Purkinje neurons and deep cerebellar nuclei neurons [10, 11]. Similar to these cerebellar cell types, the Na+ currents in GP and STN neurons are unusual in that they exhibit ‘resurgence’ [12].

Slow-spiking pacemakers

Both striatal cholinergic interneurons and SNc dopaminergic neurons are slow spiking (0.1–10 Hz) autonomous pacemakers. Although similar in this respect, the ionic mechanisms underlying pacemaking in the two cells appear to be different.

Disease states

A wide variety of neurological disorders can be traced to altered function of the basal ganglia. Parkinson's disease, Huntington's disease, dystonia, Tourette's syndrome, attention deficit hyperperactivity disorder (ADHD) and schizophrenia are among the most prominent neurological diseases with strong links with the basal ganglia. Clear links between these diseases and alterations in pacemaking have not been made, but there are few or no data to refer to. In Parkinson's disease, the most

Conclusions and future directions

Although much progress has been made in the past five years, much remains to be discovered about autonomous pacemakers in the basal ganglia. The major players in autonomous pacemaking have been identified, but how do their roles change with phasic and tonic synaptic activity similar to that found in vivo? The roles played by supporting characters such as Kv1, Kv2 and KCNQ (Kv7) channels need better definition. A complete characterization of molecular identity of channels controlling pacemaking

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

NIH NINDS awards NS 34696, NS 047085 and a Picower Foundation grant supported this work.

References (64)

  • W. Xu et al.

    Neuronal Ca(V)1.3alpha(1) L-type channels activate at relatively hyperpolarized membrane potentials and are incompletely inhibited by dihydropyridines

    J Neurosci

    (2001)
  • P.A. Olson et al.

    G-protein-coupled receptor modulation of striatal CaV1.3 L-type Ca2+ channels is dependent on a Shank-binding domain

    J Neurosci

    (2005)
  • J. Wolfart et al.

    Differential expression of the small-conductance, calcium-activated potassium channel SK3 is critical for pacemaker control in dopaminergic midbrain neurons

    J Neurosci

    (2001)
  • M.J. Zigmond et al.

    Compensations after lesions of central dopaminergic neurons: some clinical and basic implications

    Trends Neurosci

    (1990)
  • C.A. Paladini et al.

    Dopamine controls the firing pattern of dopamine neurons via a network feedback mechanism

    Proc Natl Acad Sci USA

    (2003)
  • C.R. Lee et al.

    Pallidal control of substantia nigra dopaminergic neuron firing pattern and its relation to extracellular neostriatal dopamine levels

    Neuroscience

    (2004)
  • M. Hausser et al.

    The beat goes on: spontaneous firing in mammalian neuronal microcircuits

    J Neurosci

    (2004)
  • J.P. Bolam et al.

    Synaptic organisation of the basal ganglia

    J Anat

    (2000)
  • A.M. Graybiel et al.

    The basal ganglia and adaptive motor control

    Science

    (1994)
  • C.S. Chan et al.

    HCN2 and HCN1 channels govern the regularity of autonomous pacemaking and synaptic resetting in globus pallidus neurons

    J Neurosci

    (2004)
  • A.J. Cooper et al.

    Electrophysiological and morphological characteristics of three subtypes of rat globus pallidus neurone in vitro

    J Physiol

    (2000)
  • M.T. Do et al.

    Subthreshold sodium currents and pacemaking of subthalamic neurons: modulation by slow inactivation

    Neuron

    (2003)
  • I.M. Raman et al.

    Ionic currents and spontaneous firing in neurons isolated from the cerebellar nuclei

    J Neurosci

    (2000)
  • F.S. Afshari et al.

    Resurgent Na currents in four classes of neurons of the cerebellum

    J Neurophysiol

    (2004)
  • I.M. Raman et al.

    Resurgent sodium current and action potential formation in dissociated cerebellar Purkinje neurons

    J Neurosci

    (1997)
  • Z.M. Khaliq et al.

    The contribution of resurgent sodium current to high-frequency firing in Purkinje neurons: an experimental and modeling study

    J Neurosci

    (2003)
  • I.M. Raman et al.

    Altered subthreshold sodium currents and disrupted firing patterns in Purkinje neurons of Scn8a mutant mice

    Neuron

    (1997)
  • M.T. Do et al.

    Sodium currents in subthalamic nucleus neurons from Nav1.6-null mice

    J Neurophysiol

    (2004)
  • F.H. Yu et al.

    Sodium channel beta4, a new disulfide-linked auxiliary subunit with similarity to beta2

    J Neurosci

    (2003)
  • D.B. Carr et al.

    Transmitter modulation of slow, activity-dependent alterations in sodium channel availability endows neurons with a novel form of cellular plasticity

    Neuron

    (2003)
  • A.R. Cantrell et al.

    Neuromodulation of Na+ channels: an unexpected form of cellular plasticity

    Nat Rev Neurosci

    (2001)
  • N.E. Hallworth et al.

    Apamin-sensitive small conductance calcium-activated potassium channels, through their selective coupling to voltage-gated calcium channels, are critical determinants of the precision, pace, and pattern of action potential generation in rat subthalamic nucleus neurons in vitro

    J Neurosci

    (2003)
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