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