Trends in Neurosciences
Volume 30, Issue 10, October 2007, Pages 545-553
Journal home page for Trends in Neurosciences

Review
Re-emergence of striatal cholinergic interneurons in movement disorders

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Twenty years ago, striatal cholinergic neurons were central figures in models of basal ganglia function. But since then, they have receded in importance. Recent studies are likely to lead to their re-emergence in our thinking. Cholinergic interneurons have been implicated as key players in the induction of synaptic plasticity and motor learning, as well as in motor dysfunction. In Parkinson's disease and dystonia, diminished striatal dopaminergic signalling leads to increased release of acetylcholine by interneurons, distorting network function and inducing structural changes that undoubtedly contribute to the symptoms. By contrast, in Huntington's disease and progressive supranuclear palsy, there is a fall in striatal cholinergic markers. This review gives an overview of these recent experimental and clinical studies, placing them within the context of the pathogenesis of movement disorders.

Introduction

Current views of basal ganglia dysfunction point to the striatum, where dopamine (DA) and acetylcholine (ACh) interact, as a principal locus of the pathophysiological changes in brain function underlying movement disorders, such as Parkinson's disease (PD), Huntington's disease (HD), dystonia and Tourette syndrome 1, 2, 3, 4, 5. Traditionally, central cholinergic pathways have been divided into two major categories. Cholinergic projection neurons in both basal forebrain and mesopontine nuclei give rise to ascending pathways that target subcortical and cortical areas. Conversely, cholinergic interneurons are found in regions with a dense dopaminergic innervation, such as the dorsal and ventral striatum (Box 1) 6, 7, 8, where dopaminergic afferents exert a powerful control over cholinergic transmission.

In the absence of pathology, DA inhibits the autonomous spiking of striatal cholinergic interneurons and their release of ACh 9, 10. This modulation is mediated by D2 DA receptors expressed by the interneurons. Although ACh release increases as striatal DA levels fall, the mechanisms underlying this change are not entirely clear. It seems unlikely that this is a simple disinhibition mediated by D2 receptors because the autonomous spike activity of cholinergic interneurons does rise as expected in this model. One of the principal means by which cholinergic interneurons regulate transmitter release is with terminal autoreceptors (as most neurons); in cholinergic interneurons, autoreceptors appear to be M2/M4 muscarinic receptors 11, 12. Recent work has suggested that the loss of striatal DA attenuates M4 autoreceptor signalling by upregulating RGS4 proteins in cholinergic interneurons, leading to increased ACh release [13]. Likewise, several forms of dystonia are characterized by dopaminergic dysfunction and hyperactivity of striatal cholinergic interneurons 4, 14, 15. Muscarinic receptor antagonists are effective in the symptomatic treatment of both PD and dystonia 16, 17, strengthening the linkage between these adaptations in cholinergic signalling and disease aetiology.

Deficits in striatal cholinergic signalling have been linked to neurodegenerative diseases. In both HD and progressive supranuclear palsy (PSP), functional imaging and post-mortem studies have revealed a significant loss of striatal cholinergic markers 18, 19, 20.

Section snippets

Clues from neuroanatomy and physiology

Most striatal neurons are medium spiny (MS) GABAergic projection neurons, constituting nearly 95% of the entire neuronal population 21, 22. The remaining striatal neurons are interneurons. Four subtypes of interneuron have been described 23, 24, 25. Three of these interneurons are GABAergic: one coexpresses parvalbumin, one calretinin and one nitric oxide synthase. The fourth interneuron is cholinergic 7, 8, 25. These giant aspiny interneurons have richly arborizing axons with large terminal

Cholinergic interneurons are bidirectional modulators of striatal synaptic plasticity

Long-lasting changes in synaptic efficacy at MS neuron corticostriatal synapses are thought to be the cellular basis of motor learning and associative memory processes. High-frequency stimulation of glutamatergic afferents in combination with postsynaptic depolarization (HFS-DP) can induce the expression of either long-term depression (LTD) or long-term potentiation (LTP) at this synapse 40, 41, 42. The signalling mechanisms controlling the induction appear to be complex and cell-type specific

Beyond a role in reward learning and motivation

Years ago, in vivo recordings from the striatum of monkeys, which were awake and behaving, identified an unusual class of tonically active neurons, referred to as TANs. Unlike most striatal neurons which were silent most of the time, these TANs were very active (3–9 Hz) in the absence of any overt stimulation or movement task. In associative learning paradigms, the tonic activity of TANs was modulated by the presentation of stimuli with incentive value 50, 51. The most consistent feature of the

Cholinergic interneurons in disease

Archetypes of basal ganglia organization are based on anatomical and functional evidence obtained from both animal models and patients affected by movement disorders 60, 61. These models predict the existence of distinct, parallel loops that integrate cortical areas with basal ganglia regions. The imbalance between these pathways is believed to account for the hyper- and hypo-kinetic manifestations of movement disorders. This heuristic model has allowed the identification of new targets for

Parkinson's disease

Different gene mutations that cause familial forms of PD have been identified. However, most cases are sporadic, and are thought to be the result of complex interactions between the environment and the genetic background 62, 63. Cardinal features of PD are represented by resting tremor, rigidity, bradykinesia, impaired balance, often complicated by cognitive and emotional disturbances.

Muscarinic receptor antagonists were the first accepted treatment for PD [16], and are still in clinical use,

Huntington's disease

Huntington's disease (HD) is an autosomal dominant disease caused by a mutation in the gene encoding huntingtin and is characterized by involuntary choreiform movements, and behavioural and cognitive impairment. An abnormal expansion of CAG trinucleotide repeats in the gene coding for huntingtin results in an increased series of glutamines in the N-terminus of the protein [73]. Although striatal cholinergic interneurons do not degenerate in HD [3], recent studies suggest that they might be

Future research directions

Studies spanning both basic and clinical neuroscience suggest that several movement disorders are causally linked to dysfunction of striatal cholinergic signalling. However, to date, therapeutic strategies targeting cholinergic signalling in these disorders leave much to be desired. In those conditions in which there is clear evidence for increased cholinergic signalling, such as PD and dystonia, strategies aimed at enhancing M4 autoreceptor function should be pursued. Because M4 receptors are

Acknowledgements

We would like to thank all the members of our laboratories as well as our collaborators for their invaluable contributions. This work was supported by grants from Bachmann-Strauss Dystonia and Parkinson's Foundation, Dystonia Medical Research Foundation to AP; Ministero Salute (Prog. Finalizzato and Art. 56) to GB and AP; Istituto Superiore Sanità (Malattie Rare) to AP.

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