Trends in Neurosciences
ReviewRe-emergence of striatal cholinergic interneurons in 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.
References (81)
Pathophysiology of the basal ganglia in Parkinson's disease
Trends Neurosci.
(2000)- et al.
Recent advances in Tourette syndrome research
Trends Neurosci.
(2006) - et al.
Cholinergic systems in the rat brain: III. Projections from the pontomesencephalic tegmentum to the thalamus, tectum, basal ganglia, and basal forebrain
Brain Res. Bull.
(1986) - et al.
Cholinergic neurons in the caudate-putamen complex proper are intrinsically organized: a combined Evans blue and acetylcholinesterase analysis
Brain Res. Bull.
(1981) Characterization of cholinergic interneurons in the rat neostriatum. A combination of choline acetyltransferase immunocytochemistry, Golgi-impregnation and electron microscopy
Neuroscience
(1984)Dopaminergic inhibition of striatal acetylcholine release after 6-hydroxydopamine
Eur. J. Pharmacol.
(1989)Spontaneous release of acetylcholine in striatum is preferentially regulated by inhibitory dopamine D2 receptors
Eur. J. Pharmacol.
(1996)- et al.
The frequency and distribution of medium-sized neurons with indented nuclei in the primate and rodent neostriatum
Brain Res.
(1985) Striatal interneurones: chemical, physiological and morphological characterization
Trends Neurosci.
(1995)- et al.
Functional diversity of neostriatal interneurons
Curr. Opin. Neurobiol.
(2004)
The mechanism of intrinsic amplification of hyperpolarizations and spontaneous bursting in striatal cholinergic interneurons
Neuron
Leading tonically active neurons of the striatum from reward detection to context recognition
Trends Neurosci.
D5 dopamine receptors enhance Zn2+-sensitive GABA(A) currents in striatal cholinergic interneurons through a PKA/PP1 cascade
Neuron
Acetylcholine-mediated modulation of striatal function
Trends Neurosci.
Thalamic inputs to striatal interneurons in monkeys: synaptic organization and co-localization of calcium-binding proteins
Neuroscience
Dopaminergic control of corticostriatal long-term synaptic depression in medium spiny neurons is mediated by cholinergic interneurons
Neuron
Coincident but distinct messages of midbrain dopamine and striatal tonically active neurons
Neuron
Primate models of movement disorders of basal ganglia origin
Trends Neurosci.
The functional anatomy of basal ganglia disorders
Trends Neurosci.
TorsinA protein and neuropathology in early onset generalized dystonia with GAG deletion
Neurobiol. Dis.
Altered responses to dopaminergic D2 receptor activation and N-type calcium currents in striatal cholinergic interneurons in a mouse model of DYT1 dystonia
Neurobiol. Dis.
Treatment of dystonia
Lancet Neurol.
Pathophysiology of Parkinson's disease: the MPTP primate model of the human disorder
Ann. N. Y. Acad. Sci.
Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington's disease
Science
Dopamine transmission in DYT1 dystonia
Adv. Neurol.
Muscarinic IPSPs in rat striatal cholinergic interneurones
J. Physiol.
Characterization of central inhibitory muscarinic autoreceptors by the use of muscarinic acetylcholine receptor knock-out mice
J. Neurosci.
RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion
Nat. Neurosci.
Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease)
Ann. Neurol.
Developments in the molecular biology of DYT1 dystonia
Mov. Disord.
Treatment of dystonia
Cholinergic neuronal defect without cell loss in Huntington's disease
Hum. Mol. Genet.
Cholinergic systems in progressive supranuclear palsy
Brain
Cholinergic vesicular transporters in progressive supranuclear palsy
Neurology
A Golgi study of rat neostriatal neurons: light microscopic analysis
J. Comp. Neurol.
Cholinergic interneuron characteristics and nicotinic properties in the striatum
J. Neurobiol.
Fine structural features of the acetylcholine innervation in the developing neostriatum of rat
J. Comp. Neurol.
Spontaneous activity of neostriatal cholinergic interneurons in vitro
J. Neurosci.
D2 dopamine receptor-mediated modulation of voltage-dependent Na+ channels reduces autonomous activity in striatal cholinergic interneurons
J. Neurosci.
Cited by (375)
DYT1 dystonia: Neurophysiological properties of the pallidal activity
2023, Parkinsonism and Related DisordersNicotinic acetylcholine receptors and epilepsy
2023, Pharmacological ResearchMotor deficit and lack of overt dystonia in Dlx conditional Dyt1 knockout mice
2023, Behavioural Brain Research