Cholinergic nicotinic receptor involvement in movement disorders associated with Lewy body diseases. An autoradiography study using [125I]α-conotoxinMII in the striatum and thalamus
Introduction
The neuropathological hallmark of dementia with Lewy bodies (DLB) and Parkinson's disease (PD) is the presence of Lewy bodies, which are α-synuclein-containing inclusions (Litvan et al., 1998). The clinical symptoms of DLB include dementia, recurrent visual hallucinations, and altered attention and fluctuating cognition, with many patients also developing a movement disorder resembling symptoms of PD such as limb rigidity, bradykinesia, and gait disorder (McKeith, 2002, McKeith, 2004). The motor symptoms in both DLB and PD are associated with nigrostriatal pathology (Agid, 1991, Ince et al., 1995, Perry et al., 1990, Piggott and Marshall, 1996). In both these disorders, decreased levels of nicotinic acetylcholine receptors (nAChRs) with high affinity for ligands such as nicotine, epibatidine, and 5-IA-85380 have been reported in the striatum (Court et al., 2000, Guan et al., 2002, Martin-Ruiz et al., 2000, Perry et al., 1995, Pimlott et al., 2004).
High-affinity nAChRs constitute a potentially wide spectrum of subtypes. In mammalian brain, they may be composed of five subunits comprising one or more of three types of beta subunit (β2–4) and one or more of six alpha subunit types (α2–α6) (Corringer et al., 2000, Le Novere and Changeux, 1995, Lukas et al., 1999, McGehee and Role, 1995). Most radioligands used to explore human nAChRs pathologies, for example, [3H]nicotine and [3H]epibatidine, have broad specificity for high-affinity nAChRs. [3H]cytisine binds with apparent selectivity to α4* receptors (* denotes receptors containing the indicated subunits) (Davila-Garcia et al., 1997, Gotti, 1997, Perry et al., 1995). 5-[125I]-A-85380 (5-IA-85380) is a newer ligand useful in human in vivo studies, can be used to visualize α4* receptors but probably also binds to α6* receptors (Kulak et al., 2002, Pimlott et al., 2004). In contrast, [125I]α conotoxin MII ([125I]αCtxMII), a radioligand based on a peptide extracted from the venom of a predatory snail (Conus magus) is reported to bind to α3* and α6* nAChRs (Cartier et al., 1996, Kulak et al., 1997, Kuryatov et al., 2000, McIntosh et al., 1999, Vailati et al., 1999, Whiteaker et al., 2000). However, the use of α6 nAChRs knock-out mice indicates that α3* receptors may make only a minor contribution to the binding observed with [125I]CtxMII in the mouse striatum (Champtiaux et al., 2003).
There is an accumulating body of evidence suggesting a role for α6/α3* receptors in the mammalian striatum, consistent with the presence of these subtypes of receptors located in part on dopaminergic nigrostriatal terminals (Champtiaux et al., 2002, Champtiaux et al., 2003, Kulak et al., 2001, Quik et al., 2001, Quik et al., 2003, Quik et al., 2004). Recent studies (using immunoprecipitation, knockout gene constructs, electrophysiological recordings and in vivo microdialysis) have shown that two subtypes of nAChRs, *α4β2 and *α6β2, play an important role in striatal dopamine release. Moreover, an additional subtype containing both α4 and α6 subunits in association with β2 subunits has been identified as potentially contributing to the modulation of dopamine release (Champtiaux et al., 2003). In nigrostriatal structures, α6* receptors appear to be present predominately on axonal terminals of dopaminergic neurons. In contrast, α4* receptors rather than α6* appear to be located in other sites within the nigrostriatal system, including on somatodendrites of dopaminergic neurons and GABA-ergic neurons in the substantia nigra (Champtiaux et al., 2003, Mansvelder and McGehee, 2002). Therefore, α6* receptors may be regarded as particularly important in the modulation of dopamine release from terminals of nigrostriatal neurons. A recent study correlating [125I]α-conotoxinMII binding and the density of dopamine transporters in human PD tissue (Quik et al., 2004) corroborates the important role of α6* receptors in dopamine release in the striatum.
In contrast to the striatum, there is little current understanding of the role of α6* receptors in thalamic function. Thalamic nuclei, which are a part of the voluntary movement control system (ventral lateral, ventral anterior, centromedian), receive inputs from the striatum via globus pallidus pars interna and the substantia nigra pars reticulata and project to the motor and premotor cortex (Deniau et al., 1992, Jones, 1985). A more recent study also indicates dopaminergic input to the thalamus via collaterals of nigrostriatal projections (Freeman et al., 2001).
Studies investigating [3H]nicotine (Court et al., 1999, Spurden et al., 1997), [3H]cytisine (Rubboli et al., 1994), [3H]epibatidine (Marutle et al., 1998) and [125I]5-I-A-85380 binding (Pimlott et al., 2004) indicate a high density of nAChRs in the human thalamus. Furthermore, reductions in nAChR binding density in some thalamic nuclei in DLB and PD have been demonstrated with [3H]nicotine (Court et al., 1999) and 5-IA-85380 (Pimlott et al., 2004) autoradiography.
Since α6/α3* receptors may represent selective therapeutic targets for age-related neurodegenerative disorders that are associated with movement disorders, the present autoradiographic study using [125I]CtxMII was undertaken to investigate potential changes in striatal and thalamic α6/α3* nAChRs in patients diagnosed with Lewy body disorders, with and without extra-pyramidal features. Group comparisons were made between patients diagnosed with DLB with and without extra-pyramidal features (termed DLB + EPF and DLB − EPF, respectively), PD and age-matched controls. Contiguous sections were also used to estimate striatal dopamine transporters (DAT) as a measure of the relative integrity of dopaminergic projections. In addition, tissue from three cases of Alzheimer's disease (AD) was included to act as a disease control, with minimal nigro-striatal dopaminergic pathology.
Section snippets
Chemicals
[125I]-α-conotoxinMII ([125I]Ctx MII), specific activity 2125 Ci/mmol, was synthesized by the University of Utah, USA. Radiolabeled (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(4′-methylphenyl) nortropane ([125I] PE2I), specific activity 2000 Ci/mmol, was synthesized by University of Francois Rabelais, Tours, France. Other chemicals used in autoradiography were purchased from Sigma-Aldrich, UK, unless indicated otherwise.
Human brain tissue
Tissue was collected at autopsy, sliced coronally (1-cm thickness), and
[125I]CtxMII binding
Images of representative total and nonspecific binding in the striatum, selected thalamic nuclei, and in adjacent structures are shown in Fig. 1. The values of [125I]CtxMII specific binding (mean ± SD) in patient groups are indicated in Table 2.
Visual structures (optic tract and lateral geniculate nucleus) were the most strongly labeled by [125I]CtxMII in all patient groups. Intermediate binding was observed in the striatum and select thalamic nuclei (anterioventral, parafascicular, and
Discussion
In common with other investigations performed using [125I]CtxMII in animals (Quik et al., 2001, Whiteaker et al., 2000), and in humans (Quik et al., 2004), the highest values of [125I]CtxMII binding in human brain in the present study were observed in structures related to visual information processing (optic tract and lateral geniculate nucleus) and the striatum. However, the present findings and those of Quik et al. (2004) indicate that, unlike rodents and even monkeys, [125I]CtxMII binding
Acknowledgments
The work was supported by Medical Research Council DLB Program, grant number RES0211/7003/052, and the European Union (NIDE project), grant number Res-0211-7200.
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