Dopamine D2 receptor dysfunction is rescued by adenosine A2A receptor antagonism in a model of DYT1 dystonia

Napolitano, Francesco; Pasqualetti, Massimo; Usiello, Alessandro; Santini, Emanuela; Pacini, Giulia; Sciamanna, Giuseppe; Errico, Francesco; Tassone, Annalisa; Dato, Valeria Di; Martella, Giuseppina; Cuomo, Dario; Fisone, Gilberto; Bernardi, Giorgio; Mandolesi, Georgia; Mercuri, Nicola Biagio; Standaert, David G.; Pisani, Antonio

doi:10.1016/j.nbd.2010.03.003

Cited by 94 publications

(83 citation statements)

References 56 publications

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“…However, since there is no direct evidence that such mAChR/D2R heterodimers exist, an alternative possibility could be that interactions occur at the level of the signaling pathways. This interpretation is supported by evidence that there is a dramatic decline in the ability of striatal D2Rs to activate their cognate G i/o proteins in transgenic DYT1 mice (Napolitano et al, 2010). …”

Section: Resultsmentioning

confidence: 84%

Strength of cholinergic tone dictates the polarity of dopamine D2 receptor modulation of striatal cholinergic interneuron excitability in DYT1 dystonia

Scarduzio

Zimmerman

Jaunarajs

et al. 2017

Experimental Neurology

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Balance between cholinergic and dopaminergic signaling is central to striatal control of movement and cognition. In dystonia, a common disorder of movement, anticholinergic therapy is often beneficial. This observation suggests there is a pathological increase in cholinergic tone, yet direct confirmation is lacking. In DYT1, an early-onset genetic form of dystonia caused by a mutation in the protein torsinA (TorA), the suspected heightened cholinergic tone is commonly attributed to faulty dopamine D2 receptor (D2R) signaling where D2R agonists cause excitation of striatal cholinergic interneurons (ChIs), rather than the normal inhibition of firing observed in wild-type animals, an effect known as “paradoxical excitation”. Here, we provide for the first time direct measurement of elevated striatal extracellular acetylcholine (ACh) in a knock-in mouse model of human DYT1 dystonia (TorAΔE/+ mice), confirming a striatal hypercholinergic state. We hypothesized that this elevated extracellular ACh might cause chronic over-activation of muscarinic acetylcholine receptors (mAChRs) and disrupt normal D2R function due to their shared coupling to Gi/o-proteins. We tested this concept in vitro first using a broad-spectrum mAChR antagonist, and then using a M2/M4 mAChR selective antagonist to specifically target mAChRs expressed by ChIs. Remarkably, we found that mAChR inhibition reverses the D2R–mediated paradoxical excitation of ChIs recorded in slices from TorAΔE/+ mice to a typical inhibitory response. Furthermore, we recapitulated the paradoxical D2R excitation of ChIs in striatal slices from wild type mice within minutes by simply increasing cholinergic tone through pharmacological inhibition of acetylcholinesterase (AChE) or by prolonged agonist activation of mAChRs. Collectively, these results show that enhanced mAChR tone itself is sufficient to rapidly reverse the polarity of D2R regulation of ChI excitability, correcting the previous notion that the D2R mediated paradoxical ChI excitation causes the hypercholinergic state in dystonia. Further, using a combination of genetic and pharmacological approaches, we found evidence that this switch in D2R polarity results from a change in coupling from the preferred Gi/o pathway to non-canonical β-arrestin signaling. These results highlight the need to fully understand how the mutation in TorA leads to pathologically heightened extracellular ACh. Furthermore the discovery of this novel ACh-dopamine interaction and the participation of β-arrestin in regulation of cholinergic interneurons is likely important for other basal ganglia disorders characterized by perturbation of ACh-dopamine balance, including Parkinson and Huntington diseases, l-DOPA-induced dyskinesia and schizophrenia.

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Section: Resultsmentioning

confidence: 84%

Strength of cholinergic tone dictates the polarity of dopamine D2 receptor modulation of striatal cholinergic interneuron excitability in DYT1 dystonia

Scarduzio

Zimmerman

Jaunarajs

et al. 2017

Experimental Neurology

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“…In vitro studies, however, have shown that WT mice have a reduction in the autonomous pace-making tone of SCIs in response to striatal HFS, whereas the tonic firing patterns of SCIs in Dyt1 KI mice remain elevated (i.e., LTD deficit: Dang et al, 2012; Maltese et al, 2009; Yokoi et al, 2015). This finding has been attributed to the disrupted binding affinity of D2 dopamine receptors in the indirect basal ganglia pathway (Balcioglu et al, 2007; Calabresi et al, 1992) and the resultant disinhibition of ACh release from SCIs (Dang et al, 2012; Martella et al, 2009; Napolitano et al, 2010; Pisani et al, 2006). …”

Section: Discussionmentioning

confidence: 99%

In vivo imaging reveals impaired connectivity across cortical and subcortical networks in a mouse model of DYT1 dystonia

DeSimone

Febo

Shukla

et al. 2016

Neurobiology of Disease

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Developing in vivo functional and structural neuroimaging assays in Dyt1 ΔGAG heterozygous knock-in (Dyt1 KI) mice provide insight into the pathophysiology underlying DYT1 dystonia. In the current study, we examined in vivo functional connectivity of large-scale cortical and subcortical networks in Dyt1 KI mice and wild-type (WT) controls using resting-state functional magnetic resonance imaging (MRI) and an independent component analysis. In addition, using diffusion MRI we examined how structural integrity across the basal ganglia and cerebellum directly relates to impairments in functional connectivity. Compared to WT mice, Dyt1 KI mice revealed increased functional connectivity across the striatum, thalamus, and somatosensory cortex; and reduced functional connectivity in the motor and cerebellar cortices. Further, Dyt1 KI mice demonstrated elevated free-water (FW) in the striatum and cerebellum compared to WT mice, and increased FW was correlated with impairments in functional connectivity across basal ganglia, cerebellum, and sensorimotor cortex. The current study provides the first in vivo MRI-based evidence in support of the hypothesis that the deletion of a 3-base pair (ΔGAG) sequence in the Dyt1 gene encoding torsinA has network level effects on in vivo functional connectivity and microstructural integrity across the sensorimotor cortex, basal ganglia, and cerebellum.

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“…Pettit et al, 1990; Szumlinski et al, 2009). Indeed, abnormalities of dopamine D2 receptors have been identified in DYT1 patients (Carbon et al, 2009) and mice (Napolitano et al, 2010)…”

Section: Discussionmentioning

confidence: 99%

Cell-autonomous alteration of dopaminergic transmission by wild type and mutant (ΔE) TorsinA in transgenic mice

Page

André

et al. 2010

Neurobiology of Disease

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Early onset torsion dystonia is an autosomal dominant movement disorder of variable caused by a glutamic acid, i.e. ΔE, deletion in DYT1, encoding the protein torsinA. Genetic and structural data implicate basal ganglia dysfunction in dystonia. TorsinA, however, is diffusely expressed, and therefore the primary source of dysfunction may be obscured in pan-neuronal transgenic mouse models. We utilized the tyrosine hydroxylase (TH) promoter to direct transgene expression specifically to dopaminergic neurons of the midbrain to identify cell-autonomous abnormalities. Expression of both the human wild type (hTorsinA) and mutant (ΔE-hTorsinA) protein resulted in alterations of dopamine release as detected by microdialysis and fast cycle voltammetry. Motor abnormalities detected in these mice mimicked those noted in transgenic mice with pan-neuronal transgene expression. The locomotor response to cocaine in both TH-hTorsinA and TH-ΔE-hTorsinA, in the face of abnormal extracellular DA levels relative to non-transgenic mice, suggests compensatory, post-synaptic alterations in striatal DA transmission. This is the first cell-subtype-specific DYT1 transgenic mouse that can serve to differentiate between primary and secondary changes in dystonia, thereby helping to target disease therapies.

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Dopamine D2 receptor dysfunction is rescued by adenosine A2A receptor antagonism in a model of DYT1 dystonia

Cited by 94 publications

References 56 publications

Strength of cholinergic tone dictates the polarity of dopamine D2 receptor modulation of striatal cholinergic interneuron excitability in DYT1 dystonia

Strength of cholinergic tone dictates the polarity of dopamine D2 receptor modulation of striatal cholinergic interneuron excitability in DYT1 dystonia

In vivo imaging reveals impaired connectivity across cortical and subcortical networks in a mouse model of DYT1 dystonia

Cell-autonomous alteration of dopaminergic transmission by wild type and mutant (ΔE) TorsinA in transgenic mice

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