Striatal cholinergic dysfunction as a unifying theme in the pathophysiology of dystonia

Jaunarajs, Karen L. Eskow; Bonsi, Paola; Chesselet, Marie Françoise; Standaert, David G.; Pisani, Antonio

doi:10.1016/j.pneurobio.2015.02.002

Cited by 149 publications

(130 citation statements)

References 293 publications

(400 reference statements)

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“…Catalepsy in rodents is a model of the extrapyramidal syndrome and of parkinsonisms that follow antipsychotic therapies (Eskow Jaunarajs et al, 2015; Seeman, 2010). The selective, cell-specific D2R ablation in cholinergic interneurons allowed us to reveal the neuronal mechanisms underlying haloperidol-induced effects.…”

Section: Discussionmentioning

confidence: 99%

Parkinsonism Driven by Antipsychotics Originates from Dopaminergic Control of Striatal Cholinergic Interneurons

Kharkwal

Brami‐Cherrier

Lizardi-Ortiz

et al. 2016

Neuron

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Summary Typical antipsychotics can cause disabling side effects. Specifically, antagonism of D2R signaling by the typical antipsychotic haloperidol induces parkinsonism in humans and catalepsy in rodents. Striatal dopamine D2 receptors (D2R) are major regulators of motor activity through their signaling on striatal projection neurons and interneurons. We show that D2R signaling on cholinergic interneurons contributes to an in vitro pause in firing of these otherwise tonically active neurons and to the striatal dopamine/acetylcholine balance. The selective ablation of D2R from cholinergic neurons allows discrimination between the motor-reducing and cataleptic effects of antipsychotics. The cataleptic effect of antipsychotics is triggered by blockade of D2R on cholinergic interneurons and the consequent increase of acetylcholine signaling on striatal projection neurons. These studies illuminate the critical role of D2R-mediated signaling in regulating the activity of striatal cholinergic interneurons and the mechanisms of typical antipsychotic side effects.

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Section: Discussionmentioning

confidence: 99%

Parkinsonism Driven by Antipsychotics Originates from Dopaminergic Control of Striatal Cholinergic Interneurons

Kharkwal

Brami‐Cherrier

Lizardi-Ortiz

et al. 2016

Neuron

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“…Defining this interaction will have significant impact on understanding the most common basal ganglia motor disorders which are often associated with alterations in the normal balance between dopaminergic and cholinergic systems (Pisani et al, 2007; Aosaki et al, 2010; Bonsi et al, 2011; Benarroch, 2012). Dystonia, a common motor disorder characterized by abnormal muscle contractions, is of particular relevance in this context because of abundant evidence for alterations in striatal cholinergic-dopaminergic balance (Breakefield et al, 2008; Eskow Jaunarajs et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

“…Mounting evidence suggests imbalanced cholinergic transmission plays a pivotal role in the pathophysiology of DYT1 dystonia (Eskow Jaunarajs et al, 2015). Clinically, anticholinergic drugs (e.g., trihexyphenidyl) are the most effective treatments available for DYT1 and other dystonias (Jankovic, 2013).…”

Section: Introductionmentioning

confidence: 99%

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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“…Electrophysiological evidence of impaired bi-directional plasticity and synaptic integration within the cortico-striatal-thalamic pathway of overtly asymptomatic DYT1 mouse models has been related to a paradoxical increase in the activity of SCIs (Dang et al, 2012; Martella et al, 2009; 2014; Sciamanna et al, 2011; 2012a; 2012b; see also Eskow Jaunarajs et al, 2015). The current findings support cholinergic involvement in the compromised integrity of this major functional pathway in a symptomatic mouse model.…”

Section: Discussionmentioning

confidence: 99%

Forebrain knock-out of torsinA reduces striatal free-water and impairs whole-brain functional connectivity in a symptomatic mouse model of DYT1 dystonia

DeSimone

Pappas

Febo

et al. 2017

Neurobiology of Disease

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Multiple lines of evidence implicate striatal dysfunction in the pathogenesis of dystonia, including in DYT1, a common inherited form of the disease. The impact of striatal dysfunction on connected motor circuits and their interaction with other brain regions is poorly understood. Conditional knock-out (cKO) of the DYT1 protein torsinA from forebrain cholinergic and GABA-ergic neurons creates a symptomatic model that recapitulates many characteristics of DYT1 dystonia, including the developmental onset of overt twisting movements that are responsive to anti-muscarinic drugs. We performed diffusion MRI and resting-state functional MRI on cKO mice of either sex to define abnormalities of diffusivity and functional connectivity in cortical, subcortical, and cerebellar networks. The striatum was the only region to exhibit an abnormality of diffusivity, indicating a selective microstructural deficit in cKO mice. The striatum of cKO mice exhibited widespread increases in functional connectivity with somatosensory cortex, thalamus, vermis, cerebellar cortex and nuclei, and brainstem. The current study provides the first in vivo support that direct pathological insult to forebrain torsinA in a symptomatic mouse model of DYT1 dystonia can engage genetically normal hindbrain regions into an aberrant connectivity network. These findings have important implications for the assignment of a causative region in CNS disease.

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Striatal cholinergic dysfunction as a unifying theme in the pathophysiology of dystonia

Cited by 149 publications

References 293 publications

Parkinsonism Driven by Antipsychotics Originates from Dopaminergic Control of Striatal Cholinergic Interneurons

Parkinsonism Driven by Antipsychotics Originates from Dopaminergic Control of Striatal Cholinergic Interneurons

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

Forebrain knock-out of torsinA reduces striatal free-water and impairs whole-brain functional connectivity in a symptomatic mouse model of DYT1 dystonia

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