Elsevier

Revue Neurologique

Volume 174, Issue 9, November 2018, Pages 608-614
Revue Neurologique

International meeting of the French society of neurology & SOFMA 2018
Dystonia: Are animal models relevant in therapeutics?

https://doi.org/10.1016/j.neurol.2018.07.003Get rights and content

Abstract

Dystonia refers to a heterogeneous group of movement disorders characterized by involuntary, sustained muscle contractions leading to repetitive twisting movements and abnormal postures. A better understanding of the etiology, pathogenesis and molecular mechanisms underlying dystonia may be obtained from animal models. Indeed, while studies in vitro using cell and tissue models are helpful for investigating molecular pathways, animal models remain essential for studying the pathogenesis of these disorders and exploring new potential treatment strategies. To date, the mouse is the most common choice for mammalian models in most laboratories, particularly when manipulations of the genome are planned. Dystonia animal models can be classified into two categories, etiological and symptomatic, although neither is able to recapitulate all features of these disorders in humans. Nevertheless, etiological and symptomatic animal models have advantages and limitations that should be taken into consideration according to the specific proposed hypothesis and experimental goals. Etiological mouse models of inherited dystonia can reproduce the etiology of the disorder and help to reveal biochemical and cellular alterations, although a large majority of them lack motor symptoms. Conversely, symptomatic models can partially mimic the phenotype of human dystonia and test novel pharmacological agents, and also identify the anatomical and physiological processes involved, although the etiology remains unknown. Thus, our brief survey aims to review the state of the art as regards most of the commonly used animal models available for dystonia research.

Introduction

More than three million people worldwide suffer from dystonia [1], [2], a term that represents a heterogeneous group of disorders with a variable age of onset (in either childhood or adulthood) and which etiologically may have diverse causes; while genetic and acquired forms are now recognized, most cases are idiopathic [3]. Symptoms can differ significantly in severity, affecting one muscle, a group of muscles or the entire body [4]. However, all dystonias are characterized by an inability to select the correct motor patterns needed to perform specific movements and postures. Muscle activity initiates involuntary movements, especially during maintenance of postures, and then spreads to muscles that are usually not involved in that specific action [5]. Despite the high incidence of dystonia, only a few strictly symptomatic treatments are available, including both pharmacological and surgical approaches; these are expected to ameliorate involuntary movements, correct abnormal postures, relieve pain, prevent contractures and improve quality of life.

However, the development of better therapeutic strategies has been limited by our lack of understanding of the etiology and pathogenesis of dystonia, although significant steps have been taken over the last two decades towards better knowledge of the disease pathogenesis. Genetics has been highly successful in the identification of the numerous causative genes of different forms of monogenic dystonia, thereby providing novel insights to help explore the pathophysiology of these disorders [6], [7], [8]. In addition, functional neuroimaging studies have provided evidence that the anatomical substrates of dystonia are complex, fueling the concept of dystonia as a network disorder, involving both basal ganglia-thalamocortical and cerebello-thalamocortical networks, rather than an isolated dysfunction affecting only one region of the brain [9], [10], [11].

Dystonia research can benefit from animal models in the search for novel pathogenic mechanisms and for testing new therapeutic approaches to well-characterized processes. Yet, the fundamental questions now drawing the attention of the scientific community are how the currently available and future models might be able to recapitulate the human condition, and how predictive might they be of the successful translation of drug model findings applied for clinical purposes.

Three general criteria are now used to determine how relevant an animal model is to diseases in humans:

  • face validity of a model is its ability to reproduce the motor behavioral abnormalities observed in human disease;

  • construct validity compares the pathophysiological mechanisms reported in human conditions and animal models;

  • predictive validity refers to the correspondence of efficacy with a given therapeutic approach.

Every model may be able to fulfill one or more types of validity, although this is not necessarily required, as every model can certainly contribute towards building a larger body of evidence to improve our understanding of disease mechanisms.

Section snippets

Overview of preclinical models in dystonia research

Over the last decade, there has been a sharp increase in the number of dystonia animal models being developed. Selection of a particular model system largely depends on the specific hypotheses and overall goals of the experiment: studies in vitro are often restricted to questions of biochemistry and cell biology [12], whereas mammalian models are often essential for evaluating the efficacy of candidate drugs and devices that target specific receptors and/or structures in the brain. Thus, the

Experimental strategies for new treatments

Detailed characterizations of the currently available animal models of dystonia and the development of new ones hold promise of a better understanding of the pathophysiology of these disorders and the identification of novel treatments. Indeed, several strategies can now be put in place to identify new therapeutic agents while improving existing therapies and identifying new possible targets [40]. However, it should be borne in mind that our ability to detect clinically significant benefits in

Conclusion and future perspectives

Over the last several decades, animal research has provided invaluable information on the biochemical and cellular processes involved in the pathophysiology of human dystonia. In addition, despite some clear limitations such as the difficulty of devising models of both motor and non-motor features, rodent and non-human primate models nonetheless appear to be essential for bridging the translational gap between preclinical and clinical research. However, as no model has yet fulfilled every

Disclosure of interest

The authors declare that they have no competing interest.

References (64)

  • K.R. Isaacs et al.

    Cerebellar volume decreases in the tottering mouse are specific to the molecular layer

    Brain Res Bull

    (1995)
  • R.S. Raike et al.

    Animal models of generalized dystonia

    NeuroRx

    (2005)
  • H.A. Jinnah et al.

    Experimental therapeutics for dystonia

    Neurotherapeutics

    (2008)
  • A. Pisani et al.

    Re-emergence of striatal cholinergic interneurons in movement disorders

    Trends Neurosci

    (2007)
  • K.L. Eskow Jaunarajs et al.

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

    Prog Neurobiol

    (2015)
  • A. Quartarone et al.

    Abnormal plasticity in dystonia: disruption of synaptic homeostasis

    Neurobiol Dis

    (2011)
  • A. Pisani et al.

    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

    (2006)
  • G. Sciamanna et al.

    Negative allosteric modulation of mGlu5 receptor rescues striatal D2 dopamine receptor dysfunction in rodent models of DYT1 dystonia

    Neuropharmacology

    (2014)
  • C.J. Vaughan et al.

    Treatment of spastic dystonia with transdermal nicotine

    Lancet

    (1997)
  • M.F. Chesselet

    Presynaptic regulation of neurotransmitter release in the brain: facts and hypothesis

    Neuroscience

    (1984)
  • B. Zhao et al.

    Differential dopaminergic regulation of inwardly rectifying potassium channel mediated subthreshold dynamics in striatal medium spiny neurons

    Neuropharmacology

    (2016)
  • P.S. Ramachandran et al.

    Recent advances in RNA interference therapeutics for CNS diseases

    Neurotherapeutics

    (2013)
  • G. Defazio

    The epidemiology of primary dystonia: current evidence and perspectives

    Eur J Neurol

    (2010)
  • G. Defazio et al.

    The environmental epidemiology of primary dystonia

    Tremor Other Hyperkinet Mov (NY)

    (2013)
  • A. Albanese et al.

    Phenomenology and classification of dystonia: a consensus update

    Mov Disord

    (2013)
  • K. Lohmann et al.

    Genetics of dystonia: what's known? what's new? what's next?

    Mov Disord

    (2013)
  • T. Fuchs et al.

    Genetics in dystonia: an update

    Curr Neurol Neurosci Rep

    (2013)
  • G. Charlesworth et al.

    The genetics of dystonia: new twists in an old tale

    Brain

    (2013)
  • K. Asanuma et al.

    Neuroimaging in human dystonia

    J Med Invest

    (2005)
  • S. Lehéricy et al.

    The anatomical basis of dystonia: current view using neuroimaging

    Mov Disord

    (2013)
  • A. Tewari et al.

    It's not just the basal ganglia: cerebellum as a target for dystonia therapeutics

    Mov Disord

    (2017)
  • A. Ghallab

    In vitro test systems and their limitations

    EXCLI J

    (2013)
  • Cited by (10)

    • Dystonia

      2022, Neurobiology of Brain Disorders: Biological Basis of Neurological and Psychiatric Disorders, Second Edition
    • Models of dystonia: an update

      2020, Journal of Neuroscience Methods
      Citation Excerpt :

      Indeed, more than 20 DYT loci have been designated, and accordingly, several genes identified. A comprehensive review of all dystonia models available is beyond the scope of this short survey, and we refer the reader to other excellent reviews for more exhaustive, recent descriptions (Meringolo et al., 2018; Oleas et al., 2013; Pappas et al., 2014). Currently, many genes causative of distinct forms of monogenic dystonia have been identified (Jinnah and Sun, 2019; Lohmann and Klein, 2013; Marras et al., 2016; Verbeek and Gasser, 2016), however, to date, cellular pathomechanisms underlying most dystonias are largely unknown, and it also remains to be established whether different forms of dystonia may share common mechanisms.

    • Advances in molecular and cell biology of dystonia: Focus on torsinA

      2019, Neurobiology of Disease
      Citation Excerpt :

      A major drawback is the animal models that genetically replicate the human disease do not exhibit dystonia. A matter of debate in the dystonia field for years, rodents are clearly a helpful system to study torsinA biology, but less valuable to mirror the genotype-phenotype correlation observed in humans (Meringolo et al., 2018; Jinnah et al., 2008). How could we determine which of the biological pathways dysfunctional in DYT1 models are related to dystonia?

    View all citing articles on Scopus
    View full text