DS0407 -

Alterations of motor networks in primary dystonia – AMEDYST

Understand the neurobiological mechanisms causing dystonia.

To progress in the understanding of the mechanisms of dystonia, we study animal models of this disease and we explore physiological alterations in dystonic patients. We are investigating how the functional interactions between the striatum and cerebellum are involved in the development of symptoms.

Altered interactions of motor circuits in the basal ganglia and cerebellum in hereditary dystonia

Dystonia is a relatively common motor disorder that is observed in multiple neurological diseases with genetic or neurodegenerative origin. The physiological mechanisms underlying this motor disorder are still rather unclear and this lack of knowledge prevents therapeutic progress for this disease. However, the pathophysiological mechanisms would involve a combination of abnormalities in the two major circuits controlling motor function, basal ganglia and cerebellum. <br />Our project is based partly on new animal models of dystonia that mimic pathogenic mutations of the GNAL and ADCY5 genes. Both genes encode proteins playing an important role in the physiology of striatum, the entry structure of the basal ganglia. We seek to better understand the dysfunctions caused by these mutations in striatal neurons. Given the involvement of the cerebellum in dystonia, we explore how manipulations of the cerebellar-thalamo-striatal pathway can inhibit or amplify motor disorders triggered by mutations in animals. Studies in dystonic patients are investigating the effects of trans-cranial stimulation or inhibition of the cerebellum on dystonia and alterations in brain function. The combination of explorations in the patient and animal should provide insight into mechanisms at the origin of dystonia with the aim of preventing or reducing dystonic disorders.

• We use several mouse lines, some of which are created by us. The Gnal+/- and R418W-ADCY5 lines reproduce, in mice, mutations of the Gnal and ADCY5 genes that cause movement disorders in humans. We have generated a new line allowing Gnal gene knockouts in targeted cells.
• The impact of various mutations and cholinergic receptor stimulation is investigated on striatal neurons by ex vivo methods: 1) by visualizing protein phosphorylation changes in striatal neurons by immunohistoflurorescence; 2) by measuring fluorescence changes of biosensors in neurons on brain sections.
• Electrophysiological recordings in the cerebello-thalamo-striatal pathway are associated with optogenetic stimulations of the cerebellum to compare mouse models of dystonia with control mice.
• Electrophysiological recordings are performed in dystonic patients when implanted by electrodes for deep brain stimulation. These recordings are associated with stimulations of the cerebellum.
• Functional Magnetic Resonance Imaging (fMRI) is used to compare brain activity in dystonic and control patients and to evaluate the impact of transcranial magnetic stimulation of cerebellum.

• We have shown that untreated and oxotremorine-treated Gnal+/- mice provide models of pre-symptomatic and symptomatic stages of dystonia associated with DYT25, respectively. We have established that M1-type muscarinic receptor antagonist molecules block dystonic-like movements in this model.
• We observed that treatment of mice with oxotremorine had different effects on a population of striatal neurons (indirect projection neurons) in Gnal+/- mice and wild animals. It is now needed to prove that these divergent effects are involved in the occurrence of abnormal movements observed in Gnal+/- mice under oxotremorine.
• Electrophysiological recordings of Gnal+/- mice and optogenetic stimulation of the cerebellum produced preliminary preliminary results.
• The various authorizations for clinical studies were obtained or submitted. Protocols have been validated and optimized in pilot experiments and patient recruitment is ongoing.
• We have generated a new mouse line to study motor disorders related to the ADCY5 gene.

The prospects remain preliminary since the project has not yet provided all the expected results. However, we will seek to evaluate the therapeutic potential of different classes of muscarinic antagonists as well as A2A adenosine receptor antagonists, by more precisely evaluating their effects in animal models of dystonia. Preclinical and clinical studies will test the beneficial action of various types of cerebellar stimulation, including trans-cranial in humans, to dystonia.

The project gave rise to the publication of an article in J Neuroscience (Pelosi et al 2017), a journal with a good impact factor in Neuroscience. This article resulted from the direct collaboration of Partners 1 and 2. A student defended an M2 on a topic of the AMEDYST project. In addition, 3 posters bringing together Partners 1 and 2 were presented at international and national meetings. A Symposium, organized by Partner 3, which also involves Partners 1 and 2 and whose topic covers AMEDYST topics, is to be held at the Brain and Spinal Cord Institute in March 2019.

Dystonia is a motor disorder characterized by muscle contractions causing abnormal postures and/or movements, which are disabling and painful in severe forms. Dystonia can be isolated, or associated with other neurological diseases, including Parkinson's disease, in combination with other motor disorders. The possibilities of medical treatment remain limited. The pathophysiologic mechanisms of dystonia would involve a combination of physiological abnormalities in the basal ganglia and cerebellum but are still poorly understood. The AMEDYST project examines by complementary approaches in animals and patients, (1) how functional abnormalities of the striatum, the entry structure into the basal ganglia network, generate dystonic movements and postures and (2) how the cerebello-thalamo-striatal pathway amplifies dystonic movements by acting on cholinergic striatal interneurons.

The project is mostly based on a model of mice hemizygous for the Gnal gene (Gnal+/-), which mimics the genetic alterations discovered in DYT25 dystonic patients. Gnal encodes the G protein a subunit, Gaolf, stimulating adenylyl cyclase, whose strongest brain expression is found in principal neurons of the striatum. In mice, the Gnal haplo-deficiency reduces striatal cAMP production and disrupts striatal functions, but is not sufficient to trigger dystonia onset. However, dystonia appears when Gnal+/- mice receive a cholinergic agonist, showing that an increase in cholinergic tone is critical to the onset of disease. Our project proposes to identify the effects of acetylcholine in the striatum of Gnal+/- to better understand the mechanisms of dystonia. The striatal cholinergic interneurons are controlled by thalamic afferent neurons, themselves regulated by afferents from the cerebellum. Since compelling evidence shows that disruption of cerebellar output causes dystonia, we shall investigate activity alterations in the various nodes of the cerebello-thalamo-striatal pathway in Gnal+/- mice and determine the motor dysfunction induced by their stimulation or inhibition. To establish whether the pathophysiological processes observed in mice show homology with those in human pathology, the role of cerebellum on the activity of an output structure of the basal ganglia (internal globus pallidus) will be determined by electrophysiological recordings in patients during surgery. Mutations in the adenylyl cyclase type 5 (AC5, encoded by ADCY5), strongly associated to Gaolf in the striatum, cause motor disorders, including dystonia. These mutations are more common than those of GNAL in human pathology and provide the possibility to explore the effect of impaired striatal cAMP pathway on a significant cohort of patients. We test in these patients the involvement of the cerebello-thalamo-striatal pathway by fMRI and we determine how non-invasive magnetic stimulations of cerebellum affect thalamus and striatum.

The project gathers researchers working on animal models and patients, as well as experts in physiology of the basal ganglia and cerebellum. This highly complementary consortium is adapted to the study of dystonia and is an asset to shed light on the pathophysiological processes of the disease. Our project will also demonstrate the proof-of-concept of new therapeutic approaches that are needed to treat the disease.

Project coordinator

Monsieur Denis HERVE (Inserm UMR-S 839, Institut du Fer à Moulin)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


IBENS Institut de Biologie de l’Ecole Normale Supérieure
INSERM UMR-S 1127 Institut National de la Santé et de la Recherche Médicale
IFM Inserm UMR-S 839, Institut du Fer à Moulin

Help of the ANR 647,242 euros
Beginning and duration of the scientific project: September 2016 - 42 Months

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