Selective and Sustained α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Activation in Cerebellum Induces Dystonia in Mice

Fan, Xionglin; Hughes, Keryn E.; Jinnah, H. A.; Hess, Ellen J.

doi:10.1124/jpet.111.190082

Cited by 31 publications

(21 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dystonic movements in the tottering mouse model of paroxysmal dystonia also are associated with abnormal cerebellar signaling (Chen et al, 2009), and surgical removal of the cerebellum or selective elimination of PCs also eliminates their dystonic movements (Campbell et al, 1999; Neychev et al, 2008; Raike et al, 2012; Shirley et al, 2008). Dystonic movements can even be elicited in normal rodents by local disruption of cerebellar signaling (Alvarez-Fischer et al, 2012; Pizoli et al, 2002; Raike et al, 2012), an effect that seems to be mediated by glutamate receptors (Fan et al, 2012). Electrophysiological studies of the cerebellum are clearly needed in DYT1 models to determine if the histological abnormalities are associated with aberrant cerebellar signaling, and delineating which of the many structural and functional alterations is most relevant for causing abnormal movements is an important challenge for future research.…”

Section: Discussionmentioning

confidence: 99%

Subtle microstructural changes of the cerebellum in a knock-in mouse model of DYT1 dystonia

Song¹,

Bernhard²,

Hess³

et al. 2014

Neurobiology of Disease

Self Cite

View full text Add to dashboard Cite

The dystonias are a group of disorders characterized by involuntary twisting and repetitive movements. DYT1 dystonia is an inherited form of dystonia caused by a mutation in the TOR1A gene, which encodes torsinA. TorsinA is expressed in many regions of the nervous system, and the regions responsible for causing dystonic movements remain uncertain. Most prior studies have focused on the basal ganglia, although there is emerging evidence for abnormalities in the cerebellum too. In the current studies, we examined the cerebellum for structural abnormalities in a knock-in mouse model of DYT1 dystonia. The gross appearance of the cerebellum appeared normal in the mutant mice, but stereological measures revealed the cerebellum to be 5% larger in mutant compared to control mice. There were no changes in the numbers of Purkinje cells, granule cells, or neurons of the deep cerebellar nuclei. However, Golgi histochemical studies revealed Purkinje cells to have thinner dendrites, and fewer and less complex dendritic spines. There also was a higher frequency of heterotopic Purkinje cells displaced into the molecular layer. These results reveal subtle structural abnormalities of the cerebellum that are similar to those reported for the basal ganglia in the DYT1 knock-in mouse model.

show abstract

Section: Discussionmentioning

confidence: 99%

Subtle microstructural changes of the cerebellum in a knock-in mouse model of DYT1 dystonia

Song¹,

Bernhard²,

Hess³

et al. 2014

Neurobiology of Disease

Self Cite

View full text Add to dashboard Cite

show abstract

“…Pharmacological induction of abnormal cerebellar signaling through the intracerebellar administration of AMPA receptor agonists or ouabain, an inhibitor of the Na + /K + ATPase ion pump, induces generalized dystonia in normal mice, but mice that lack Purkinje cells do not respond to similar challenges [51–53]. Like pharmacologic challenge with ouabain, knockdown of the α3 isoform of the Na + /K + ATPase within the cerebellum also causes dystonia in normal mice; loss of function mutations in the α3 isoform of the Na + /K + ATPase cause RDP in human.…”

Section: How Does the Cerebellum Fit Into The Functional Neuroanatomymentioning

confidence: 99%

Current Opinions and Areas of Consensus on the Role of the Cerebellum in Dystonia

et al. 2016

Self Cite

View full text Add to dashboard Cite

A role for the cerebellum in causing ataxia, a disorder characterized by uncoordinated movement, is widely accepted. Recent work has suggested that alterations in activity, connectivity, and structure of the cerebellum are also associated with dystonia, a neurological disorder characterized by abnormal and sustained muscle contractions often leading to abnormal maintained postures. In this manuscript, the authors discuss their views on how the cerebellum may play a role in dystonia. The following topics are discussed: The relationships between neuronal/network dysfunctions and motor abnormalities in rodent models of dystonia.Data about brain structure, cerebellar metabolism, cerebellar connections, and noninvasive cerebellar stimulation that support (or not) a role for the cerebellum in human dystonia.Connections between the cerebellum and motor cortical and sub-cortical structures that could support a role for the cerebellum in dystonia. Overall points of consensus include: Neuronal dysfunction originating in the cerebellum can drive dystonic movements in rodent model systems.Imaging and neurophysiological studies in humans suggest that the cerebellum plays a role in the pathophysiology of dystonia, but do not provide conclusive evidence that the cerebellum is the primary or sole neuroanatomical site of origin.

show abstract

“…Some surgical studies also suggest involvement of the cerebellum, since dentatectomy (Hitchcock, 1973, Davis, 2000) or deep brain stimulation of regions of the thalamus receiving cerebellar afferents can relieve dystonia in some cases (Fukaya et al, 2007, Goto et al, 2008, Morishita et al, 2010, Hedera et al, 2013). Finally, there is strong evidence from animal models that abnormal activity of the cerebellum can cause dystonia (LeDoux et al, 1993, LeDoux et al, 1995, LeDoux et al, 1998, Pizoli et al, 2002, Xiao and Ledoux, 2005, Neychev et al, 2008, Calderon et al, 2011, Alvarez-Fischer et al, 2012, Fan et al, 2012, Raike et al, 2012). Similar to results for the basal ganglia, there is strong convergent evidence that the cerebellum plays an important role in dystonia.…”

Section: Introductionmentioning

confidence: 99%

Dystonia as a network disorder: What is the role of the cerebellum?

2014

View full text Add to dashboard Cite

The dystonias are a group of disorders defined by sustained or intermittent muscle contractions that result in involuntary posturing or repetitive movements. There are many different clinical manifestations and causes. Although they traditionally have been ascribed to dysfunction of the basal ganglia, recent evidence has suggested dysfunction may originate from other regions, particularly the cerebellum. This recent evidence has led to an emerging view that dystonia is a network disorder that involves multiple brain regions. The new network model for the pathogenesis of dystonia has raised many questions, particularly regarding the role of the cerebellum. For example, if dystonia may arise from cerebellar dysfunction, then why are there no cerebellar signs in dystonia? Why are focal cerebellar lesions or degenerative cerebellar disorders more commonly associated with ataxia rather than dystonia? Why is dystonia more commonly associated with basal ganglia lesions rather than cerebellar lesions? Can answers obtained from animals be extrapolated to humans? Is there any evidence that the cerebellum is not involved? Finally, what is the practical value of this new model of pathogenesis for the neuroscientist and clinician? This article explores potential answers to these questions.

show abstract

Selective and Sustained α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Activation in Cerebellum Induces Dystonia in Mice

Cited by 31 publications

References 46 publications

Subtle microstructural changes of the cerebellum in a knock-in mouse model of DYT1 dystonia

Subtle microstructural changes of the cerebellum in a knock-in mouse model of DYT1 dystonia

Current Opinions and Areas of Consensus on the Role of the Cerebellum in Dystonia

Dystonia as a network disorder: What is the role of the cerebellum?

Contact Info

Product

Resources

About