Alternative Approaches to Modeling Hereditary Dystonias

Fremont, Rachel; Khodakhah, Kamran

doi:10.1007/s13311-012-0113-1

Cited by 9 publications

(9 citation statements)

References 99 publications

(107 reference statements)

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“…None of these Atp1a3 mutated mice exhibited overt dystonia. The reasons for the lack of spontaneous dystonia phenotype in Atp1a3 mutated mice are not clear (Fremont & Khodakhah, 2012). In particular, no spontaneous motor disturbance was observed in the latter two Atp1a3 knockout heterozygous mice lines, indicating that haploinsufficiency of the gene is not sufficient to induce evident motor symptoms, including dystonia, during the life span of mice under commonly used stress conditions and that some dominant‐negative effects on the wild‐type α3 subunit by mutated proteins may underlie the mechanism of onset of dystonia.…”

Section: Discussionmentioning

confidence: 99%

Enhanced inhibitory neurotransmission in the cerebellar cortex of Atp1a3‐deficient heterozygous mice

Ikeda

Satake

Onaka

et al. 2013

The Journal of Physiology

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Key points• Mutations of ATP1A3 cause rapid-onset dystonia with parkinsonism (RDP) and alternating hemiplegia of childhood (AHC).• The mRNA of Atp1a3 was highly expressed in molecular-layer interneurons and Purkinje cells in the developing mouse cerebellar cortex, and the gene product was observed as dots in the molecular layer, on the surface of Purkinje cell soma and the pinceaux.• Here we report that Atp1a3 +/− mice showed increased symptoms of dystonia when being administrated kainate into cerebellum. We also found enhanced inhibitory neurotransmission between molecular-layer interneurons and Purkinje cells in the developing cerebellum of Atp1a3 +/− mice.• These findings suggest that ATP1A3 haploinsufficiency in the cerebellum has some effect on the inhibitory, but not the excitatory, circuitry and the interaction among different cell types during development. Disturbances of the cerebellar inhibitory network seem to be the underlying pathophysiological mechanism of dystonia among the increasing spectrum of complex neurological symptoms in RDP and AHC.Abstract Dystonia is characterized by excessive involuntary and prolonged simultaneous contractions of both agonist and antagonist muscles. Although the basal ganglia have long been proposed as the primary region, recent studies indicated that the cerebellum also plays a key role in the expression of dystonia. One hereditary form of dystonia, rapid-onset dystonia with parkinsonism (RDP), is caused by loss of function mutations of the gene for the Na pump α3 subunit (ATP1A3). Little information is available on the affected brain regions and mechanism for dystonia by the mutations in RDP. The Na pump is composed of α and β subunits and maintains ionic gradients of Na + and K + across the cell membrane. The gradients are utilized for neurotransmitter reuptake and their alteration modulates neural excitability. To provide insight into the molecular aetiology of RDP, we generated and analysed knockout heterozygous mice (Atp1a3 +/− ). Atp1a3 +/− showed increased symptoms of dystonia that is induced by kainate injection into the cerebellar vermis. Atp1a3 mRNA was highly expressed in Purkinje cells and molecular-layer interneurons, and its product was concentrated at Purkinje cell soma, the site of abundant vesicular γ-aminobutyric acid transporter (VGAT) signal, suggesting the presynaptic localization of the α3 subunit in the inhibitory synapse. Electrophysiological studies showed that the inhibitory neurotransmission at molecular-layer interneuron-Purkinje cell synapses was enhanced in Atp1a3 +/− cerebellar cortex, and that the enhancement originated via a presynaptic mechanism. Our results shed light on the role of Atp1a3 in the inhibitory synapse, and potential involvement of inhibitory synaptic dysfunction for the pathophysiology of dystonia.

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Section: Discussionmentioning

confidence: 99%

Enhanced inhibitory neurotransmission in the cerebellar cortex of Atp1a3‐deficient heterozygous mice

Ikeda

Satake

Onaka

et al. 2013

The Journal of Physiology

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“…Mice homozygous for this mutation also exhibit early lethality whereas heterozygotes survive and exhibit seizures and ataxia but no clear dystonia (Clapcote et al, 2009). The failure of these transgenic models in replicating RDP has been attributed to developmental compensatory mechanisms in mice that may be different than those present in humans (Calderon et al, 2011, Fremont and Khodakhah, 2012, Fremont et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

“…The success of the pharmacologic model was attributed to the fact that any potential developmental compensatory mechanisms were bypassed by acutely reducing sodium pump function with ouabain in adult mice (Calderon et al, 2011, Fremont and Khodakhah, 2012, Fremont et al, 2014). We reasoned that acute, post developmental reduction in the sodium pump function must remain a central feature of the new model.…”

Section: Introductionmentioning

confidence: 99%

Aberrant Purkinje cell activity is the cause of dystonia in a shRNA-based mouse model of Rapid Onset Dystonia–Parkinsonism

Fremont

Tewari

Khodakhah

2015

Neurobiology of Disease

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Loss-of-function mutations in the α3 isoform of the sodium pump are responsible for Rapid Onset Dystonia-Parkinsonism (RDP). A pharmacologic model of RDP replicates the most salient features of RDP, and implicates both the cerebellum and basal ganglia in the disorder; dystonia is associated with aberrant cerebellar output, and the parkinsonism-like features are attributable to the basal ganglia. The pharmacologic agent used to generate the model, ouabain, is selective for sodium pumps. However, close to the infusion sites in vivo it likely affects all sodium pump isoforms. Therefore, it remains to be established whether selective loss of α3-containing sodium pumps replicates the pharmacologic model. Moreover, while the pharmacologic model suggested that aberrant firing of Purkinje cells was the main cause of abnormal cerebellar output, it did not allow the scrutiny of this hypothesis. To address these questions RNA interference using small hairpin RNAs (shRNAs) delivered via adeno-associated viruses (AAV) was used to specifically knockdown α3-containing sodium pumps in different regions of the adult mouse brain. Knockdown of the α3-containing sodium pumps mimicked both the behavioral and electrophysiological changes seen in the pharmacologic model of RDP, recapitulating key aspects of the human disorder. Further, we found that knockdown of the α3 isoform altered the intrinsic pacemaking of Purkinje cells, but not the neurons of the deep cerebellar nuclei. Therefore, acute knockdown of proteins associated with inherited dystonias may be a good strategy for developing phenotypic genetic mouse models where traditional transgenic models have failed to produce symptomatic mice.

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“…Unfortunately, genetic 111 models of hereditary dystonia have often failed to recapitulate many of the key motor symptoms of the 112 disorder. One possibility for this phenomenon is compensation for the gene that has been knocked out 113 during brain development in rodents (Fremont and Khodakhah, 2012). 114…”

Section: Introduction 40mentioning

confidence: 99%

Acute cerebellar knockdown ofSgcereproduces salient features of Myoclonus-dystonia (DYT11) in mice

Khodakhah

Washburn

Freemont

et al. 2019

Preprint

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Myoclonus dystonia (DYT11) is a movement disorder caused by loss-of-function mutations in SGCE and characterized by involuntary jerking and dystonia that frequently improve after drinking alcohol. Existing transgenic mouse models of DYT11 exhibit only mild motor symptoms, possibly due to rodent-specific developmental compensation mechanisms, which have limited the study of neural mechanisms underlying DYT11. To circumvent potential compensation, we used short hairpin RNA (shRNA) to acutely knock down Sgce in the adult mouse and found that this approach produced dystonia and repetitive, myoclonic-like movements in mice that improved after administration of ethanol. Acute knockdown of Sgce in the cerebellum, but not the basal ganglia, produced motor symptoms, likely due to aberrant cerebellar activity. The acute knockdown model described here reproduces the salient features of DYT11 and provides a platform to study the mechanisms underlying symptoms of the disorder, and to explore potential therapeutic options.

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Alternative Approaches to Modeling Hereditary Dystonias

Cited by 9 publications

References 99 publications

Enhanced inhibitory neurotransmission in the cerebellar cortex of Atp1a3‐deficient heterozygous mice

Enhanced inhibitory neurotransmission in the cerebellar cortex of Atp1a3‐deficient heterozygous mice

Aberrant Purkinje cell activity is the cause of dystonia in a shRNA-based mouse model of Rapid Onset Dystonia–Parkinsonism

Acute cerebellar knockdown ofSgcereproduces salient features of Myoclonus-dystonia (DYT11) in mice

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