Abnormal High-Frequency Burst Firing of Cerebellar Neurons in Rapid-Onset Dystonia-Parkinsonism

Fremont, Rachel; Calderon, Diany Paola; Maleki, Saeed; Khodakhah, Kamran

doi:10.1523/jneurosci.1409-14.2014

Cited by 110 publications

(135 citation statements)

References 74 publications

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“…Cerebellar Purkinje cells and neurons in the cerebellar nuclei exhibit burst firing patterns in rodent models of ataxia (Gao et al 2012), dystonia (Fremont et al 2014;LeDoux 2011), and even multiple sclerosis (Saab et al 2004). This irregular burst firing may be a contributing factor to the abnormal motor behavior seen in these animals (Alvina and Khodakhah 2010).…”

Section: Discussionmentioning

confidence: 99%

In vivo analysis of Purkinje cell firing properties during postnatal mouse development

Arancillo

White

Lin

et al. 2015

Journal of Neurophysiology

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Arancillo M, White JJ, Lin T, Stay TL, Sillitoe RV. In vivo analysis of Purkinje cell firing properties during postnatal mouse development. J Neurophysiol 113: 578 -591, 2015. First published October 29, 2014 doi:10.1152/jn.00586.2014.-Purkinje cell activity is essential for controlling motor behavior. During motor behavior Purkinje cells fire two types of action potentials: simple spikes that are generated intrinsically and complex spikes that are induced by climbing fiber inputs. Although the functions of these spikes are becoming clear, how they are established is still poorly understood. Here, we used in vivo electrophysiology approaches conducted in anesthetized and awake mice to record Purkinje cell activity starting from the second postnatal week of development through to adulthood. We found that the rate of complex spike firing increases sharply at 3 wk of age whereas the rate of simple spike firing gradually increases until 4 wk of age. We also found that compared with adult, the pattern of simple spike firing during development is more irregular as the cells tend to fire in bursts that are interrupted by long pauses. The regularity in simple spike firing only reached maturity at 4 wk of age. In contrast, the adult complex spike pattern was already evident by the second week of life, remaining consistent across all ages. Analyses of Purkinje cells in alert behaving mice suggested that the adult patterns are attained more than a week after the completion of key morphogenetic processes such as migration, lamination, and foliation. Purkinje cell activity is therefore dynamically sculpted throughout postnatal development, traversing several critical events that are required for circuit formation. Overall, we show that simple spike and complex spike firing develop with unique developmental trajectories.

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Section: Discussionmentioning

confidence: 99%

In vivo analysis of Purkinje cell firing properties during postnatal mouse development

Arancillo

White

Lin

et al. 2015

Journal of Neurophysiology

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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%

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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“…Electrophysiological studies in dystonic mice reveal abnormal high-frequency bursting activity in cerebellar nuclei, the sole output of cerebellar circuitry [11]. The activity appears as aberrant.…”

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confidence: 99%

Dissecting the Links Between Cerebellum and Dystonia

Malone

Manto²,

Hass

2014

Cerebellum

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Dystonia is a common movement disorder characterized by sustained muscle contractions. These contractions generate twisting and repetitive movements or typical abnormal postures, often exacerbated by voluntary movement. Dystonia can affect almost all the voluntary muscles. For several decades, the discussion on the pathogenesis has been focused on basal ganglia circuits, especially striatal networks. So far, although dystonia has been observed in some forms of ataxia such as dominant ataxias, the link between the cerebellum and dystonia has remained unclear. Recent human studies and experimental data mainly in rodents show that the cerebellum circuitry could also be a key player in the pathogenesis of some forms of dystonia. In particular, studies based on behavioral adaptation paradigm shed light on the links between dystonia and cerebellum. The spectrum of movement disorders in which the cerebellum is implicated is continuously expanding, and manipulation of cerebellar circuits might even emerge as a candidate therapy in the coming years.

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Abnormal High-Frequency Burst Firing of Cerebellar Neurons in Rapid-Onset Dystonia-Parkinsonism

Cited by 110 publications

References 74 publications

In vivo analysis of Purkinje cell firing properties during postnatal mouse development

In vivo analysis of Purkinje cell firing properties during postnatal mouse development

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

Dissecting the Links Between Cerebellum and Dystonia

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