The ataxic mouse as a model for studying downbeat nystagmus

Stahl, John S.; Thumser, Zachary C.; Oommen, Brian S.

doi:10.3233/ves-120463

Cited by 5 publications

(2 citation statements)

References 52 publications

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“…Hyperactivity of the eye movement response to static pitch tilts (the tilt maculo-ocular reflex) has been suggested as a murine homolog of DBN, but that speculation has yet to be proven [48], [71]. Furthermore, whereas there are extensive data indicating a facilitating role of the flocculus in the eye movement responses to rotation, the role of the flocculus in the response to static tilts is uncertain, making it impossible to infer the changes in the outputs of vestibulocerebellar Purkinje cells on the basis of any drug-induced changes in the tilt maculo-ocular reflex.…”

Section: Discussionmentioning

confidence: 99%

4-Aminopyridine Does Not Enhance Flocculus Function in Tottering, a Mouse Model of Vestibulocerebellar Dysfunction and Ataxia

Stahl

Thumser

2013

PLoS ONE

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The potassium channel antagonist 4-aminopyridine (4-AP) improves a variety of motor abnormalities associated with disorders of the cerebellum. The most rigorous quantitative data relate to 4-AP's ability to improve eye movement deficits in humans referable to dysfunction of the cerebellar flocculus. Largely based on work in the ataxic mouse mutant tottering (which carries a mutation of the Cacna1a gene of the P/Q voltage-activated calcium channel), 4-AP is hypothesized to function by enhancing excitability or rhythmicity of floccular Purkinje cells. We tested this hypothesis by determining whether systemic or intrafloccular administration of 4-AP would ameliorate the eye movement deficits in tottering that are attributable to flocculus dysfunction, including the reductions in amplitude of the yaw-axis vestibulo-ocular reflex (VOR) and vision-enhanced vestibulo-ocular reflex (VVOR), and the optokinetic reflex (OKR) about yaw and roll axes. Because tottering's deficits increase with age, both young and elderly mutants were tested to detect any age-dependent 4-AP effects. 4-AP failed to improve VOR, VVOR, and OKR gains during sinusoidal stimuli, although it may have reduced the tendency of the mutants' responses to VOR and VVOR to decline over the course of a one-hour recording session. For constant-velocity optokinetic stimuli, 4-AP generated some enhancement of yaw OKR and upward-directed roll OKR, but the effects were also seen in normal C57BL/6 controls, and thus do not represent a specific reversal of the electrophysiological consequences of the tottering mutation. Data support a possible extra-floccular locus for the effects of 4-AP on habituation and roll OKR. Unilateral intrafloccular 4-AP injections did not affect ocular motility, except to generate mild eye elevations, consistent with reduced floccular output. Because 4-AP did not produce the effects expected if it normalized outputs of floccular Purkinje cells, there is a need for further studies to elucidate the drug's mechanism of action on cerebellar motor dysfunction.

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Section: Discussionmentioning

confidence: 99%

4-Aminopyridine Does Not Enhance Flocculus Function in Tottering, a Mouse Model of Vestibulocerebellar Dysfunction and Ataxia

Stahl

Thumser

2013

PLoS ONE

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“…Due to technical difficulty performing this method in rodents, there are a limited number of studies in guinea pigs (Yang & Young, 2005) and only one report in mice (Sheykholeslami et al, 2009). MOR in response to maintained tilt created by off vertical axis rotation (OVAR) has also been used to assess otolith organ function in mice (Beraneck & Cullen, 2007; Oommen & Stahl, 2008; Romand et al, 2013; Stahl & Oommen, 2008; Stahl et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

Preserved otolith organ function in caspase-3-deficient mice with impaired horizontal semicircular canal function

et al. 2015

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Genetically engineered mice are valuable models for elucidation of auditory and vestibular pathology. Our goal was to establish a comprehensive vestibular function testing system in mice using: 1) horizontal angular vestibular-ocular reflex (hVOR) to evaluate semicircular canal function, and 2) otolith-ocular reflex (OOR) to evaluate otolith organ function, and to validate the system by characterizing mice with vestibular dysfunction. We used pseudo-off vertical axis rotation (pOVAR) to induce an otolith-only stimulus using a custom-made centrifuge. For the OOR, horizontal slow phase eye velocity (HEV) and vertical eye position (VEP) was evaluated as a function of acceleration. Using this system, we characterized hVOR and OOR in the caspase-3 (Casp3) mutant mice. Casp3 −/− mice had severely impaired hVOR gain, while Casp3 +/− mice had an intermediate response compared to WT mice. Evaluation of OOR revealed that at low to mid frequencies and stimulus intensity, Casp3 mutants and WT mice had similar responses. At higher frequencies and stimulus intensity, the Casp3 mutants displayed mildly reduced otolith organ related responses. These findings suggest that the Casp3 gene is important for the proper function of the semicircular canals but less important for the otolith organ function.

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Downbeat nystagmus: evidence for enhancement of utriculo-ocular pathways by ocular vestibular evoked myogenic potentials?

Bremova-Ertl¹,

Glasauer

Strupp

2015

Eur Arch Otorhinolaryngol

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Downbeat nystagmus (DBN) is caused by an impairment of Purkinje cells in the flocculus. The decreased cerebellar inhibitory input affects otolith pathways. Since ocular and cervical vestibular evoked myogenic potentials (o-/cVEMP) test the otoliths, the VEMP were measured in DBN patients and in controls. Sixteen patients with DBN, 14 cerebellar oculomotor disorder patients without DBN (COMD), and 16 healthy controls were examined with o-/cVEMP. Computational modeling was used to predict VEMP differences between groups. DBN patients had significantly higher oVEMP peak-to-peak (PP) amplitudes than COMD patients without DBN and controls. Cervical VEMP did not differ. The computational model of DBN predicted a twofold oVEMP increase for DBN patients. These findings suggest an enhancement of the utriculo-ocular response. The unchanged cVEMP indicate no effect on the otolith-cervical reflex in DBN. Computational modeling suggests that the utriculo-ocular enhancement is caused by an impaired vertical neural integrator resulting in the increased influence of utricular signals. This also explains the gravitational dependence of DBN.

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The ataxic mouse as a model for studying downbeat nystagmus

Cited by 5 publications

References 52 publications

4-Aminopyridine Does Not Enhance Flocculus Function in Tottering, a Mouse Model of Vestibulocerebellar Dysfunction and Ataxia

4-Aminopyridine Does Not Enhance Flocculus Function in Tottering, a Mouse Model of Vestibulocerebellar Dysfunction and Ataxia

Preserved otolith organ function in caspase-3-deficient mice with impaired horizontal semicircular canal function

Downbeat nystagmus: evidence for enhancement of utriculo-ocular pathways by ocular vestibular evoked myogenic potentials?

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