Impact of 4-aminopyridine on vestibulo–ocular reflex performance

Abstract

Vestibulo–ocular reflexes (VOR) are mediated by frequency-tuned pathways that separately transform the different dynamic and static aspects of head motion/position-related sensory signals into extraocular motor commands. Voltage-dependent potassium conductances such as those formed by Kv1.1 are important for the ability of VOR circuit elements to encode highly transient motion components. Here we describe the impact of the Kv1.1 channel blocker 4-aminopyridine (4-AP) on spontaneous and motion-evoked discharge of superior oblique motoneurons. Spike activity was recorded from the motor nerve in isolated preparations of Xenopus laevis tadpoles. Under static conditions, bath application of 1–10 µM 4-AP increased the spontaneous firing rate and provoked repetitive bursts of spikes. During motion stimulation 4-AP also augmented and delayed the peak firing rate suggesting that this drug affects the magnitude and timing of vestibular-evoked eye movements. The exclusive Kv1.1 expression in thick vestibular afferent fibers in larval Xenopus at this developmental stage suggests that the altered extraocular motor output in the presence of 4-AP mainly derives from a firing rate increase of irregular firing vestibular afferents that propagates along the VOR circuitry. Clinically and pharmacologically, the observed 4-AP-mediated increase of peripheral vestibular input under resting and dynamic conditions can contribute to the observed therapeutic effects of 4-AP in downbeat and upbeat nystagmus as well as episodic ataxia type 2, by an indirect increase of cerebellar Purkinje cell discharge.

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Acknowledgements

The authors acknowledge financial support from the German Science Foundation (CRC 870; STR 478/3-1; RTG 2175) and the German Federal Ministry of Education and Research under the Grant code 01 EO 0901.

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Correspondence to Hans Straka.

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The authors declare no competing financial interests.

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All studies have been approved by the appropriate ethics committee (ROB-55.2-2532.Vet_03-17-24) and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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This manuscript is part of a supplement sponsored by the German Federal Ministry of Education and Research within the funding initiative for integrated research and treatment centers.

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I Gusti Bagus, M., Gordy, C., Sanchez-Gonzalez, R. et al. Impact of 4-aminopyridine on vestibulo–ocular reflex performance. J Neurol 266, 93–100 (2019). https://doi.org/10.1007/s00415-019-09452-4

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Keywords

  • Vestibulo–ocular reflex
  • Semicircular canal
  • Extraocular motoneurons
  • Potassium channels