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

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 flocc...

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Autores principales: Stahl, John S., Thumser, Zachary C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581497/
https://www.ncbi.nlm.nih.gov/pubmed/23451282
http://dx.doi.org/10.1371/journal.pone.0057895
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author Stahl, John S.
Thumser, Zachary C.
author_facet Stahl, John S.
Thumser, Zachary C.
author_sort Stahl, John S.
collection PubMed
description 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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spelling pubmed-35814972013-02-28 4-Aminopyridine Does Not Enhance Flocculus Function in Tottering, a Mouse Model of Vestibulocerebellar Dysfunction and Ataxia Stahl, John S. Thumser, Zachary C. PLoS One Research Article 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. Public Library of Science 2013-02-25 /pmc/articles/PMC3581497/ /pubmed/23451282 http://dx.doi.org/10.1371/journal.pone.0057895 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Stahl, John S.
Thumser, Zachary C.
4-Aminopyridine Does Not Enhance Flocculus Function in Tottering, a Mouse Model of Vestibulocerebellar Dysfunction and Ataxia
title 4-Aminopyridine Does Not Enhance Flocculus Function in Tottering, a Mouse Model of Vestibulocerebellar Dysfunction and Ataxia
title_full 4-Aminopyridine Does Not Enhance Flocculus Function in Tottering, a Mouse Model of Vestibulocerebellar Dysfunction and Ataxia
title_fullStr 4-Aminopyridine Does Not Enhance Flocculus Function in Tottering, a Mouse Model of Vestibulocerebellar Dysfunction and Ataxia
title_full_unstemmed 4-Aminopyridine Does Not Enhance Flocculus Function in Tottering, a Mouse Model of Vestibulocerebellar Dysfunction and Ataxia
title_short 4-Aminopyridine Does Not Enhance Flocculus Function in Tottering, a Mouse Model of Vestibulocerebellar Dysfunction and Ataxia
title_sort 4-aminopyridine does not enhance flocculus function in tottering, a mouse model of vestibulocerebellar dysfunction and ataxia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581497/
https://www.ncbi.nlm.nih.gov/pubmed/23451282
http://dx.doi.org/10.1371/journal.pone.0057895
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