FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons

Vikram G. Shakkottai; Maolei Xiao; Lin Xu; Michael Wong; Jeanne M. Nerbonne; David M. Ornitz; Kelvin A. Yamada

doi:10.1016/j.nbd.2008.09.019

FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons

Vikram G. Shakkottai, Maolei Xiao, Lin Xu, Michael Wong, Jeanne M. Nerbonne, David M. Ornitz, Kelvin A. Yamada

Research output: Contribution to journal › Article › peer-review

101 Scopus citations

Abstract

A missense mutation in the fibroblast growth factor 14 (FGF14) gene underlies SCA27, an autosomal dominant spinocerebellar ataxia in humans. Mice with a targeted disruption of the Fgf14 locus (Fgf14^-/-) develop ataxia resembling human SCA27. We tested the hypothesis that loss of FGF14 affects the firing properties of Purkinje neurons, which play an important role in motor control and coordination. Current clamp recordings from Purkinje neurons in cerebellar slices revealed attenuated spontaneous firing in Fgf14^-/- neurons. Unlike in the wild type animals, more than 80% of Fgf14^-/- Purkinje neurons were quiescent and failed to fire repetitively in response to depolarizing current injections. Immunohistochemical examination revealed reduced expression of Nav1.6 protein in Fgf14^-/- Purkinje neurons. Together, these observations suggest that FGF14 is required for normal Nav1.6 expression in Purkinje neurons, and that the loss of FGF14 impairs spontaneous and repetitive firing in Purkinje neurons by altering the expression of Nav1.6 channels.

Original language	English (US)
Pages (from-to)	81-88
Number of pages	8
Journal	Neurobiology of Disease
Volume	33
Issue number	1
DOIs	https://doi.org/10.1016/j.nbd.2008.09.019
State	Published - Jan 2009
Externally published	Yes

Keywords

Intracellular fibroblast growth factor 14 (iFGF14)
Nav 1.6
Purkinje neurons
SCA27
Spinocerebellar ataxia

ASJC Scopus subject areas

Neurology

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10.1016/j.nbd.2008.09.019

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@article{a1600eacf0144296a59063fccfdea636,

title = "FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons",

abstract = "A missense mutation in the fibroblast growth factor 14 (FGF14) gene underlies SCA27, an autosomal dominant spinocerebellar ataxia in humans. Mice with a targeted disruption of the Fgf14 locus (Fgf14-/-) develop ataxia resembling human SCA27. We tested the hypothesis that loss of FGF14 affects the firing properties of Purkinje neurons, which play an important role in motor control and coordination. Current clamp recordings from Purkinje neurons in cerebellar slices revealed attenuated spontaneous firing in Fgf14-/- neurons. Unlike in the wild type animals, more than 80% of Fgf14-/- Purkinje neurons were quiescent and failed to fire repetitively in response to depolarizing current injections. Immunohistochemical examination revealed reduced expression of Nav1.6 protein in Fgf14-/- Purkinje neurons. Together, these observations suggest that FGF14 is required for normal Nav1.6 expression in Purkinje neurons, and that the loss of FGF14 impairs spontaneous and repetitive firing in Purkinje neurons by altering the expression of Nav1.6 channels.",

keywords = "Intracellular fibroblast growth factor 14 (iFGF14), Nav 1.6, Purkinje neurons, SCA27, Spinocerebellar ataxia",

author = "Shakkottai, {Vikram G.} and Maolei Xiao and Lin Xu and Michael Wong and Nerbonne, {Jeanne M.} and Ornitz, {David M.} and Yamada, {Kelvin A.}",

note = "Funding Information: This work was supported by the Hope Center for Neurological Disorders, the National Ataxia Foundation and by an NIH Neuroscience Blueprint Center Core P30 NS057105 grant to Washington University and 1R03NS62431-1. Some of this work was performed in a facility supported by NCRR grant C06 RR015502. The monoclonal antibody FGF14N56/21 was obtained from the UC Davis/NINDS/NIMH NeuroMab Facility, supported by NIH grant U24NS050606 and maintained by the University of California at Davis.",

year = "2009",

month = jan,

doi = "10.1016/j.nbd.2008.09.019",

language = "English (US)",

volume = "33",

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journal = "Neurobiology of Disease",

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AU - Shakkottai, Vikram G.

AU - Xiao, Maolei

AU - Xu, Lin

AU - Wong, Michael

AU - Nerbonne, Jeanne M.

AU - Ornitz, David M.

AU - Yamada, Kelvin A.

N1 - Funding Information: This work was supported by the Hope Center for Neurological Disorders, the National Ataxia Foundation and by an NIH Neuroscience Blueprint Center Core P30 NS057105 grant to Washington University and 1R03NS62431-1. Some of this work was performed in a facility supported by NCRR grant C06 RR015502. The monoclonal antibody FGF14N56/21 was obtained from the UC Davis/NINDS/NIMH NeuroMab Facility, supported by NIH grant U24NS050606 and maintained by the University of California at Davis.

PY - 2009/1

Y1 - 2009/1

N2 - A missense mutation in the fibroblast growth factor 14 (FGF14) gene underlies SCA27, an autosomal dominant spinocerebellar ataxia in humans. Mice with a targeted disruption of the Fgf14 locus (Fgf14-/-) develop ataxia resembling human SCA27. We tested the hypothesis that loss of FGF14 affects the firing properties of Purkinje neurons, which play an important role in motor control and coordination. Current clamp recordings from Purkinje neurons in cerebellar slices revealed attenuated spontaneous firing in Fgf14-/- neurons. Unlike in the wild type animals, more than 80% of Fgf14-/- Purkinje neurons were quiescent and failed to fire repetitively in response to depolarizing current injections. Immunohistochemical examination revealed reduced expression of Nav1.6 protein in Fgf14-/- Purkinje neurons. Together, these observations suggest that FGF14 is required for normal Nav1.6 expression in Purkinje neurons, and that the loss of FGF14 impairs spontaneous and repetitive firing in Purkinje neurons by altering the expression of Nav1.6 channels.

AB - A missense mutation in the fibroblast growth factor 14 (FGF14) gene underlies SCA27, an autosomal dominant spinocerebellar ataxia in humans. Mice with a targeted disruption of the Fgf14 locus (Fgf14-/-) develop ataxia resembling human SCA27. We tested the hypothesis that loss of FGF14 affects the firing properties of Purkinje neurons, which play an important role in motor control and coordination. Current clamp recordings from Purkinje neurons in cerebellar slices revealed attenuated spontaneous firing in Fgf14-/- neurons. Unlike in the wild type animals, more than 80% of Fgf14-/- Purkinje neurons were quiescent and failed to fire repetitively in response to depolarizing current injections. Immunohistochemical examination revealed reduced expression of Nav1.6 protein in Fgf14-/- Purkinje neurons. Together, these observations suggest that FGF14 is required for normal Nav1.6 expression in Purkinje neurons, and that the loss of FGF14 impairs spontaneous and repetitive firing in Purkinje neurons by altering the expression of Nav1.6 channels.

KW - Intracellular fibroblast growth factor 14 (iFGF14)

KW - Nav 1.6

KW - Purkinje neurons

KW - SCA27

KW - Spinocerebellar ataxia

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FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons

Abstract

Keywords

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