Fibroblast growth factor homologous factors control neuronal excitability through modulation of voltage-gated sodium channels.
Neurons integrate and encode complex synaptic inputs into action potential outputs through a process termed "intrinsic excitability." Here, we report the essential contribution of fibroblast growth factor homologous factors (FHFs), a family of voltage-gated sodium channel binding proteins, to this process. Fhf1-/-Fhf4-/- mice suffer from severe ataxia and other neurological deficits. In mouse cerebellar slice recordings, WT granule neurons can be induced to fire action potentials repetitively (approximately 60 Hz), whereas Fhf1-/-Fhf4-/- neurons often fire only once and at an elevated voltage spike threshold. Sodium channels in Fhf1-/-Fhf4-/- granule neurons inactivate at more negative membrane potential, inactivate more rapidly, and are slower to recover from the inactivated state. Altered sodium channel physiology is sufficient to explain excitation deficits, as tested in a granule cell computer model. These findings offer a physiological mechanism underlying human spinocerebellar ataxia induced by Fhf4 mutation and suggest a broad role for FHFs in the control of excitability throughout the CNS.
Goldfarb
Mitchell
M
Department of Biological Sciences, Hunter College of City University, New York, NY 10021, USA. goldfarb@genectr.hunter.cuny.edu
Schoorlemmer
Jon
J
Williams
Anthony
A
Diwakar
Shyam
S
Wang
Qing
Q
Huang
Xiao
X
Giza
Joanna
J
Tchetchik
Dafna
D
Kelley
Kevin
K
Vega
Ana
A
Matthews
Gary
G
Rossi
Paola
P
Ornitz
David M
DM
D'Angelo
Egidio
E
D000200:Action Potentials; D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000033:anatomy & histology / Q000166:cytology; D004558:Electric Stimulation; D004594:Electrophysiology; D051519:Fibroblast Growth Factor 4 / Q000172:deficiency / Q000502:physiology*; D005346:Fibroblast Growth Factors / Q000172:deficiency / Q000502:physiology*; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D008959:Models, Neurological; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000502:physiology*
C108110:Fgf12 protein, mouse; D051519:Fibroblast Growth Factor 4; D015222:Sodium Channels; D005346:Fibroblast Growth Factors