Fibroblast Growth Factor Homologous Factors Control Neuronal Excitability through Modulation of Voltage-Gated Sodium Channels
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.
- University of Milan Italy
- University of Mary United States
- Spanish National Research Council Spain
- University of Milan Italy
- University of Pavia Italy
570, Patch-Clamp Techniques, Neuroscience(all), Models, Neurological, Fibroblast growth factor, Fibroblast Growth Factor 4, 610, Action Potentials, In Vitro Techniques, Motor Activity, MOLNEURO, Sodium Channels, Membrane Potentials, Mice, Cerebellum, voltage-gated sodium channel, Animals, neuronal excitability, Cells, Cultured, Mice, Knockout, Neurons, Electric Stimulation, Electrophysiology, Fibroblast Growth Factors, SIGNALING, cerebellar granular cells, Ion Channel Gating
570, Patch-Clamp Techniques, Neuroscience(all), Models, Neurological, Fibroblast growth factor, Fibroblast Growth Factor 4, 610, Action Potentials, In Vitro Techniques, Motor Activity, MOLNEURO, Sodium Channels, Membrane Potentials, Mice, Cerebellum, voltage-gated sodium channel, Animals, neuronal excitability, Cells, Cultured, Mice, Knockout, Neurons, Electric Stimulation, Electrophysiology, Fibroblast Growth Factors, SIGNALING, cerebellar granular cells, Ion Channel Gating
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