Fibroblast Growth Factor Homologous Factors Control Neuronal Excitability through Modulation of Voltage-Gated Sodium Channels

Abstract

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.

Functional evolutionary history of the mouse Fgf gene family

“…The iFgf subfamily comprises Fgf11-Fgf14. Fgf12 and Fgf14 knockout mice are viable and have neurological phenotypes (Wang et al, 2002;Xiao et al, 2007;Goldfarb et al, 2007;. Although Fgf11 and Fgf13 knockout mice have not been re-ported, the expression of these genes in the central and peripheral nervous system suggests that these genes will also be found to function in neurodevelopment or neurophysiology.…”

Roles of intracellular fibroblast growth factors in neural development and functions

“…Intracellular FGFs are often colocalized with Na v channels at the initial segments of axons and nodes of Ranvier [10, 31,32]. Therefore, these FGFs might modulate the intiation and the propagation of action potentials [11, [33][34][35].…”

“…Studies show that Fgf12 knockout mice display muscle weakness [5] (Table 1). FGF14-deficient mice develop ataxia, paroxysmal hyperkinetic movement disorder and cognitive impairment [13,32,40]. This may be attributed to the loss of FGF14, which impairs the intrinsic excitability of cerebellar Purkinje neurons [15] and the long-term potentiation of synapses in the hippocampal CA1 region [16,31,40].…”

“…Therefore, the delayed neuronal migration and increased collateral branching of axons could disrupt the formation of the neural circuits and networks required for generating cognitive functions. At the moment, it remains unclear how synaptogenesis, action potential firing and synaptic transmission might be affected by loss of FGF13 function in adulthood, but some effects are expected because FGF13 may regulate neuronal excitability through modulating Na v channels [10, 17,32]. Therefore, FGF13-deficient mice may be a useful animal model for studying XLMR-related mechanisms.…”

Interleukin-6 inhibits voltage-gated sodium channel activity of cultured rat spinal cord neurons

“…It has been reported that in the fibroblast growth factor homologous factors knockout mice, the electrophysiology properties of voltage-gated sodium channels are changed, resulting in the cerebellar granule neurons incapable of being induced to repetitively fire AP (18). In addition, a mutation of the Na V 1.7 channel alters the excitability in different types of neurons (19).…”