Abstract
Genetically inherited mutations in the fibroblast growth factor 14 (FGF14) gene lead to spinocerebellar ataxia type 27 (SCA27), an autosomal dominant disorder characterized by heterogeneous motor and cognitive impairments. Consistently, genetic deletion of Fgf14 in Fgf14−/− mice recapitulates salient features of the SCA27 human disease. In vitro molecular studies in cultured neurons indicate that the FGF14F145S SCA27 allele acts as a dominant negative mutant suppressing the FGF14 wild type function and resulting in inhibition of voltage-gated Na+ and Ca2+ channels. To gain insights in the cerebellar deficits in the animal model of the human disease, we applied whole-cell voltage-clamp in the acute cerebellar slice preparation to examine the properties of parallel fibers (PF) to Purkinje neuron synapses in Fgf14−/− mice and wild type littermates. We found that the AMPA receptor-mediated excitatory postsynaptic currents evoked by PF stimulation (PF-EPSCs) were significantly reduced in Fgf14−/− animals, while short-term plasticity, measured as paired-pulse facilitation (PPF), was enhanced. Measuring Sr2+-induced release of quanta from stimulated synapses, we found that the size of the PF-EPSCs was unchanged, ruling out a postsynaptic deficit. This phenotype was corroborated by decreased expression of VGLUT1, a specific presynaptic marker at PF-Purkinje neuron synapses. We next examined the mGluR1 receptor-induced response (mGluR1-EPSC) that under normal conditions requires a gradual build-up of glutamate concentration in the synaptic cleft, and found no changes in these responses in Fgf14−/− mice. These results provide evidence of a critical role of FGF14 in maintaining presynaptic function at PF-Purkinje neuron synapses highlighting critical target mechanisms to recapitulate the complexity of the SCA27 disease.
Highlights
fibroblast growth factor 14 (FGF14) is a member of the intracellular fibroblast growth factor family comprising four gene products (FGF11–FGF14) and their respective splice isoforms (Itoh and Ornitz, 2008)
Previous studies have established that the Fgf14−/− mouse model recapitulates an array of motor and cognitive phenotypes that are found in humans carrying the FGF14F145S mutation (Wang et al, 2002), the genetically inherited cause of spinocerebellar ataxia type 27 (SCA27)
Our results demonstrate that genetic deletion of Fgf14 leads to impairment of synaptic transmission at the parallel fibers (PF) to Purkinje neuron synapse, phenotypes that might contribute to the cerebellar ataxia observed in the SCA27 human disease
Summary
FGF14 is a member of the intracellular fibroblast growth factor family comprising four gene products (FGF11–FGF14) and their respective splice isoforms (Itoh and Ornitz, 2008). IFGFs have recently gained emerging interest in the context of normal brain function and brain disorders (Hsu et al, 2014) Milestone studies in this field began with the identification of the naturally occurring FGF14F145S mutation as the hereditary cause of spinocerebellar ataxia 27 (SCA27) in a large three-generation Dutch family (van Swieten et al, 2003; Brusse et al, 2006). Further genetic analyses corroborating the initial findings revealed frameshift and amino acid exchange mutations, deletions, (Dalski et al, 2005; Coebergh et al, 2014) and chromosome translocations (Misceo et al, 2009) It revealed single nucleotide polymorphisms of FGF14 (Dalski et al, 2005; Chen et al, 2012) in SCA27 patients unrelated to the initial family, extending the role of FGF14 to a broader group of human subjects. Apart from SCA27, evidence of FGF14 chromosomal translocations has been found in a patient afflicted with paroxysmal non-kinesigenic dyskinesia (PNKD; Shimojima et al, 2012) expanding the repertoire of human disorders linked to FGF14
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