Disruption of Fgf13 Causes Synaptic Excitatory-Inhibitory Imbalance and Genetic Epilepsy and Febrile Seizures Plus
Disruption of Fgf13 Causes Synaptic Excitatory-Inhibitory Imbalance and Genetic Epilepsy and Febrile Seizures Plus
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DOI：
10.1523/jneurosci.3470-14.2015
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发表时间：
2015-06-10
影响因子：
5.3
通讯作者：
McNamara, James O.
中科院分区：
文献类型：
--
作者：
Puranam, Ram S.;He, Xiao Ping;McNamara, James O.
我们鉴定了一个X和14号染色体易位的家族，该家族与认知障碍和一种称为“遗传性癫痫和热性惊厥+”（GEFS（+））的复杂遗传疾病有关。我们证明了X染色体上的断点破坏了编码电压门控Na+通道的辅助蛋白成纤维细胞生长因子13（Fgf13）的基因。其中一个Fgf13等位基因被删除的雌性小鼠表现出高血压诱导的癫痫发作和癫痫。解剖学研究显示Fgf 13 mRNA在海马兴奋性和抑制性神经元中均有表达。电生理记录显示Fgf13突变体海马神经元抑制性突触输入减少，兴奋性突触输入增加。我们推测Fgf13的表达减少会损害抑制性中间神经元的兴奋性，从而导致海马局部回路的兴奋性增强和癫痫的临床表型。这些发现揭示了这种综合征的新原因，并强调了FGF 13在控制神经元兴奋性中的强大作用。
We identified a family in which a translocation between chromosomes X and 14 was associated with cognitive impairment and a complex genetic disorder termed "Genetic Epilepsy and Febrile Seizures Plus" (GEFS(+)). We demonstrate that the breakpoint on the X chromosome disrupted a gene that encodes an auxiliary protein of voltage-gated Na+ channels, fibroblast growth factor 13 (Fgf13). Female mice in which one Fgf13 allele was deleted exhibited hyperthermia-induced seizures and epilepsy. Anatomic studies revealed expression of Fgf13 mRNA in both excitatory and inhibitory neurons of hippocampus. Electrophysiological recordings revealed decreased inhibitory and increased excitatory synaptic inputs in hippocampal neurons of Fgf13 mutants. We speculate that reduced expression of Fgf13 impairs excitability of inhibitory interneurons, resulting in enhanced excitability within local circuits of hippocampus and the clinical phenotype of epilepsy. These findings reveal a novel cause of this syndrome and underscore the powerful role of FGF13 in control of neuronal excitability.