Shimada Tadayuki, Yoshida Tomoyuki, Yamagata Kanato
Synaptic Plasticity Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya, Tokyo, 156-8506, Japan, and
Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan.
J Neurosci. 2016 Apr 20;36(16):4534-48. doi: 10.1523/JNEUROSCI.1715-15.2016.
Aberrant branch formation of granule cell axons (mossy fiber sprouting) is observed in the dentate gyrus of many patients with temporal lobe epilepsy and in animal models of epilepsy. However, the mechanisms underlying mossy fiber sprouting remain elusive. Based on the hypothesis that seizure-mediated gene expression induces abnormal mossy fiber growth, we screened activity-regulated genes in the hippocampus and found that neuritin, an extracellular protein anchored to the cell surface, was rapidly upregulated after electroconvulsive seizures. Overexpression of neuritin in the cultured rat granule cells promoted their axonal branching. Also, kainic acid-dependent axonal branching was abolished in the cultured granule cells fromneuritinknock-out mice, suggesting that neuritin may be involved in activity-dependent axonal branching. Moreover,neuritinknock-out mice showed less-severe seizures in chemical kindling probably by reduced mossy fiber sprouting and/or increased seizure resistance. We found that inhibition of the fibroblast growth factor (FGF) receptor attenuated the neuritin-dependent axonal branching. FGF administration also increased branching in granule neurons, whereasneuritinknock-out mice did not show FGF-dependent axonal branching. In addition, FGF and neuritin treatment enhanced the recruitment of FGF receptors to the cell surface. These findings suggest that neuritin and FGF cooperate in inducing mossy fiber sprouting through FGF signaling. Together, these results suggest that FGF and neuritin-mediated axonal branch induction are involved in the aggravation of epilepsy.
This study reveals the molecular mechanism underlying mossy fiber sprouting. Mossy fiber sprouting is the aberrant axonal branching of granule neurons in the hippocampus, which is observed in patients with epilepsy. Excess amounts of neuritin, a protein upregulated by neural activity, promoted axonal branching in granule neurons. A deficiency of neuritin suppressed mossy fiber sprouting and resulted in mitigation of seizure severity. Neuritin and fibroblast growth factor (FGF) cooperated in stimulating FGF signaling and enhancing axonal branching. Neuritin is necessary for FGF-mediated recruitment of FGF receptors to the cell surface. The recruitment of FGF receptors would promote axonal branching. The discovery of this new mechanism should contribute to the development of novel antiepileptic drugs to inhibit axonal branching via neuritin-FGF signaling.
在许多颞叶癫痫患者的齿状回以及癫痫动物模型中，均观察到颗粒细胞轴突的异常分支形成（苔藓纤维出芽）。然而，苔藓纤维出芽背后的机制仍不清楚。基于癫痫发作介导的基因表达诱导苔藓纤维异常生长这一假说，我们筛选了海马体中受活动调节的基因，发现神经突素（一种锚定在细胞表面的细胞外蛋白）在电惊厥发作后迅速上调。在培养的大鼠颗粒细胞中过表达神经突素会促进其轴突分支。此外，来自神经突素基因敲除小鼠的培养颗粒细胞中，海人酸依赖性轴突分支被消除，这表明神经突素可能参与了活动依赖性轴突分支。此外，神经突素基因敲除小鼠在化学点燃模型中癫痫发作较轻，可能是因为苔藓纤维出芽减少和/或癫痫抵抗性增加。我们发现抑制成纤维细胞生长因子（FGF）受体可减弱神经突素依赖性轴突分支。给予FGF也会增加颗粒神经元的分支，而神经突素基因敲除小鼠未表现出FGF依赖性轴突分支。此外，FGF和神经突素处理可增强FGF受体向细胞表面的募集。这些发现表明，神经突素和FGF通过FGF信号传导共同诱导苔藓纤维出芽。总之，这些结果表明FGF和神经突素介导的轴突分支诱导参与了癫痫的加重。
本研究揭示了苔藓纤维出芽背后的分子机制。苔藓纤维出芽是海马体中颗粒神经元的异常轴突分支，在癫痫患者中可见。神经突素是一种受神经活动上调的蛋白质，其过量会促进颗粒神经元的轴突分支。神经突素缺乏会抑制苔藓纤维出芽，并减轻癫痫发作的严重程度。神经突素和成纤维细胞生长因子（FGF）协同刺激FGF信号传导并增强轴突分支。神经突素是FGF介导的FGF受体向细胞表面募集所必需的。FGF受体的募集会促进轴突分支。这一新机制的发现应有助于开发新型抗癫痫药物，通过神经突素-FGF信号传导抑制轴突分支。
