Roy Paula R, Link Nichole
Department of Neurobiology, University of Utah, Salt Lake City, Utah 84112.
Department of Neurobiology, University of Utah, Salt Lake City, Utah 84112
eNeuro. 2025 May 5;12(5). doi: 10.1523/ENEURO.0545-24.2025. Print 2025 May.
Seizures affect a large proportion of the global population and occur due to abnormal neuronal activity in the brain. Unfortunately, widespread genetic and phenotypic heterogeneity contributes to insufficient treatment options. It is critical to identify the genetic underpinnings of how seizures occur to better understand seizure disorders and improve therapeutic development. We used the model to identify that IGF-II mRNA-binding protein (Imp) is linked to the onset of this phenotype. Specific reduction of Imp in neurons causes seizures after mechanical stimulation. Importantly, gross motor behavior is unaffected, showing Imp loss does not affect general neuronal activity. Developmental loss of Imp is sufficient to cause seizures in adults; thus, Imp-modulated neuron development affects mature neuronal function. Since Imp is an RNA-binding protein, we sought to identify the mRNA target that Imp regulates in neurons to ensure proper neuronal activity after mechanical stress. We find that the Imp protein binds () mRNA, and the reduction of Sdc also causes mechanically induced seizures. Expression of Sdc in -deficient neurons rescues seizure defects, showing that Sdc is sufficient to restore normal behavior after mechanical stress. We suggest that the Imp protein binds mRNA in neurons, and this functional interaction is important for normal neuronal biology and animal behavior in a mechanically induced seizure model. Since Imp and Sdc are conserved, our work highlights a neuronal-specific pathway that might contribute to seizure disorder when mutated in humans.
癫痫发作影响着全球很大一部分人口，其发生是由于大脑中神经元活动异常所致。不幸的是，广泛的遗传和表型异质性导致治疗选择不足。确定癫痫发作发生的遗传基础对于更好地理解癫痫疾病和改善治疗方法的开发至关重要。我们使用该模型确定胰岛素样生长因子-II mRNA结合蛋白（Imp）与这种表型的发作有关。神经元中Imp的特异性减少会在机械刺激后引发癫痫发作。重要的是，总体运动行为不受影响，这表明Imp的缺失不会影响一般的神经元活动。Imp在发育过程中的缺失足以导致成年个体癫痫发作；因此，Imp调节的神经元发育会影响成熟神经元的功能。由于Imp是一种RNA结合蛋白，我们试图确定Imp在神经元中调节的mRNA靶点，以确保在机械应激后神经元活动正常。我们发现Imp蛋白与（）mRNA结合，Sdc的减少也会导致机械诱导的癫痫发作。在缺乏的神经元中表达Sdc可挽救癫痫缺陷，表明Sdc足以在机械应激后恢复正常行为。我们认为Imp蛋白在神经元中与mRNA结合，并且这种功能相互作用在机械诱导的癫痫模型中对正常神经元生物学和动物行为很重要。由于Imp和Sdc是保守的，我们的工作突出了一条神经元特异性途径，当在人类中发生突变时可能导致癫痫疾病。
