癫痫是一种常见的神经系统疾病,不仅影响成人,也影响婴儿和儿童。因为癫痫已经研究了很长时间,有几种药理学上有效的抗惊厥药,which,然而,不适合所有患者的治疗。癫痫的起源已经在损伤后的发生以及作为与各种脑疾病的伴随疾病方面得到了广泛的研究,如肿瘤,缺血事件,等。然而,在过去的几十年里,有许多报道表明遗传和表观遗传因素在癫痫发生中起重要作用。因此,需要进一步鉴定可能与癫痫发作易感性较高相关的基因和基因座.使用小鼠敲除模型的癫痫发生是非常有益的,但它有其局限性。其中之一是由于基因的完全缺失不是,在许多情况下,与人类癫痫相关综合征相似。产生癫痫小鼠模型的另一种方法是N-乙基-N-亚硝基脲(ENU)定向诱变。最近,使用这种方法,我们产生了一种新的小鼠品系,Soc(苏格拉底,以前是s8-3),癫痫样活动。利用分子生物学方法,钙神经成像,和免疫细胞化学,我们能够描述菌株的特征。从soc突变脑中分离的神经元保留了体外分化并形成网络的能力。然而,soc突变神经元的特征是自发激发活性增加。与WT神经元相比,它们还表现出高度的Ca2+活性。此外,它们显示NMDA受体的表达增加,AMPA受体的Ca2+传导GluA2亚基的表达降低,抑制磷酸肌醇3-激酶的表达,和细胞质膜的BK通道参与针对癫痫发生的保护。在胚胎和出生后的发育过程中,几种编码离子通道的基因在体内表达下调,也是。我们的数据表明soc突变会导致大脑中兴奋-抑制平衡的破坏,它可以作为癫痫的小鼠模型。
Epilepsy is one of the common neurological diseases that affects not only adults but also infants and children. Because epilepsy has been studied for a long time, there are several pharmacologically effective anticonvulsants, which, however, are not suitable as therapy for all patients. The genesis of epilepsy has been extensively investigated in terms of its occurrence after injury and as a concomitant disease with various brain diseases, such as tumors, ischemic events, etc. However, in the last decades, there are multiple reports that both genetic and epigenetic factors play an important role in epileptogenesis. Therefore, there is a need for further identification of genes and loci that can be associated with higher susceptibility to epileptic seizures. Use of mouse knockout models of epileptogenesis is very informative, but it has its limitations. One of them is due to the fact that complete deletion of a gene is not, in many cases, similar to human epilepsy-associated syndromes. Another approach to generating mouse models of epilepsy is N-Ethyl-N-nitrosourea (ENU)-directed mutagenesis. Recently, using this approach, we generated a novel mouse strain, soc (socrates, formerly s8-3), with epileptiform activity. Using molecular biology methods, calcium neuroimaging, and immunocytochemistry, we were able to characterize the strain. Neurons isolated from soc mutant brains retain the ability to differentiate in vitro and form a network. However, soc mutant neurons are characterized by increased spontaneous excitation activity. They also demonstrate a high degree of Ca2+ activity compared to WT neurons. Additionally, they show increased expression of NMDA receptors, decreased expression of the Ca2+-conducting GluA2 subunit of AMPA receptors, suppressed expression of phosphoinositol 3-kinase, and BK channels of the cytoplasmic membrane involved in protection against epileptogenesis. During embryonic and postnatal development, the expression of several genes encoding ion channels is downregulated in vivo, as well. Our data indicate that soc mutation causes a disruption of the excitation-inhibition balance in the brain, and it can serve as a mouse model of epilepsy.