Department of Neurology, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, China.
Cereb Cortex. 2018 Oct 1;28(10):3491-3504. doi: 10.1093/cercor/bhx215.
Epilepsy is a serious neurological condition characterized by recurrent unprovoked seizures. The exact etiology of epilepsy is not fully understood. Here, we demonstrated that the expression of contactin-associated protein-like 4 (CNTNAP4) was decreased in the temporal neocortex of epileptic patients and in the hippocampus and cortex of epileptic mice. Lentivirus-mediated knock-down of CNTNAP4 in the hippocampus increased mice susceptibility to epilepsy. Conversely, lentivirus-mediated overexpression of CNTNAP4 decreased epileptic behavior in mice. CNTNAP4 affected neuronal excitability and inhibitory synaptic transmission via postsynaptic receptors in Mg2+-free epilepsy cell model. Down-regulation or overexpression of CNTNAP4 in the hippocampus influenced the expression of gamma-aminobutyric acid A receptor β2/3 (GABAARβ2/3) membrane protein, without affecting total GABAARβ2/3 protein concentration in epileptic mice. Protein interactions between CNTNAP4, GABAARβ2/3 and gamma-aminobutyric acid receptor-associated protein (GABARAP) were observed in the hippocampus of epileptic mice. These findings suggest CNTNAP4 may be involved in the occurrence and development of epilepsy through the regulation of GABAAR function, and may be a promising target for the development of epilepsy treatment.
癫痫是一种以反复无诱因癫痫发作为特征的严重神经系统疾病。癫痫的确切病因尚未完全了解。在这里，我们证明接触蛋白相关蛋白样 4（CNTNAP4）的表达在癫痫患者的颞叶皮层和癫痫小鼠的海马体和皮层中降低。海马体中的慢病毒介导的 CNTNAP4 敲低增加了小鼠对癫痫的易感性。相反，慢病毒介导的 CNTNAP4 过表达降低了小鼠的癫痫行为。CNTNAP4 通过无镁癫痫细胞模型中的突触后受体影响神经元兴奋性和抑制性突触传递。海马体中 CNTNAP4 的下调或过表达影响γ-氨基丁酸 A 受体β2/3（GABAARβ2/3）膜蛋白的表达，而不影响癫痫小鼠中 GABAARβ2/3 总蛋白浓度。在癫痫小鼠的海马体中观察到 CNTNAP4、GABAARβ2/3 和 γ-氨基丁酸受体相关蛋白（GABARAP）之间的蛋白相互作用。这些发现表明 CNTNAP4 可能通过调节 GABAAR 功能参与癫痫的发生和发展，并且可能是开发癫痫治疗的有前途的靶点。
