Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Krembil Research Institute, Division of Fundamental Neurobiology, Toronto Western Hospital, Toronto, Ontario M5T 0S8, Canada.
Krembil Research Institute, Division of Fundamental Neurobiology, Toronto Western Hospital, Toronto, Ontario M5T 0S8, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 3G9, Canada.
Neurobiol Dis. 2021 Dec;160:105529. doi: 10.1016/j.nbd.2021.105529. Epub 2021 Oct 9.
Loss of function mutations of the WW domain-containing oxidoreductase (WWOX) gene are associated with severe and fatal drug-resistant pediatric epileptic encephalopathy. Epileptic seizures are typically characterized by neuronal hyperexcitability; however, the specific contribution of WWOX to that hyperexcitability has yet to be investigated. Using a mouse model of neuronal Wwox-deletion that exhibit spontaneous seizures, in vitro whole-cell and field potential electrophysiological characterization identified spontaneous bursting activity in the neocortex, a marker of the underlying network hyperexcitability. Spectral analysis of the neocortical bursting events highlighted increased phase-amplitude coupling, and a propagation from layer II/III to layer V. These bursts were NMDAR and gap junction dependent. In layer II/III pyramidal neurons, Wwox knockout mice demonstrated elevated amplitude of excitatory post-synaptic currents, whereas the frequency and amplitude of inhibitory post-synaptic currents were reduced, as compared to heterozygote and wild-type littermate controls. Furthermore, these neurons were depolarized and demonstrated increased action potential frequency, sag current, and post-inhibitory rebound. These findings suggest WWOX plays an essential role in balancing neocortical excitability and provide insight towards developing therapeutics for those suffering from WWOX disorders.
WW 结构域氧化还原酶（WWOX）基因的功能丧失突变与严重且致命的耐药性小儿癫痫性脑病有关。癫痫发作通常表现为神经元过度兴奋；然而，WWOX 对这种过度兴奋的具体贡献尚未被研究。使用表现出自发性癫痫发作的神经元 Wwox 缺失的小鼠模型，体外全细胞和场电位电生理特性分析确定了新皮层中的自发性爆发活动，这是潜在网络过度兴奋的标志物。新皮层爆发事件的频谱分析强调了相位-幅度耦合的增加，以及从层 II/III 到层 V 的传播。这些爆发依赖于 NMDA 受体和缝隙连接。在层 II/III 锥体神经元中，与杂合子和野生型同窝仔对照相比，Wwox 敲除小鼠表现出兴奋性突触后电流幅度增加，而抑制性突触后电流的频率和幅度降低。此外，这些神经元去极化并表现出增加的动作电位频率、sag 电流和抑制后反弹。这些发现表明 WWOX 在平衡新皮层兴奋性方面发挥着重要作用，并为那些患有 WWOX 疾病的人开发治疗方法提供了思路。
