Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269.
Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269
eNeuro. 2021 May 19;8(3). doi: 10.1523/ENEURO.0024-21.2021. Print 2021 May-Jun.
Epileptic encephalopathies represent a group of disorders often characterized by refractory seizures, regression in cognitive development, and typically poor prognosis. Dysfunction of KCNQ2 and KCNQ3 channels has emerged as a major cause of neonatal epilepsy. However, our understanding of the cellular mechanisms that may both explain the origins of epilepsy and inform treatment strategies for KCNQ2 and KCNQ3 dysfunction is still lacking. Here, using mesoscale calcium imaging and pharmacology, we demonstrate that in mouse neonatal brain slices, conditional loss of from forebrain excitatory neurons ( mice) or constitutive deletion of leads to sprawling hyperactivity across the neocortex. Surprisingly, the generation of time-varying hypersynchrony in slices from mice does not require fast synaptic transmission. This is in contrast to control littermates and constitutive knock-out mice where activity is primarily driven by fast synaptic transmission in the neocortex. Unlike in the neocortex, hypersynchronous activity in the hippocampal formation from conditional and constitutive knock-out mice persists in the presence of synaptic transmission blockers. Thus, we propose that loss of KCNQ2 or KCNQ3 function differentially leads to network hyperactivity across the forebrain in a region-specific and macro-circuit-specific manner.
癫痫性脑病是一组疾病，其特征通常为难治性癫痫发作、认知发育倒退和预后不良。KCNQ2 和 KCNQ3 通道功能障碍已成为新生儿癫痫的主要原因。然而，我们对于可能同时解释癫痫起源并为 KCNQ2 和 KCNQ3 功能障碍提供治疗策略的细胞机制的理解仍然不足。在这里，我们使用中尺度钙成像和药理学方法，证明在新生小鼠脑片中，条件性敲除前脑兴奋性神经元中的 （ 小鼠）或组成性敲除 导致整个大脑皮层出现蔓延性过度活跃。令人惊讶的是， 小鼠脑片中时变超同步性的产生并不需要快速的突触传递。这与对照同窝仔鼠和组成性 敲除小鼠形成鲜明对比，后者的活动主要由大脑皮层中的快速突触传递驱动。与大脑皮层不同，来自 条件性和 组成性敲除小鼠的海马结构中的超同步活动在存在突触传递阻滞剂的情况下仍然存在。因此，我们提出 KCNQ2 或 KCNQ3 功能的丧失以区域特异性和宏观回路特异性的方式导致整个前脑网络过度活跃。
