ATP-sensitive potassium (KATP) channels couple cell metabolism to cellular electrical activity. Humans affected by severe activating mutations in KATP channels suffer from developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). While the aetiology of diabetes in DEND syndrome is well understood, the pathophysiology of the neurological symptoms remains unclear. We hypothesised that impaired activity of parvalbumin-positive interneurons (PV-INs) may result in seizures and cognitive problems. We found, by performing electrophysiological experiments, that expressing the DEND mutation Kir6.2-V59M selectively in mouse PV-INs reduced intrinsic gamma frequency preference and short-term depression as well as disturbed cognition-associated gamma oscillations and hippocampal sharp waves. Furthermore, the risk of seizures was increased and the day-night shift in gamma activity disrupted. Blocking KATP channels with tolbutamide partially rescued the network oscillations. The non-reversible part may, to some extent, result from observed altered PV-IN dendritic branching and PV-IN arrangement within CA1. In summary, PV-INs play a key role in DEND syndrome, and this provides a framework for establishing treatment options.

中文翻译：

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KATP 通道突变扰乱海马网络活动和夜间伽马位移

ATP 敏感钾 (KATP) 通道将细胞代谢与细胞电活动耦合起来。受到 KATP 通道严重激活突变影响的人类会遭受发育迟缓、癫痫和新生儿糖尿病（DEND 综合征）的困扰。虽然 DEND 综合征中糖尿病的病因已广为人知，但神经系统症状的病理生理学仍不清楚。我们假设小白蛋白阳性中间神经元（PV-IN）的活性受损可能导致癫痫发作和认知问题。通过进行电生理学实验，我们发现，在小鼠 PV-IN 中选择性表达 DEND 突变 Kir6.2-V59M 可减少内在伽马频率偏好和短期抑郁，以及与认知相关的伽马振荡和海马尖波的紊乱。此外，癫痫发作的风险增加，伽马活性的昼夜转换被破坏。用甲苯磺丁脲阻断 KATP 通道部分缓解了网络振荡。在某种程度上，不可逆部分可能是由于观察到 CA1 内 PV-IN 树突分支和 PV-IN 排列的改变所致。总之，PV-IN 在 DEND 综合征中发挥着关键作用，这为建立治疗方案提供了框架。