文章基本信息

标题：Cognitive deficits and impaired hippocampal long-term potentiation in K _ATP-induced DEND syndrome
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作者：Shaul Yahil ; David F. Wozniak ; Zihan Yan 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：45
DOI：10.1073/pnas.2109721118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Gain-of-function (GOF) mutations in the ATP-sensitive potassium (K ATP) channel cause neonatal diabetes, with some individuals exhibiting developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. In this study, we uncover the direct effects of neuronal expression of K ATP-GOF mutations, and not diabetes per se, on the neurological features of DEND. Our results show a close link between neuronal K ATP-GOF expression and cognitive dysfunction in DEND and reveal that antidiabetic sulfonylureas, which successfully treat diabetes, mitigate some sensorimotor problems but not cognitive deficits. These results have critical implications for humans, revealing the need for novel drugs to treat learning and memory deficits not only for K ATP-induced DEND but also for other pathologies arising from altered ion channels in the brain. ATP-sensitive potassium (K ATP) gain-of-function (GOF) mutations cause neonatal diabetes, with some individuals exhibiting developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. Mice expressing K ATP-GOF mutations pan-neuronally (nK ATP-GOF) demonstrated sensorimotor and cognitive deficits, whereas hippocampus-specific hK ATP-GOF mice exhibited mostly learning and memory deficiencies. Both nK ATP-GOF and hK ATP-GOF mice showed altered neuronal excitability and reduced hippocampal long-term potentiation (LTP). Sulfonylurea therapy, which inhibits K ATP, mildly improved sensorimotor but not cognitive deficits in K ATP-GOF mice. Mice expressing K ATP-GOF mutations in pancreatic β-cells developed severe diabetes but did not show learning and memory deficits, suggesting neuronal K ATP-GOF as promoting these features. These findings suggest a possible origin of cognitive dysfunction in DEND and the need for novel drugs to treat neurological features induced by neuronal K ATP-GOF.
关键词：KATP; DEND; behavior; electrophysiology; cognition