Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110.
Proc Natl Acad Sci U S A. 2021 Nov 9;118(45). doi: 10.1073/pnas.2109721118.
ATP-sensitive potassium (K) gain-of-function (GOF) mutations cause neonatal diabetes, with some individuals exhibiting developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. Mice expressing K-GOF mutations pan-neuronally (nK-GOF) demonstrated sensorimotor and cognitive deficits, whereas hippocampus-specific hK-GOF mice exhibited mostly learning and memory deficiencies. Both nK-GOF and hK-GOF mice showed altered neuronal excitability and reduced hippocampal long-term potentiation (LTP). Sulfonylurea therapy, which inhibits K, mildly improved sensorimotor but not cognitive deficits in K-GOF mice. Mice expressing K-GOF mutations in pancreatic β-cells developed severe diabetes but did not show learning and memory deficits, suggesting neuronal K-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-GOF.
三磷酸腺苷敏感性钾（K）通道功能获得性（GOF）突变可引起新生儿糖尿病，部分患者伴有发育迟缓、癫痫和新生儿糖尿病伴癫痫（DEND）综合征。全神经元表达 K-GOF 突变（nK-GOF）的小鼠表现出感觉运动和认知功能缺陷，而海马特异性 hK-GOF 小鼠则主要表现出学习和记忆缺陷。nK-GOF 和 hK-GOF 小鼠均表现出神经元兴奋性改变和海马长时程增强（LTP）减少。磺酰脲类药物治疗可抑制 K，轻度改善 K-GOF 小鼠的感觉运动功能，但不能改善认知功能缺陷。在胰岛β细胞中表达 K-GOF 突变的小鼠可发展为严重糖尿病，但未表现出学习和记忆缺陷，提示神经元 K-GOF 可能促进这些特征的发生。这些发现提示了 DEND 认知功能障碍的可能起源，也需要新的药物来治疗神经元 K-GOF 诱导的神经功能特征。
