1. Cognitive deficits and impaired hippocampal long-term potentiation in K ATP -induced DEND syndrome.
- Author
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Yahil S, Wozniak DF, Yan Z, Mennerick S, and Remedi MS
- Subjects
- Animals, Diabetes Mellitus etiology, Diabetes Mellitus metabolism, Disease Models, Animal, Epilepsy etiology, Epilepsy metabolism, Female, Gain of Function Mutation, Infant, Newborn, Diseases etiology, Infant, Newborn, Diseases metabolism, Learning Disabilities drug therapy, Learning Disabilities etiology, Long-Term Potentiation, Male, Memory Disorders drug therapy, Memory Disorders etiology, Mice, Transgenic, Psychomotor Disorders etiology, Psychomotor Disorders metabolism, Sulfonylurea Compounds therapeutic use, Cognition Disorders etiology, Diabetes Mellitus psychology, Epilepsy psychology, Hippocampus metabolism, Infant, Newborn, Diseases psychology, KATP Channels genetics, Motor Disorders etiology, Psychomotor Disorders psychology
- Abstract
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 KATP -GOF mutations pan-neuronally (nKATP -GOF) demonstrated sensorimotor and cognitive deficits, whereas hippocampus-specific hKATP -GOF mice exhibited mostly learning and memory deficiencies. Both nKATP -GOF and hKATP -GOF mice showed altered neuronal excitability and reduced hippocampal long-term potentiation (LTP). Sulfonylurea therapy, which inhibits KATP , mildly improved sensorimotor but not cognitive deficits in KATP -GOF mice. Mice expressing KATP -GOF mutations in pancreatic β-cells developed severe diabetes but did not show learning and memory deficits, suggesting neuronal KATP -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 KATP -GOF., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)- Published
- 2021
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