Cognitive deficits and impaired hippocampal long-term potentiation in K(ATP)-induced DEND syndrome

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.