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.