LAUSR

Significance Gain-of-function (GOF) mutations in the ATP-sensitive potassium (KATP) 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 KATP-GOF mutations, and not diabetes per se, on the neurological features of DEND. Our results show a close link between neuronal KATP-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 KATP-induced DEND but also for other pathologies arising from altered ion channels in the brain. ATP-sensitive potassium (KATP) 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.