Digital Digital Cognitive deficits and impaired hippocampal long-term Cognitive deficits and impaired hippocampal long-term potentiation in K ATP-induced DEND syndrome 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) syn- drome. Mice expressing K ATP -GOF mutations pan-neuronally (nK ATP -GOF) demonstrated sensorimotor and cognitive de fi cits, whereas hippocampus-speci fi c hK ATP -GOF mice exhibited mostly learning and memory de fi ciencies. 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 de fi cits in K ATP -GOF mice. Mice expressing K ATP -GOF mutations in pan- creatic β -cells developed severe diabetes but did not show learning and memory de fi cits, suggesting neuronal K ATP -GOF as promoting these features. These fi ndings 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. KATP expression of K ATP - GOF mutations, and not diabetes per se, on the neurological features of DEND. Our results show a close link between neuronal K ATP -GOF expression and cognitive dysfunction in DEND and reveal that antidiabetic sulfonylureas, which successfully treat diabetes, mitigate some sensorimotor prob- lems but not cognitive de fi cits. These results have critical implications for humans, revealing the need for novel drugs to treat learning and memory de fi cits not only for K ATP induced DEND but also for other pathologies arising from altered ion channels in the brain. in nK ATP - GOF mice. Indeed, since no significant spatial learning deficits were observed in the hK ATP -GOF mice, we cannot conclude that poor performance on the probe trial is due to slower swimming speeds but may reflect a selective retention deficit. A specific contextual conditioning deficit in the absence of an auditory cue impairment in hK ATP -GOF reinforces the hippocampal specific- ity and symptomatology of this model and suggests that additional findings in auditory fear conditioning in nK ATP -GOF mice have an extrahippocampal origin. These results are in agreement with intellectual learning and memory deficits observed in human DEND (4–8, 23). Our studies not only parallel the cognitive deficits reported in humans carrying K ATP -GOF mutations (29–31) but also underscore the role of hippocampal K ATP channels in learning and memory processes. We have provided substantial evidence here that the neuronal expression of K ATP -GOF subunits leads to motor dysfunction and spatial learning and memory deficits in K ATP -GOF mice. Surpris-ingly, somewhat similar effects were previously reported in global K ATP -KO mice (17). However, the application of Glib directly into central neurons by intraseptal injection improved spontaneous alternation and memory defects induced by galanin or morphine in rats (18, 19), which suggests that the loss of K ATP in nonhippocampal neurons may contribute to the learning and memory deficits in the global K ATP -KO animal. In our study, impaired LTP induction in hippocampal slices from K ATP -GOF mice was associated with cognitive deficits. K ATP channels are pre- and postsynaptically in CA1 hippocampal neurons Thus, K ATP -GOF mutations may provide a to by persistently reducing presynaptic membrane and Ca 2 + influx while postsynaptically reducing N-methyl-D-aspartate receptor function + channel block. K ATP -GOF