Cognitive deficits and impaired hippocampal long-term potentiation in KATP-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.

ATP-sensitive potassium (K_ATP) channels are a unique link between cellular metabolism and membrane excitability. K_ATP gain-of-function (GOF) mutations have been identified as the most common cause of neonatal diabetes (1, 2), which, in many cases, manifests neurological features in a novel syndrome known as developmental delay, epilepsy, and neonatal diabetes (DEND) (3–6). Neurological symptoms of DEND include motor and developmental delays, severe epileptic phenotypes, and lifelong intellectual disabilities (7, 8). Diabetic features arise from suppression of insulin secretion by expression of K_ATP-GOF channels in pancreatic insulin-producing β-cells, and mice pan-neuronally expressing a DEND-associated K_ATP-GOF mutation showed sensorimotor deficits attributed to loss of excitability in cerebellar Purkinje neurons (9, 10). However, the involvement of K_ATP-GOF mutations in other neurological features as well as the treatability of these features remain unknown.K_ATP channels are hetero-octameric complexes comprising four pore-forming Kir6.x and four sulfonylurea receptor subunits, with Kir6.2 and SUR1 compositions predominating in neurons of the hippocampus and cerebellum (11, 12) as well as in pancreatic insulin-producing β-cells (13). SUR1 subunits provide pharmacological sensitivity to K_ATP channel openers (diazoxide) and blockers (e.g., sulfonylureas such as glibenclamide and tolbutamide). Kir6.2 and SUR1 subunits each contain RKR endoplasmic reticulum retention motifs, with the expression of both subunits required to form functional channels (14). Mice globally lacking K_ATP demonstrate spatial learning deficits (15, 16), intrahippocampal application of the K_ATP channel opener diazoxide impairs spatial learning and memory (17), and intraseptal application of glibenclamide improved spatial memory defects induced by galanin or morphine in rats (18, 19). K_ATP currents regulate spike rates and spontaneous bursting activity in hippocampal CA1/CA3 neurons (20) and gate epileptic seizures (21), suggesting that neurological features may arise from alterations to excitability in hippocampal neurons (10). In human neonatal diabetes, sulfonylureas are effective in normalizing blood glucose (22) and often successful in restoring muscular tone, but they are not nearly as effective in treating neurological, especially cognitive, features of DEND (4, 23–25). These findings raise questions about the pathophysiology of DEND, particularly the relative contributions of neuronal and pancreatic expression of K_ATP-GOF channels in the development of neurological features. Here, we explored the origin, underlying mechanisms, and treatability of the cognitive deficits of DEND in mouse models expressing K_ATP-GOF channels in central neurons (pan-neuronal or hippocampus specific) or in pancreatic β-cells.