Date of Award
Doctor of Philosophy (PhD)
ATP-sensitive potassium (KATP) channels link cellular metabolism and membrane excitability in many tissues, including brain and pancreas. Gain-of-function (GOF) mutations to KATP channels cause neonatal diabetes, with some patients exhibiting developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. Diabetic symptoms have been attributed to loss of membrane excitability and insulin secretion in pancreatic β-cells, though the origin of neurological deficits and the effects of neuronal KATP-GOF mutations more generally remain elusive. In this dissertation, I will present evidence that mice expressing KATP-GOF mutations pan-neuronally (nKATP-GOF) demonstrated sensorimotor and cognitive deficits, whereas hippocampus-specific hKATP-GOF mice exhibited predominantly learning and memory deficits. In acute hippocampal slices, both nKATP-GOF and hKATP-GOF mice demonstrated impaired hippocampal plasticity and altered long-term potentiation (LTP) induction. Severely diabetic mice with KATP-GOF expression only in pancreatic β-cells (βKATP-GOF) did not show cognitive deficits, suggesting overactive neuronal KATP as the origin of these features. Sulfonylurea therapy, which inhibits KATP and is successfully used to treat diabetes, mildly improved sensorimotor but not the cognitive deficits of DEND.
Chair and Committee
Yahil, Shaul Vladimir, "The Role of Neuronal ATP-sensitive Potassium Channels in Learning and Memory" (2021). Arts & Sciences Electronic Theses and Dissertations. 2631.