Cellular Metabolism Modulates Ion Channels That Regulate Neuronal Excitability
CitationLutas, Andrew. 2015. Cellular Metabolism Modulates Ion Channels That Regulate Neuronal Excitability. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractEpilepsy is a common neurological disorder, affecting around 1% of the world’s population. For many, drugs are available that can prevent their seizures. However, for close to one third of those who suffer from epilepsy, current medicines simply do not work. Surprisingly, a change in diet can dramatically stop seizures when medications cannot. This diet, known as the ketogenic diet, involves switching from a typical western diet of high carbohydrate content to one of almost entirely fats, which induces a state of ketosis or elevated circulating ketone bodies. The liver generates these ketone bodies from fat to be used by other tissues in the body as a fuel. In particular, during ketosis, the brain begins to utilize ketone bodies in addition to the usual fuel, glucose. The ketogenic diet is very effective at preventing seizures, but remains poorly understood. How might a change in fuel utilization in the brain have such a profound impact on epilepsy?
One of the best known links between cellular metabolism and excitability is the ATP-sensitive potassium (KATP) channel. When the intracellular ratio of [ATP]:[ADP] decreases sufficiently, these channels open to generate a hyperpolarizing effect on cells. In the brain, this activity of the channel can limit the spiking of neurons. Remarkably, we have found that the presence of ketone bodies can also favor the openings of these channels providing a hypothesis for how the ketogenic diet might act to prevent seizures. Yet, the mechanism for how changes in fuel metabolism in brain cells leads to increased KATP channel opening is not known.
This thesis presents work aimed at understanding whether decreases in glucose metabolism in neurons is capable of activating KATP channels to affect neuronal firing. We find that, while disruption of glucose metabolism can activate KATP channels, it requires that mitochondrial ATP production is lowered. In addition, disrupting glucose metabolism can also affect a nonselective cation current in spontaneously active neurons, leading to a slowing of firing. Together, these findings provide new understanding of metabolic conditions in neurons that modulate ion channel activity and ultimately neuronal excitability.
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