K(ATP) channels, metabolism, and neuronal excitability

Abstract

Epilepsy is a debilitating condition affecting between 1 and 2% of the U.S. population. In cases where epileptic patients respond poorly to pharmacological or surgical interventions, the incidence of seizures can be reduced (or eliminated altogether) by a high-fat, low-carbohydrate dietary therapy called the ketogenic diet (KD), which draws its name from the fact that subjects on the diet have elevated circulating levels of ketone bodies (KB's). Because of both the efficacy of the diet and the mystery surrounding its mechanism, a deeper understanding of the link between metabolism and neuronal excitability would be extremely useful in the development of additional alternative therapies for epilepsy (and other disorders of hyperexcitable brains), especially owing to the extreme difficulty of maintaining patients on the rather unpalatable KD.

The ATP-sensitive potassium channel (K_ATP channel) makes an excellent candidate molecule as a mediator of the link between metabolism and neuronal activity because of its unique gating properties; most notably, the channel opens in response to drops in intracellular [ATP]:[ADP] ratios. Published results have shown that application of KB's to slices of brain tissue from juvenile rodents can slow the rate of spontaneous neuronal firing, an effect that appears to be mediated by K_ATP channels.

This dissertation therefore aims to examine further the connection between metabolic state, K_ATP channels, and neuronal excitability. In two different regions of the mouse brain thought to be involved in the gating and propagation of epileptic seizures, three different approaches to this question were taken. First, spike-activity dependent elevations in the open probability of single K_ATP channels were recorded in hippocampal granule cells. Preliminary results demonstrating an elevation in the open probability of these channels upon KB application were also obtained. Second, metabolic control—through both intracellular and extracellular metabolites—of whole-cell K_ATP currents in individual acutely dissociated neurons of the substantia nigra pars reticulata (SNr) was studied. Finally, the role of K_ATP channels in neurotransmission at the hippocampal mossy fiber-to-CA3 pyramidal cell synapse was explored.

The results of these studies may work towards further elucidating the connection between metabolism and neuronal activity, through at least this one molecular link.