1. Dampening of Hyperexcitability in CA1 Pyramidal Neurons by Polyunsaturated Fatty Acids Acting on Voltage-Gated Ion Channels
- Author
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Sara I. Börjesson, Fredrik Elinder, Linnea Lundberg, Erik Fransén, and Jenny Tigerholm
- Subjects
Medicin och hälsovetenskap ,Patch-Clamp Techniques ,lcsh:Medicine ,Voltage-Gated Sodium Channels ,Biochemistry ,Medical and Health Sciences ,Ion Channels ,Membrane Potentials ,Temporal Lobe Epilepsy ,lcsh:Science ,Membrane potential ,Neurons ,Multidisciplinary ,Chemistry ,Fatty Acids ,food and beverages ,Hyperpolarization (biology) ,Resting potential ,Lipids ,Potassium channel ,Neurology ,Potassium Channels, Voltage-Gated ,Fatty Acids, Unsaturated ,Medicine ,lipids (amino acids, peptides, and proteins) ,Ion Channel Gating ,Research Article ,Computer Modeling ,Models, Biological ,Humans ,Computer Simulation ,Patch clamp ,Biology ,CA1 Region, Hippocampal ,Ion channel ,Nutrition ,Computational Neuroscience ,Epilepsy ,Voltage-gated ion channel ,Sodium channel ,lcsh:R ,Proteins ,Computational Biology ,Infant ,Cellular Neuroscience ,Computer Science ,Synapses ,Biophysics ,lcsh:Q ,sense organs ,Neuroscience - Abstract
A ketogenic diet is an alternative treatment of epilepsy in infants. The diet, rich in fat and low in carbohydrates, elevates the level of polyunsaturated fatty acids (PUFAs) in plasma. These substances have therefore been suggested to contribute to the anticonvulsive effect of the diet. PUFAs modulate the properties of a range of ion channels, including K and Na channels, and it has been hypothesized that these changes may be part of a mechanistic explanation of the ketogenic diet. Using computational modelling, we here study how experimentally observed PUFA-induced changes of ion channel activity affect neuronal excitability in CA1, in particular responses to synaptic input of high synchronicity. The PUFA effects were studied in two pathological models of cellular hyperexcitability associated with epileptogenesis. We found that experimentally derived PUFA modulation of the A-type K (K-A) channel, but not the delayed-rectifier K channel, restored healthy excitability by selectively reducing the response to inputs of high synchronicity. We also found that PUFA modulation of the transient Na channel was effective in this respect if the channels steady-state inactivation was selectively affected. Furthermore, PUFA-induced hyperpolarization of the resting membrane potential was an effective approach to prevent hyperexcitability. When the combined effect of PUFA on the K-A channel, the Na channel, and the resting membrane potential, was simulated, a lower concentration of PUFA was needed to restore healthy excitability. We therefore propose that one explanation of the beneficial effect of PUFAs lies in its simultaneous action on a range of ion-channel targets. Furthermore, this work suggests that a pharmacological cocktail acting on the voltage dependence of the Na-channel inactivation, the voltage dependences of K-A channels, and the resting potential can be an effective treatment of epilepsy. Funding Agencies|Swedish Research Council|621-2007-422313043|USA NIH|MH061492-06A2|Swedish Heart-Lung Foundation||Swedish Brain Foundation||County Council of Ostergotland||King Gustaf V and Queen Victorias Freemasons Foundation
- Published
- 2012