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Dampening of Hyperexcitability in CA1 Pyramidal Neurons by Polyunsaturated Fatty Acids Acting on Voltage-Gated Ion Channels
KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. (Stockholm Brain Institute)
Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University.
KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University.
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2012 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 7, no 9, e44388- p.Article in journal (Refereed) Published
Abstract [en]

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 channel's 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.

Place, publisher, year, edition, pages
2012. Vol. 7, no 9, e44388- p.
Keyword [en]
epilepsy, synchronicity, hyperexcitability, ion channel modulation, PUFA
National Category
Neurosciences Bioinformatics (Computational Biology)
URN: urn:nbn:se:kth:diva-93676DOI: 10.1371/journal.pone.0044388ISI: 000309556100013ScopusID: 2-s2.0-84866695930OAI: diva2:517274
Swedish Research Council, 621-2007-4223 13043

QC 20121120. Updated from manuscript to article in journal.

Available from: 2012-04-23 Created: 2012-04-23 Last updated: 2012-11-29Bibliographically approved
In thesis
1. Mechanisms of excitability in the central and peripheral nervous systems: Implications for epilepsy and chronic pain
Open this publication in new window or tab >>Mechanisms of excitability in the central and peripheral nervous systems: Implications for epilepsy and chronic pain
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The work in this thesis concerns mechanisms of excitability of neurons. Specifically, it deals with how neurons respond to input, and how their response is controlled by ion channels and other active components of the neuron. I have studied excitability in two systems of the nervous system, the hippocampus which is responsible for memory and spatial navigation, and the peripheral C–fibre which is responsible for sensing and conducting sensory information to the spinal cord.

Within the work, I have studied the role of excitability mechanisms in normal function and in pathological conditions. For hippocampus the normal function includes changes in excitability linked to learning and memory. However, it also is intimately linked to pathological increases in excitability observed in epilepsy. In C–fibres, excitability controls sensitivity to responses to stimuli. When this response becomes enhanced, this can lead to pain.

I have used computational modelling as a tool for studying hyperexcitability in neurons in the central nervous system in order to address mechanisms of epileptogenesis. Epilepsy is a brain disorder in which a subject has repeated seizures (convulsions) over time. Seizures are characterized by increased and highly synchronized neural activity. Therefore, mechanisms that regulate synchronized neural activity are crucial for the understanding of epileptogenesis. Such mechanisms must differentiate between synchronized and semi synchronized synaptic input. The candidate I propose for such a mechanism is the fast outward current generated by the A-type potassium channel (KA).

Additionally, I have studied the propagation of action potentials in peripheral axons, denoted C–fibres. These C–fibres mediate information about harmful peripheral stimuli from limbs and organs to the central nervous system and are thereby linked to pathological pain. If a C–fibre is activated repeatedly, the excitability is altered and the mechanisms for this alteration are unknown. By computational modelling, I have proposed mechanisms which can explain this alteration in excitability.

In summary, in my work I have studied roles of particular ion channels in excitability related to functions in the nervous system. Using computational modelling, I have been able to relate specific properties of ion channels to functions of the nervous system such as sensing and learning, and in particular studied the implications of mechanisms of excitability changes in diseases.


Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2012. xii, 100 p.
TRITA-CSC-A, ISSN 1653-5723 ; 2012:02
Dendritic excitability, synchronized synaptic input, multicompartment model, epilepsy, axonal excitability, silent C–fibres, Hodgkin–Huxley dynamics, conduction velocity, KA
National Category
Computer Science
urn:nbn:se:kth:diva-93496 (URN)978-91-7501-307-7 (ISBN)
Public defence
2012-05-08, F3, Lindstedtsvägen 26, KTH, Stockholm, 10:00 (English)

QC 20102423

Available from: 2012-04-23 Created: 2012-04-18 Last updated: 2014-06-02Bibliographically approved

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