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Reversing Nerve Cell Pathology by Optimizing Modulatory Action on Target Ion Channels
KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.ORCID iD: 0000-0003-0281-9450
2011 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 101, no 8, 1871-1879 p.Article in journal (Refereed) Published
Abstract [en]

In diseases of the brain, the distribution and properties of ion channels display deviations from healthy control subjects. We studied three cases of ion channel alteration related to epileptogenesis. The first case of ion channel alteration represents an enhanced sodium current, the second case addresses the downregulation of the transient potassium current K(A), and the third case relates to kinetic properties of K(A) in a patient with temporal lobe epilepsy. Using computational modeling and optimization, we aimed at reversing the pathological characteristics and restoring normal neural function by altering ion channel properties. We identified two key aspects of neural dysfunction in epileptogenesis: an enhanced response to synaptic input in general and to highly synchronized synaptic input in particular. In previous studies, we showed that the potassium channel K(A) played a major role in neural responses to highly synchronized input. It was therefore selected as the target upon which modulators would act. In biophysical simulations, five experimentally characterized endogenous modulations on the K(A) channel were included. Relative concentrations of these modulators were controlled by a numerical optimizer that compared model output to predefined neural output, which represented a normal physiological response. Several solutions that restored the neuron function were found. In particular, distinct subtype compositions of the auxiliary proteins Kv channel-interacting proteins 1 and dipeptidyl aminopeptidase-like protein 6 were able to restore changes imposed by the enhanced sodium conductance or suppressed K(A) conductance. Moreover, particular combinations of protein kinese C, calmodulin-dependent protein kinase II, and arachidonic acid were also able to restore these changes as well as the channel pathology found in a patient with temporal lobe epilepsy. The solutions were further analyzed for sensitivity and robustness. We suggest that the optimization procedure can be used not only for neurons, but also for other organs with excitable cells, such as the heart and pancreas where channelopathies are found.

Place, publisher, year, edition, pages
2011. Vol. 101, no 8, 1871-1879 p.
Keyword [en]
National Category
Biophysics Neurosciences Bioinformatics (Computational Biology)
URN: urn:nbn:se:kth:diva-47975DOI: 10.1016/j.bpj.2011.08.055ISI: 000296075800010ScopusID: 2-s2.0-80054702134OAI: diva2:457182
QC 20111117Available from: 2011-11-17 Created: 2011-11-15 Last updated: 2012-04-23Bibliographically 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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