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A-type Potassium Channels in Dendritic Integration: Role in Epileptogenesis
KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. (CB)
2009 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

During cognitive tasks, synchronicity of neural activity varies and is correlated with performance. However, there may be an upper limit to normal synchronised activity – specifically, epileptogenic activity is characterized byexcess spiking at high synchronicity. An epileptic seizure has a complicated course of events and I therefore focused on the synchronised activity preceding a seizure (fast ripples). These high frequency oscillations (200–1000 Hz) have been identified as possible signature markers of epileptogenic activity and may be involved in generating seizures. Moreover, a range of ionic currents have been suggested to be involved in distinct aspects of epileptogenesis. Based on pharmacological and genetic studies, potassium currents have been implicated, in particular the transient A–type potassium channel (KA). Our first objective was to investigate if KA could suppress synchronized input while minimally affecting desynchronised input. The second objective was to investigate if KA could suppress fast ripple activity. To study this I use a detailed compartmental model of a hippocampal CA1 pyramidal cell. The ion channels were described by Hodgkin–Huxley dynamics.

The result showed that KA selectively could suppress highly synchronized input. I further used two models of fast ripple input and both models showed a strong reduction in the cellular spiking activity when KA was present. In an ongoing in vitro brain slice experiment our prediction from the simulations is being tested. Preliminary results show that the cellular response was reduced by 30 % for synchronised input, thus confirming our theoretical predictions. By suppressing fast ripples KA may prevent the highly synchronised spiking activity to spread and thereby preventing the seizure. Many antiepileptic drugs down regulate cell excitability by targeting sodium channels or GABA–receptors. These antiepileptic drugs affect the cell during normal brain activity thereby causing significant side effects. KA mainly suppresses the spiking activity when the cell is exposed to abnormally high synchronised input. An enhancement in the KA current might therefore be beneficial in reducing seizures while not affecting normal brain activity.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2009. , x, 54 p.
Series
TRITA-CSC-A, ISSN 1653-5723 ; 2009:18
Keyword [en]
epileptogenesis, fast ripples, synchronicity, dendritic potentials, transient A–type potassium current, KV 4.2
National Category
Information Science
Identifiers
URN: urn:nbn:se:kth:diva-11291ISBN: 978-91-7415-471-9 (print)OAI: oai:DiVA.org:kth-11291DiVA: diva2:272185
Presentation
2009-11-04, RB35, Roslagstullsbacken 35, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2009-10-16 Created: 2009-10-14 Last updated: 2017-05-23Bibliographically approved
List of papers
1. Role of A-type potassium currents in excitability, network synchronicity, and epilepsy
Open this publication in new window or tab >>Role of A-type potassium currents in excitability, network synchronicity, and epilepsy
2010 (English)In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 20, no 7, 877-887 p.Article in journal (Refereed) Published
Abstract [en]

A range of ionic currents have been suggested to be involved in distinct aspects of epileptogenesis. Based on pharmacological and genetic studies, potassium currents have been implicated, in particular the transient A-type potassium current (K-A). Epileptogenic activity comprises a rich repertoire of characteristics, one of which is synchronized activity of principal cells as revealed by occurrences of for instance fast ripples. Synchronized activity of this kind is particularly efficient in driving target cells into spiking. In the recipient cell, this synchronized input generates large brief compound excitatory postsynaptic potentials (EPSPs). The fast activation and inactivation of K-A lead us to hypothesize a potential role in suppression of such EPSPs. In this work, using computational modeling, we have studied the activation of K-A by synaptic inputs of different levels of synchronicity. We find that K-A participates particularly in suppressing inputs of high synchronicity. We also show that the selective suppression stems from the current's ability to become activated by potentials with high slopes. We further show that K-A suppresses input mimicking the activity of a fast ripple. Finally, we show that the degree of selectivity of K-A can be modified by changes to its kinetic parameters, changes of the type that are produced by the modulatory action of KChIPs and DPPs. We suggest that the wealth of modulators affecting K-A might be explained by a need to control cellular excitability in general and suppression of responses to synchronicity in particular. We also suggest that compounds changing K-A-kinetics may be used to pharmacologically improve epileptic status.

Keyword
epileptogenesis, fast ripples, synchronicity, dendritic potentials, transient A-type potassium current, Kv4.2
National Category
Neurosciences Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-25915 (URN)10.1002/hipo.20694 (DOI)000279482800008 ()2-s2.0-77954017676 (Scopus ID)
Note
QC 20101104 QC 20111215Available from: 2010-11-04 Created: 2010-11-04 Last updated: 2012-04-23Bibliographically approved
2. KA channels suppress cellular responses to fast ripple activity – implications for epilepsy
Open this publication in new window or tab >>KA channels suppress cellular responses to fast ripple activity – implications for epilepsy
2009 (English)In: BMC neuroscience (Online), ISSN 1471-2202, Vol. 10, no Suppl 1, P226- p.Article in journal (Refereed) Published
National Category
Neurosciences Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-25916 (URN)10.1186/1471-2202-10-S1-P226 (DOI)
Note
QC 20101104. Eighteenth Annual Computational Neuroscience Meeting: CNS*2009 Berlin, Germany. 18–23 July 2009 Available from: 2010-11-04 Created: 2010-11-04 Last updated: 2011-12-22Bibliographically approved
3. KA channels reduce dendritic depolarization from synchronized synaptic input: implication for neural processing and epilepsy
Open this publication in new window or tab >>KA channels reduce dendritic depolarization from synchronized synaptic input: implication for neural processing and epilepsy
2008 (English)In: BMC neuroscience (Online), ISSN 1471-2202, Vol. 9, no Suppl 1, P45- p.Article in journal (Refereed) Published
National Category
Neurosciences Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-25919 (URN)10.1186/1471-2202-9-S1-P45 (DOI)
Note
QC 20101104. Seventeenth Annual Computational Neuroscience Meeting: CNS*2008 Portland, OR, USA. 19–24 July 2008 Available from: 2010-11-04 Created: 2010-11-04 Last updated: 2011-12-22Bibliographically approved

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