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Role of A-type potassium currents in excitability, network synchronicity, and epilepsy
KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.ORCID iD: 0000-0003-0281-9450
KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
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.

Place, publisher, year, edition, pages
2010. Vol. 20, no 7, 877-887 p.
Keyword [en]
epileptogenesis, fast ripples, synchronicity, dendritic potentials, transient A-type potassium current, Kv4.2
National Category
Neurosciences Bioinformatics (Computational Biology)
Identifiers
URN: urn:nbn:se:kth:diva-25915DOI: 10.1002/hipo.20694ISI: 000279482800008Scopus ID: 2-s2.0-77954017676OAI: oai:DiVA.org:kth-25915DiVA: diva2:360753
Note
QC 20101104 QC 20111215Available from: 2010-11-04 Created: 2010-11-04 Last updated: 2017-12-12Bibliographically approved
In thesis
1. A-type Potassium Channels in Dendritic Integration: Role in Epileptogenesis
Open this publication in new window or tab >>A-type Potassium Channels in Dendritic Integration: Role in Epileptogenesis
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
epileptogenesis, fast ripples, synchronicity, dendritic potentials, transient A–type potassium current, KV 4.2
National Category
Information Science
Identifiers
urn:nbn:se:kth:diva-11291 (URN)978-91-7415-471-9 (ISBN)
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
2. 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.
Series
TRITA-CSC-A, ISSN 1653-5723 ; 2012:02
Keyword
Dendritic excitability, synchronized synaptic input, multicompartment model, epilepsy, axonal excitability, silent C–fibres, Hodgkin–Huxley dynamics, conduction velocity, KA
National Category
Computer Science
Identifiers
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)
Opponent
Supervisors
Note

QC 20102423

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

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