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Mechanisms of excitability in the central and peripheral nervous systems: Implications for epilepsy and chronic pain
KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
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 [en]
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: urn:nbn:se:kth:diva-93496ISBN: 978-91-7501-307-7 (print)OAI: oai:DiVA.org:kth-93496DiVA: diva2:516617
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
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. Reversing Nerve Cell Pathology by Optimizing Modulatory Action on Target Ion Channels
Open this publication in new window or tab >>Reversing Nerve Cell Pathology by Optimizing Modulatory Action on Target Ion Channels
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.

Keyword
CA1 PYRAMIDAL NEURONS, TEMPORAL-LOBE EPILEPSY, POTASSIUM CURRENTS, KETOGENIC DIET, K+ CHANNELS, IN-VIVO, RAT, KV4.2, EXCITABILITY, EXPRESSION
National Category
Biophysics Neurosciences Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-47975 (URN)10.1016/j.bpj.2011.08.055 (DOI)000296075800010 ()2-s2.0-80054702134 (Scopus ID)
Note
QC 20111117Available from: 2011-11-17 Created: 2011-11-15 Last updated: 2017-12-08Bibliographically approved
3. Dampening of Hyperexcitability in CA1 Pyramidal Neurons by Polyunsaturated Fatty Acids Acting on Voltage-Gated Ion Channels
Open this publication in new window or tab >>Dampening of Hyperexcitability in CA1 Pyramidal Neurons by Polyunsaturated Fatty Acids Acting on Voltage-Gated Ion Channels
Show others...
2012 (English)In: PLoS ONE, ISSN 1932-6203, E-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.

Keyword
epilepsy, synchronicity, hyperexcitability, ion channel modulation, PUFA
National Category
Neurosciences Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-93676 (URN)10.1371/journal.pone.0044388 (DOI)000309556100013 ()2-s2.0-84866695930 (Scopus ID)
Funder
Swedish Research Council, 621-2007-4223 13043
Note

QC 20121120. Updated from manuscript to article in journal.

Available from: 2012-04-23 Created: 2012-04-23 Last updated: 2017-12-07Bibliographically approved
4. Integration of synchronous synaptic input in CA1 pyramidal neuron depends on spatial and temporal distributions of the input
Open this publication in new window or tab >>Integration of synchronous synaptic input in CA1 pyramidal neuron depends on spatial and temporal distributions of the input
2013 (English)In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 23, no 1, 87-99 p.Article in journal (Refereed) Published
Abstract [en]

Highly synchronized neural firing has been discussed in relation to learning and memory, for instance sharp-wave activity in hippocampus. We were interested to study how a postsynaptic CA1 pyramidal neuron would integrate input of different levels of synchronicity. In previous work using computational modeling we studied how the integration depends on dendritic conductances. We found that the transient A-type potassium channel KA was able to selectively suppress input of high synchronicity. In recent years, compartmentalization of dendritic integration has been shown. We were therefore interested to study the influence of localization and pattern of synaptic input over the dendritic tree of the CA1 pyramidal neuron. We find that the selective suppression increases when synaptic inputs are placed on oblique dendrites further out from the soma. The suppression also increases along the radial axis from the apical trunk out to the end of oblique dendrites. We also find that the KA channel suppresses the occurrence of dendritic spikes. Moreover, recent studies have shown interaction between synaptic inputs. We therefore studied the influence of apical tuft input on the integration studied above. We find that excitatory input provides a modulatory influence reducing the capacity of KA to suppress synchronized activity, thus facilitating the excitatory drive of oblique dendritic input. Conversely, inhibitory tuft input increases the suppression by KA providing a larger control of oblique depolarizing factors on the CA1 pyramidal neuron in terms of what constitutes the most effective level of synchronicity. Furthermore, we show that the selective suppression studied above depends on the conductance of the KA channel. KA, as several other potassium channels, is modulated by several neuromodulators, for instance acetylcholine and dopamine, both of which have been discussed in relation to learning and memory. We suggest that dendritic conductances and their modulatory systems may be part of the regulation of processing of information, in particular for how network synchronicity affects learning and memory.

Keyword
A-type potassium channel, Kv 4.2, sharp waves, dendritic spikes
National Category
Neurosciences Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-93679 (URN)10.1002/hipo.22061 (DOI)000312537800010 ()2-s2.0-84870954627 (Scopus ID)
Funder
Swedish Research Council, 621-2007-4223 13043
Note

QC 20130121

Available from: 2012-04-23 Created: 2012-04-23 Last updated: 2017-12-07Bibliographically approved
5. Modeling activity-dependent changes of axonal spike conduction in primary afferent C-nociceptors
Open this publication in new window or tab >>Modeling activity-dependent changes of axonal spike conduction in primary afferent C-nociceptors
Show others...
2014 (English)In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 111, no 9, 1721-1735 p.Article in journal (Refereed) Published
Abstract [en]

Action potential initiation and conduction along peripheral axons is a dynamic process that displays pronounced activity dependence. In patients with neuropathic pain, differences in the modulation of axonal conduction velocity by activity suggest that this property may provide insight into some of the pathomechanisms. To date, direct recordings of axonal membrane potential have been hampered by the small diameter of the fibers. We have therefore adopted an alternative approach to examine the basis of activity-dependent changes in axonal conduction by constructing a comprehensive mathematical model of human cutaneous C-fibers. Our model reproduced axonal spike propagation at a velocity of 0.69 m/s commensurate with recordings from human C-nociceptors. Activity-dependent slowing (ADS) of axonal propagation velocity was adequately simulated by the model. Interestingly, the property most readily associated with ADS was an increase in the concentration of intra-axonal sodium. This affected the driving potential of sodium currents, thereby producing latency changes comparable to those observed for experimental ADS. The model also adequately reproduced post-action potential excitability changes (i.e., recovery cycles) observed in vivo. We performed a series of control experiments replicating blockade of particular ion channels as well as changing temperature and extracellular ion concentrations. In the absence of direct experimental approaches, the model allows specific hypotheses to be formulated regarding the mechanisms underlying activity-dependent changes in C-fiber conduction. Because ADS might functionally act as a negative feedback to limit trains of nociceptor activity, we envisage that identifying its mechanisms may also direct efforts aimed at alleviating neuronal hyperexcitability in pain patients.

Keyword
activity-dependent slowing, recovery cycles, mechano-insensitive nociceptor, computer modeling
National Category
Neurosciences Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-93681 (URN)10.1152/jn.00777.2012 (DOI)000335779300002 ()2-s2.0-84900796575 (Scopus ID)
Funder
Swedish Research Council, 621-2007-4223
Note

QC 20140602. Updated from manuscript to article in journal.

Available from: 2012-04-23 Created: 2012-04-23 Last updated: 2017-12-07Bibliographically approved

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