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Dendritic and axonal ion channels supporting neuronal integration: From pyramidal neurons to peripheral nociceptors
KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The nervous system, including the brain, is a complex network with billions of complex neurons. Ion channels mediate the electrical signals that neurons use to integrate input and produce appropriate output, and could thus be thought of as key instruments in the neuronal orchestra. In the field of neuroscience we are not only curious about how our brains work, but also strive to characterize and develop treatments for neural disorders, in which the neuronal harmony is distorted. By modulating ion channel activity (pharmacologically or otherwise) it might be possible to effectively restore neuronal harmony in patients with various types of neural (including channelopathic) disorders. However, this exciting strategy is impeded by the gaps in our understanding of ion channels and neurons, so more research is required. Thus, the aim of this thesis is to improve the understanding of how specific ion channel types contribute to shaping neuronal dynamics, and in particular, neuronal integration, excitability and memory. For this purpose I have used computational modeling, an approach which has recently emerged as an excellent tool for understanding dynamically complex neurophysiological phenomena.

In the first of two projects leading to this thesis, I studied how neurons in the brain, and in particular their dendritic structures, are able to integrate synaptic inputs arriving at low frequencies, in a behaviorally relevant range of ~8 Hz. Based on recent experimental data on synaptic transient receptor potential channels (TRPC), metabotropic glutamate receptor (mGluR) dynamics and glutamate decay times, I developed a novel model of the ion channel current ITRPC, the importance of which is clear but largely neglected due to an insufficient understanding of its activation mechanisms. We found that ITRPC, which is activated both synaptically (via mGluR) and intrinsically (via Ca2+) and has a long decay time constant (τdecay), is better suited than the classical rapidly decaying currents (IAMPA and INMDA) in supporting low-frequency temporal summation. It was further concluded that τdecay varies with stimulus duration and frequency, is linearly dependent on the maximal glutamate concentration, and might require a pair-pulse protocol to be properly assessed.

In a follow-up study I investigated small-amplitude (a few mV) long-lasting (a few seconds) depolarizations in pyramidal neurons of the hippocampal cortex, a brain region important for memory and spatial navigation. In addition to confirming a previous hypothesis that these depolarizations involve an interplay of ITRPC and voltage-gated calcium channels, I showed that they are generated in distal dendrites, are intrinsically stable to weak excitatory and inhibitory synaptic input, and require spatial and temporal summation to occur. I further concluded that the existence of multiple stable states cannot be ruled out, and that, in spite of their small somatic amplitudes, these depolarizations may strongly modulate the probability of action potential generation.

In the second project I studied the axonal mechanisms of unmyelinated peripheral (cutaneous) pain-sensing neurons (referred to as C-fiber nociceptors), which are involved in chronic pain. To my knowledge, the C-fiber model we developed for this purpose is unique in at least three ways, since it is multicompartmental, tuned from human microneurography (in vivo) data, and since it includes several biologically realistic ion channels, Na+/K+ concentration dynamics, a Na-K-pump, morphology and temperature dependence. Based on simulations aimed at elucidating the mechanisms underlying two clinically relevant phenomena, activity-dependent slowing (ADS) and recovery cycles (RC), we found an unexpected support for the involvement of intracellular Na+ in ADS and extracellular K+ in RC. We also found that the two major Na+ channels (NaV1.7 and NaV1.8) have opposite effects on RC. Furthermore, I showed that the differences between mechano-sensitive and mechano-insensitive C-fiber types might reside in differing ion channel densities.

To conclude, the work of this thesis provides key insights into neuronal mechanisms with relevance for memory, pain and neural disorders, and at the same time demonstrates the advantage of using computational modeling as a tool for understanding and discovering fundamental properties of central and peripheral neurons.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2012. , x, 126 p.
Series
TRITA-CSC-A, ISSN 1653-5723 ; 2012:09
Keyword [en]
ion channels, computational modeling, simulations, dendrites, axons, TRP, hippocampus, C-fiber nociceptors, pain
National Category
Computer Science
Identifiers
URN: urn:nbn:se:kth:diva-102362ISBN: 978-91-7501-475-3 (print)OAI: oai:DiVA.org:kth-102362DiVA: diva2:552449
Public defence
2012-10-09, F3, Lindstedtsv. 26, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council, 621-2007-3774
Note

QC 20120914

Available from: 2012-09-14 Created: 2012-09-14 Last updated: 2014-06-17Bibliographically approved
List of papers
1. Low-frequency summation of synaptically activated transient receptor potential channel-mediated depolarizations
Open this publication in new window or tab >>Low-frequency summation of synaptically activated transient receptor potential channel-mediated depolarizations
2011 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 34, no 4, 578-593 p.Article in journal (Refereed) Published
Abstract [en]

Neurons sum their input by spatial and temporal integration. Temporally, presynaptic firing rates are converted to dendritic membrane depolarizations by postsynaptic receptors and ion channels. In several regions of the brain, including higher association areas, the majority of firing rates are low. For rates below 20 Hz, the ionotropic receptors alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and N-methyl-d-aspartate (NMDA) receptor will not produce effective temporal summation. We hypothesized that depolarization mediated by transient receptor potential (TRP) channels activated by metabotropic glutamate receptors would be more effective, owing to their slow kinetics. On the basis of voltage-clamp and current-clamp recordings from a rat slice preparation, we constructed a computational model of the TRP channel and its intracellular activation pathway, including the metabotropic glutamate receptor. We show that synaptic input frequencies down to 3-4 Hz and inputs consisting of as few as three to five pulses can be effectively summed. We further show that the time constant of integration increases with increasing stimulation frequency and duration. We suggest that the temporal summation characteristics of TRP channels may be important at distal dendritic arbors, where spatial summation is limited by the number of concurrently active synapses. It may be particularly important in regions characterized by low and irregular rates.

Keyword
computational model, dendritic integration, entorhinal cortex, integration time constant, mGluR
National Category
Neurosciences Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-38955 (URN)10.1111/j.1460-9568.2011.07791.x (DOI)000293907400007 ()21777305 (PubMedID)2-s2.0-80051673126 (Scopus ID)
Funder
Swedish Research Council, 621-2007-3774
Available from: 2011-09-06 Created: 2011-09-05 Last updated: 2017-12-08Bibliographically approved
2. TRPC channels activated by group 1 mG1uR in Entorhinal pyramidal neurons support integration of low frequency (<10 Hz) synaptic inputs
Open this publication in new window or tab >>TRPC channels activated by group 1 mG1uR in Entorhinal pyramidal neurons support integration of low frequency (<10 Hz) synaptic inputs
2009 (English)In: BMC Neuroscience, ISSN 1471-2202, Vol. 10, no Suppl 1, P26- p.Article in journal (Refereed) Published
National Category
Neurosciences Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-25000 (URN)10.1186/1471-2202-10-S1-P26 (DOI)
Note
QC 20101005Available from: 2010-10-05 Created: 2010-10-05 Last updated: 2012-09-14Bibliographically approved
3. Long-lasting small-amplitude TRP-mediated dendritic depolarizations in CA1 pyramidal neurons are intrinsically stable and originate from distal tuft regions
Open this publication in new window or tab >>Long-lasting small-amplitude TRP-mediated dendritic depolarizations in CA1 pyramidal neurons are intrinsically stable and originate from distal tuft regions
2012 (English)In: European Journal of Neuroscience, ISSN 0953-816X, E-ISSN 1460-9568, Vol. 36, no 7, 2917-2925 p.Article in journal (Refereed) Published
Abstract [en]

In several regions of the nervous system, neurons display bi- or multistable intrinsic properties. Such stable states may be subthreshold and long-lasting, and can appear as a sustained afterdepolarization. In hippocampal CA1 pyramidal neurons, small-amplitude (1 mV) long-lasting (seconds) afterdepolarizations have been reported and are thought to depend on calcium-activated nonselective (CAN) currents recently identified as transient receptor potential (TRP) channels. Continuing our previous experimental and computational work on synaptically metabotropic glutamate receptor (mGluR)-activated TRP currents, we here explore small-amplitude long-lasting depolarizations in a detailed multicompartmental model of a CA1 pyramidal neuron. We confirm a previous hypothesis suggesting that the depolarization results from an interplay of TRP and voltage-gated calcium channels, and contribute to the understanding of the depolarization in several ways. Specifically, we show that: (i) the long-lasting depolarization may be intrinsically stable to weak excitatory and inhibitory input, (ii) the phenomenon is essentially located in distal apical dendrites, (iii) induction is facilitated if simultaneous input arrives at several dendritic branches, and if calcium- and/or mGluR-evoked signals undergo summation, suggesting that both spatial and temporal synaptic summation might be required for the depolarization to occur and (iv) we also show that the integration of inputs to oblique dendrites is strongly modulated by the presence of small-amplitude long-lasting depolarizations in distal tuft dendrites. To conclude, we suggest that small-amplitude long-lasting dendritic depolarizations may contribute to sustaining neural information during behavioural tasks in cases where information is separated in time, as in trace conditioning and delay tasks.

Keyword
bistability, CAN current, computational modelling, slow afterdepolarization, transient receptor potential
National Category
Neurosciences
Identifiers
urn:nbn:se:kth:diva-102357 (URN)10.1111/j.1460-9568.2012.08199.x (DOI)000309460600007 ()22758919 (PubMedID)2-s2.0-84866980705 (Scopus ID)
Funder
Swedish Research Council, 621-2007-3774
Note

QC 20121114

Available from: 2012-09-14 Created: 2012-09-14 Last updated: 2017-12-07Bibliographically approved
4. Modelling post spike excitability changes in peripheral C-fibres
Open this publication in new window or tab >>Modelling post spike excitability changes in peripheral C-fibres
Show others...
2012 (English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Identifiers
urn:nbn:se:kth:diva-102360 (URN)
Note

QS 2012

Available from: 2012-09-14 Created: 2012-09-14 Last updated: 2016-02-02Bibliographically 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
6. C-type peripheral nociceptors differ in axonal ion channel densities
Open this publication in new window or tab >>C-type peripheral nociceptors differ in axonal ion channel densities
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Neurosciences
Identifiers
urn:nbn:se:kth:diva-102361 (URN)
Note

QS 2012

Available from: 2012-09-14 Created: 2012-09-14 Last updated: 2012-09-14Bibliographically approved

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