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Following each action potential, C-fiber nociceptors undergo cyclical changes in excitability, including a period of superexcitability, before recovering their basal excitability state. The increase in superexcitability during this recovery cycle depends upon their immediate firing history of the axon, but also determines the instantaneous firing frequency that encodes pain intensity. To explore the mechanistic underpinnings of the recovery cycle phenomenon a biophysical model of a C-fiber has been developed. The model represents the spatial extent of the axon including its passive properties as well as ion channels and the Na/K-ATPase ion pump. Ionic concentrations were represented inside and outside the membrane. The model was able to replicate the typical transitions in excitability from subnormal to supernormal observed empirically following a conducted action potential. In the model, supernormality depended on the degree of conduction slowing which in turn depends upon the frequency of stimulation, in accordance with experimental findings. In particular, we show that activity-dependent conduction slowing is produced by the accumulation of intraaxonal sodium. We further show that the supernormal phase results from a reduced potassium current K-dr as a result of accumulation of periaxonal potassium in concert with a reduced influx of sodium through Na(v)1.7 relative to Na(v)1.8 current. This theoretical prediction was supported by data from an in vitro preparation of small rat dorsal root ganglion somata showing a reduction in the magnitude of tetrodotoxin-sensitive relative to tetrodotoxin - resistant whole cell current. Furthermore, our studies provide support for the role of depolarization in supernormality, as previously suggested, but we suggest that the basic mechanism depends on changes in ionic concentrations inside and outside the axon. The understanding of the mechanisms underlying repetitive discharges in recovery cycles may provide insight into mechan, QC 20150504

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., QC 20140602. Updated from manuscript to article in journal.

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, QC 20130121

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., QC 20121120. Updated from manuscript to article in journal.

QS 2012

C-fibers, unmyelinated afferent axons, convey information from the periphery of the nervous system to the spinal cord. They transmit signals originating from noxious stimulation evoking the sensations of itch and pain in the central nervous system. Different classes of C-fibers are characterized by functional, morphological and biochemical characteristics. In pain studies, a classification into mechano-insensitive (CMi) and mechano responsive fibers (CM) has proven useful as changes in proportions and response characteristics of these fibers have been observed in neuropathy patients (Weidner et al. 1999, 2000; Orstavik 2003, 2010). In this study, using computational modeling of a C-fiber, we have studied the possible contribution of different ion channel subtypes (Na-TTXs, Nav1.8, Nav1.9, Kdr, KA, KM, K(Na), h) as well as the Na/K-ATPase pump to conductive properties of C-fibers. In particular we investigated mechanisms that could generate the fiber-specific differences between CM and CMi fibers with regard to activity dependent slowing (ADS) and recovery cycles (RC). In our study we represent the axon by three cylindrical sections, one representing the peripheral thin end (branch, 2.5 cm), one the central part (parent, 10 cm) and a conical section between these (0.5 cm). In total 730 compartments are used. Temperature is set to 32 degrees C in branch and 37 degrees in parent sections. We represent variable ion concentrations of Na and K intra axonally, periaxonally and extracellularly, from which reversal potentials are calculated. We use ion channel models based on Hodgkin Huxley formalism. An ion pump (Na/K-ATPase) is included. We find that TTX-sensitive Na and Nav1.8 have the strongest influence on action potential conduction velocity as is expected since these are the major components of the rising phase of the action potential. Preliminary observations indicate that a small subset of Na and K currents play a key role in determining differences in activity depe, QC 20150330

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 proced, QC 20111117

Initiation and propagation of action potentials along unmyelinated C-fibers are the first steps of the pain pathway. Propagation velocity and its fiber class-specific activity-dependent slowing (ADS) is intimately linked to fibre excitability. In chronic pain patients, ADS alterations have been suggested to reflect increased excitability, possibly underlying clinical pain. Due to their small diameter, peripheral axons of nociceptors in patients are not accessible for intraaxonal recordings of their ion channel properties. We have therefore constructed a model of a C-fibre to study the relationship between ion channel composition and velocity changes as well as excitability. Ion channels are modeled from data of DRG somata using a Hodgkin-Huxley formalism (Na currents: TTX-sensitive, Nav1.8, Nav1.9, K currents: Kdr, A-type, Kv7.3, non-specific cationic: HCN). Moreover, ion pumps (Na/K-ATPase) and concentrations of intra and extraaxonal sodium and potassium are also included. The geometry and temperature of the fibre represents a section of the superficial branch and the deeper parent and is represented by a multicompartmental structure where each compartment contains passive as well as ion channel and pump elements. Using parameter estimation techniques, we optimized ion channel and pump expression pattern such that basic electrophysiological characteristics of the action potential and its velocity matched the experimental data. Moreover, we have also replicated activity dependent slowing. In ongoing work, we extend optimization to also include recovery cycles. The model will be used to study hypothesis of the relationship between individual ion channel subtypes and axonal excitability related to pain, generating independent information on impact of selective neuronal targets., QC 20150330

QC 20150212

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., QC 20101104 QC 20111215

QC 20101104. Eighteenth Annual Computational Neuroscience Meeting: CNS*2009Berlin, Germany. 18–23 July 2009

QC 20101104. Seventeenth Annual Computational Neuroscience Meeting: CNS*2008Portland, OR, USA. 19–24 July 2008