Marcus E. Petersson

Modeling activity-dependent changes of axonal spike conduction in primary afferent C-nociceptors

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.

Low-frequency summation of synaptically activated transient receptor potential channel-mediated depolarizations

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 α‐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.

Differential Axonal Conduction Patterns of Mechano-Sensitive and Mechano-Insensitive Nociceptors - A Combined Experimental and Modelling Study

Cutaneous pain sensations are mediated largely by C-nociceptors consisting of both mechano-sensitive (CM) and mechano-insensitive (CMi) fibres that can be distinguished from one another according to their characteristic axonal properties. In healthy skin and relative to CMi fibres, CM fibres show a higher initial conduction velocity, less activity-dependent conduction velocity slowing, and less prominent post-spike supernormality. However, after sensitization with nerve growth factor, the electrical signature of CMi fibres changes towards a profile similar to that of CM fibres. Here we take a combined experimental and modelling approach to examine the molecular basis of such alterations to the excitation thresholds. Changes in electrical activation thresholds and activity-dependent slowing were examined in vivo using single-fibre recordings of CM and CMi fibres in domestic pigs following NGF application. Using computational modelling, we investigated which axonal mechanisms contribute most to the electrophysiological differences between the fibre classes. Simulations of axonal conduction suggest that the differences between CMi and CM fibres are strongly influenced by the densities of the delayed rectifier potassium channel (Kdr), the voltage-gated sodium channels NaV1.7 and NaV1.8, and the Na+/K+-ATPase. Specifically, the CM fibre profile required less Kdr and NaV1.8 in combination with more NaV1.7 and Na+/K+-ATPase. The difference between CM and CMi fibres is thus likely to reflect a relative rather than an absolute difference in protein expression. In support of this, it was possible to replicate the experimental reduction of the ADS pattern of CMi nociceptors towards a CM-like pattern following intradermal injection of nerve growth factor by decreasing the contribution of Kdr (by 50%), increasing the Na+/K+-ATPase (by 10%), and reducing the branch length from 2 cm to 1 cm. The findings highlight key molecules that potentially contribute to the NGF-induced switch in nociceptors phenotype, in particular NaV1.7 which has already been identified clinically as a principal contributor to chronic pain states such as inherited erythromelalgia.

Long-lasting small-amplitude TRP-mediated dendritic depolarizations in CA1 pyramidal neurons are intrinsically stable and originate from distal tuft regions

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.

TRPC channels activated by group I mGluR in Entorhinal pyramidal neurons support integration of low frequency (<10 Hz) synaptic inputs

TRPC channels activated by group 1 mG1uR in Entorhinal pyramidal neurons support integration of low frequency (<10 Hz) synaptic inputs

Ionic mechanisms of action potential propagation velocity changes in peripheral C-fibers. Implications for pain

Ionic mechanisms of action potential propagation velocity changes in peripheral C-fibers. Implications for pain

Low-frequency summation of synaptically activated TRP channel-mediated depolarizations

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 α‐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.

Low-frequency summation of synaptically activated transient receptor potential channel-mediated depolarizations: Low-frequency summation by TRP channels

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 α‐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.

Role of TRP channels in dendritic integration and subthreshold membrane potential plateaus

Cortical as well as subcortical neurons display plateau properties [1]. The plateaus may be voltage and/or calcium gated and depend on Na, Ca or mixed cation (TRP) currents. Depending on the nature of the synaptic input, neurons may respond by entering one of several multiple stable states, in the form of either subthreshold or persistent firing. We have studied the activation of a TRP current, in which synaptic excitatory input activates metabotropic glutamate receptors in turn leading to a TRP-mediated slow EPSP, both experimentally [2] and computationally [3]. In the computational work we have studied the contribution of the TRP current on dendritic integration of input of low (1-10 Hz) frequency. The model is based on a CA1 pyramidal cell model [4] developed to study dendritic processing. The spatial compartmentalization had been obtained from a digitized neuron and contains 183 compartments. It includes ion channels described by a Hodgkin-Huxley formalism and has the following channels: Na, NaP, CaR, CaT, CaL, Kdr, KA, KM, K(Ca)BK, K(Ca)slow, Kleak, h. To this model we added models for a metabotropic glutamate receptor as well as a TRP channel, the latter being adapted from a CAN channel model. Continuing our computational work, we have recently studied how the dendritic integration properties depend on the time constant of the calcium activating the TRP-current. In the model calcium comes from L-type Cav1.3 channels with a low threshold but there may also be contributions from T-type channels. We find that the effective integration time constant, the decay time constant of the neuronal membrane, increases when the amplitude of the calcium concentration increases. Moreover, recent experimental work [5] has shown that the decay time constant of calcium increases as a result of increased calcium concentration. This prompted us to study effects of adding a slower decay time constant in addition to the one present in the model used so far. Intriguingly, we find that a stable subthreshold plateau appears when a slower (200 ms) calcium decay time constant is present but not when only the original faster (30 ms) is present. This plateau of the resting potential is stable for weaker synaptic excitatory or inhibitory input, but stronger input can switch the membrane between the two levels, see figure ​figure1.1. We find that the subthreshold plateau is essentially local to individual dendritic branches, and that the cell enters a persistent spiking [1] mode when several branches enters plateau mode. This bistability in membrane potential due to intrinsic conductances may be compared to the network driven changes of subthreshold membrane potential during cortical up and down states, suggested to switch the neuron between different modes of integration/operation. Figure 1 The membrane voltage (Vm) is resting close to -70 mV. At the arrival of an excitatory synaptic stimulus, Vm enters a more depolarized, subthreshold plateau, which is stable to weak inhibitory input (t = 3000 ms). Vm returns to its resting state only if ...