 Computational modeling of C-fiber neurons found that addition of slowly activating K+ channels (KCNQ/M-channels) in the dorsal root ganglia (DRG) reduced the maximum following frequency of action potential propagation from 110 Hz to 30 Hz.  The influence of KCNQ channels on following frequency was strongly dependent on somatic Na+ channel density, especially for models with short stem axon lengths (<200 μm), indicating an interaction between somatic electrogenesis and KCNQ channel effects.  When even slower outward currents like Ca2+-activated K+ channels were included in the model, following frequency was further reduced to the experimentally measured range of 5-10

1. Effects of Slow Outward CurrentsEffects of Slow Outward CurrentsEffects of Slow Outward CurrentsEffects of Slow Outward Currents
ConclusionsConclusionsConclusionsConclusions
Effects of Somatic NaEffects of Somatic NaVV
Effects of Somatic NaEffects of Somatic NaVVModel C-fiberModel C-fiberModel C-fiberModel C-fiber
Effects of M-currentEffects of M-currentEffects of M-currentEffects of M-current
AbstractAbstractAbstractAbstract
Unmyelinated C-fiber sensory neurons relay pain signals
from the periphery, across the dorsal root ganglia (DRG), to the
spinal cord. Within the DRG, the axon bifurcates into a
centrally-projecting axon and a stem segment connecting to the
soma. This bifurcation, or T-junction, is site of reduced safety
factor for orthodromic spike propagation; the maximum
frequency a spike train can reliably bridge the DRG, referred to
as ‘following frequency’, is 5-10 Hz (Gemes et al., 2013).
Relatively little is known about how ion channels within the
DRG contribute to the filtering of reliable spike propagation.
Here we examined how various ion channel within the DRG
affect spike reliability using a computational model of a C-fiber
neuron. We found that in a reduced model (containing only NaV
and KDR channels) the following frequency was 110 Hz. Addition
of slowly-activating K+
(KCNQ or M-channels) channels in the
vicinity of the T-junction reduced following frequency to 30 Hz.
The reduction in following frequency was strongly dependent on
somatic NaV density for models with relatively short stem axon
lengths, suggesting that KCNQ channels’ influence may be
affected by somatic electrogenesis for neurons with
electrotonically-close cell bodies. When much slower, outward
current mechanisms were added to the model, such as Ca2+
-
dependent K+
channels, following frequency fell to 6 Hz (within
the experimentally-measured range). Our findings suggest that
approaches enhancing slow outward conductances within the
DRG may provide a potential therapeutic target for relieving
chronic pain.
MethodsMethodsMethodsMethods
A model segment of DRG-spanning C-fiber was constructed
using NEURON (http://www.neuron.yale.edu) on an Intel-
based Macintosh computer (see Figure 1). In the fundamental
model, NaV and KDR channels were added to all compartments
at a density of 0.04 mS/cm2
with the exception of the soma,
where default NaV density was 0.02 mS/cm2
. Trains of 20
action potentials from 10-110 Hz were delivered to the
peripheral axon segment to determine following frequency.
The effects of M-current were examined by inserting KCNQ
channels into the stem, soma, and 100 µm stretches of the
axon segments proximal to the T-junction for densities of 0.02-
0.08 mS/cm2
. Somatic NaV was subsequently raised to 0.04
mS/cm2
and stem length was varied from 50-400 µm to
observe the electrotonic influence of the somatic NaV on the M-
current. Addition of L-type Ca2+
channels, Ca2+
dynamics, and
SK channels to the model was used to determine the effects of
slow, outward currents on propagation reliability.
 M-current reduced the following frequency of C-fibers to a
minimum value of 30 Hz. Ectopic, antidomic spikes generated by
the soma/stem axon may be elicited by KCNQ channel presence.
 M-current and following frequency were significantly influenced by
electrotonically short stem axons (< 200 µm).
 Slow, outward currents within the DRG reduced the following
frequency to experimentally-measured ranges via a hyperpolarizing
voltage shift. Locally enhancing these currents in the DRG may be a
possible route for novel treatment of chronic pain.
Gemes G, Koopmeiners A, Rigaud M, Lirk P, Sapunar D, Bangaru ML, Vilceanu D, Garrison SR,
Ljubkovic M, Mueller SJ, Stucky CL, and Hogan QH. Failure of action potential propagation in
sensory neurons: mechanisms and loss of afferent filtering in C-type units after painful nerve
injury. J Physiol 591: 1111-1131, 2012.
ReferencesReferencesReferencesReferences
Figure 1: Representative model C-fiber and recordings. A: Schematic of the
connectivity and relative geometry of the C-fiber model. Responses were elicited
by stimulating the peripheral axon 4.6 mm from the T-junction. Default stem length
was 75 µm. B: Voltage transients at 100 and 50 µm before (top traces) and after
(bottom traces) the T-junction (distance = 0 µm). Bimodal shape is due to the
orthodromically propagating spike (early mode) and the reflecting spike (late
mode), which originates from the soma and stem axon.
Spike Propagation Through the Dorsal Root Ganglia for
Unmyelinated Sensory Neurons: a Modeling Study
Danielle SundtDanielle Sundt11
, Nikita Gamper, Nikita Gamper22
, David B. Jaffe, David B. Jaffe11
11
UTSA Neuroscience Institute and the Department of Biology, University of Texas at San Antonio
22
Faculty of Biological Sciences, University of Leeds, UK
25 µm
25 µm
1.4 µm
0.8 µm 0.4 µm
Peripheral Axon Central Axon
Stem Axon
T-junction
A B
Central
Peripheral
40 mV
100 ms
T-junction
A 120
100
80
60
40
20
0
FollowingFrequency(Hz)
0.80.60.40.20
KCNQ Density (mS/cm2
)
B
Figure 2: KCNQ density reduces following frequency through the T-junction.
A: Spike failure occurred at a stimulation frequency of 50 Hz for a KCNQ density of
0.4 mS/cm2
. B: Increasing KCNQ density resulted in less reliable spike propagation
through the T-junction. Solid line represents best exponential fit. C1: At two
peripheral locations distal to the T-junction, the first four spikes propagated reliably
from the more distal (5.1 mm) to the more proximal (2.6 mm) location. An ectopic
spike (denoted by asterisk) was generated at the more proximal location, blocking
the generation of the expected fifth orthodromic spike. C2: Enlarged waveforms of
the fourth and fifth spikes of the 2.6 mm trace of C1. The ectopic spike was only
generated when KCNQ channels were present. D: Within the periphery at a
distance of 100 µm from the T-junction, the AHP was augmented during the first
four spikes when KCNQ channels were present (dashed line represents baseline
AHP). The antidromic spikelet (late mode) increased in amplitude. 350 µm away
from the T-junction, the spikelet surpassed threshold, generating the ectopic spike.
10 mV
5 ms
+ KCNQ
– KCNQ
20 mV
10 ms
5.1 mm
2.6 mm
*
C1
100 µm
D
C2
10 mV
10 ms
350 µm
+ KCNQ
– KCNQ
120
100
80
60
40
20
0
FollowingFrequency(Hz)
0.80.60.40.20.0
KCNQ Density (mS/cm2
)
Somatic NaV Density
20 mS/cm2
40 mS/cm2
200
150
100
50
0
FollowingFrequency(Hz)
40035030025020015010050
Stem Length (µm)
Somatic NaV Density
20 mS/cm2
40 mS/cm2
A B
Figure 3: Interaction of Na+
channels with M-currents. Solid lines represent
best exponential fits. A: Following frequencies, for both somatic NaV density values,
decreased with increasing KCNQ channel density. Doubling somatic NaV density
shifted following frequencies to relatively higher values. B: Electrotonically short
stem axons influence following frequency. Stem axons shorter than 200 µm greatly
decreased following frequency for both somatic NaV densities. Somatic NaV density
had little effect on the following frequency.
A1
A2
Figure 4: Slow hyperpolarizing current reduces the following frequency.
A: In the absence of GSK, voltage transients at 100, 50, and 0 µm in the peripheral
branch from the T-junction exhibited a bimodal response (A1). Addition of 1 mS/cm2
SK channel density eliminated somatic firing, resulting in a unimodal transient (A2).
B: Reliability of successful spike propagation was heavily influenced by GNa. At GNa
= 40 mS/cm2
, following frequency was 6 Hz. Raising GNa to 60 mS/cm2
increased
the following frequency to 20 Hz.
B
20 mV
1 ms
100 µm
50 µm
0 µm
GSK = 1 mS/cm2
GSK = 0 mS/cm2
100
90
80
70
60
50
40
30
2 3 4 5 6 7 8
10
2 3 4 5 6 7 8
100
40
60
PercentPropagation
GNa (mS/cm2
)
Frequency (Hz)