High-threshold K+ current increases gain by offsetting a frequency-dependent increase in low-threshold K+ current - PubMed (original) (raw)
High-threshold K+ current increases gain by offsetting a frequency-dependent increase in low-threshold K+ current
Fernando R Fernandez et al. J Neurosci. 2005.
Abstract
High-frequency firing neurons are found in numerous central systems, including the auditory brainstem, thalamus, hippocampus, and neocortex. The kinetics of high-threshold K+ currents (IK(HT)) from the Kv3 subfamily has led to the proposal that these channels offset cumulative Na+ current inactivation and stabilize tonic high-frequency firing. However, all high-frequency firing neurons, examined to date, also express low-threshold K+ currents (IK(LT)) that have slower kinetics and play an important role in setting the subthreshold and filtering properties of the neuron. IK(LT) has also been shown to dampen excitability and is therefore likely to oppose high-frequency firing. In this study, we examined the role of IK(HT) in pyramidal cells of the electrosensory lobe of weakly electric fish, which are characterized by high-frequency firing, a very wide frequency range, and high levels of IK(HT). In particular, we examined the mechanisms that allow IK(HT) to set the gain of the F-I relationship by interacting with another low-threshold K+ current. We found that IK(HT) increases the gain of the F-I relationship and influences spike waveform almost exclusively in the high-frequency firing range. The frequency dependence arises from IK(HT) influencing both the IK(LT) and Na+ currents. IK(HT) thus plays a significant role in stabilizing high-frequency firing by preventing a steady-state accumulation of IK(LT) that is as important as preventing Na+ current inactivation.
Figures
Figure 1.
Kinetics of K+ currents in whole-cell recordings from ELL pyramidal cells. A, Representative examples of the TEA-sensitive (IKHT) and TEA-insensitive (IKLT) current evoked by square voltage steps from -70 to 40 mV for IKHT and -70 to 10 mV for IKLT in 10 mV increments. Model currents are shown for comparison (right). B, Open probability (Po) plotted as a function of voltage for IKHT and IKLT (n = 5). Data are fit using a Boltzmann function, which is used in the model to reproduce the steady-state values (see Materials and Methods). The mean _V_1/2 of activation for IKHT and IKLT was -15.3 ± 0.6 mV (n = 5) and -36.5 ± 1.2 mV (n = 5), respectively. C, Time constants of activation (τact) and deactivation (τdeact) plotted as a function of voltage (n = 5). Model data (fit) have been superimposed for comparison. Note that contrary to a two-state Hodgkin-Huxley model, the deactivation time constants for IKHT are relatively slow compared with activation. Time course of activation and deactivation are fit with a fourth power and standard exponential function, respectively. The relationship between time constant and voltage is fit with Lorentzian functions (see Materials and Methods). Model data accurately reproduce the activation and deactivation time course of both low- and high-threshold currents.
Figure 2.
Block of high-threshold K+ currents has a frequency-dependent effect on the F-I relationship and spike waveform shape of ELL pyramidal cells. A, Bath-applied 500 μ
m
TEA selectively reduces the gain response of the F-I relationship in the high-frequency region while having little effect at low frequencies. The difference in firing frequency between control and TEA conditions is subtracted and plotted as a function of the control frequency (middle panel). The average difference between the low-frequency (80-120 Hz) and high-frequency (200-240 Hz) firing rates is significantly different (right) between TEA and control conditions (*p < 0.01; n = 4). B, Bath-applied 500 μ
m
TEA has a larger effect on general waveform shape at high frequencies while having little impact when the neuron is firing at low frequencies. The 10th spike in the spike trains is shown enlarged and superimposed (right panel).
Figure 3.
Block of high-threshold K+ current has a frequency-dependent effect on spike parameters. A-D, Four spike parameters are measured: AHP (A), rate of spike decay (B), spike half-width (C), and spike height (D). The left panels show a representative case of the specific spike parameter plotted as a function of firing frequency in control (▪) and TEA condition (○). The right panels show the effects of TEA on spike parameters normalized to control under two conditions: low frequency (80-120 Hz) and high frequency (200-240 Hz). For all four parameters, TEA has a statistically significant effect at high frequencies while having a small effect at low frequencies compared with control (*p < 0.05, **p ≤ 0.001 between low and high frequency; n = 4). In the first three conditions (A-C), spike parameters in TEA are binned into low- or high-frequency ranges and normalized to control values averaged through the entire frequency range. In the case of spike height (D), the populations were inhomogeneous within these frequency ranges. Therefore, values in TEA are normalized to the corresponding frequency range in control.
Figure 4.
Block of high-threshold K+ current has a frequency-dependent effect on the rate of spike rise. A, The rate of spike rise is used to infer the available Na+ current. Bath-applied 500 μ
m
TEA significantly decreases the rate of spike rise at high frequencies (200-240 Hz) but has no effect at low frequencies (80-120 Hz) compared with control (*p < 0.001; n = 4). Rate of spike rise with TEA is normalized to control value averaged through the entire frequency range. B, Representative cases showing that the spike height and size of the AHP are strongly correlated with the rate of spike rise (left panel). Under normal conditions (▪), spike height and AHP size are relatively stable at different frequencies (see Fig. 2 B for representative spike traces). The application of TEA (○) spreads the distribution of spike height and AHP size, which correlates with a decrease in the rate of spike rise.
Figure 5.
Incorporation of K+ currents in a firing model reproduces experimental observations. A, The F-I relationship generated by the model with IKHT (▪) and without IKHT (○). Like the experimental results, the removal of IKHT preferentially affects the F-I relationship at high frequencies. B, Spike waveforms from the model with IKHT (black line) and without IKHT (gray lines) are shown superimposed. Note that spike waveforms are similar at low frequencies but diverge at high frequencies. The right inset indicates the similarity of spike responses at low and high frequencies when IKHT is intact. C, Preventing Na+ current inactivation by artificially resetting the h variable after each spike (h = 0.09) (▵) in the absence of IKHT does not fully restore the F-I relationship compared with control. A subsequent increase of IKLT density shifts the F-I relationship further to the right, indicating that IKLT is unable to substitute for IKHT in preventing Na+ inactivation. D, Reducing Na+ current inactivation does not fully recover the spike waveform. Superimposed spike waveforms with h reset in the presence of IKHT (black line) or absence of IKHT (gray lines) are shown. Using the h reset fully restored the rate of spike rise and spike amplitude but only partially restored the rate of spike repolarization, spike half-width, and AHP size (right). In the low and high frequency with IKHT (B, right), spike waveforms are identical, whereas with the h reset and no IKHT (D, right) spike waveforms in the two frequency ranges differ in terms of rate of spike repolarization, spike half-width, and AHP size. All spikes shown are the fifth spike of each train.
Figure 6.
Low-threshold K+ current shows a frequency-dependent accumulation during the interspike interval. A, Spike waveforms from the firing model taken at low and high firing frequencies in the presence or absence of IKHT. Like the experimental results, the AHP size in the model is reduced in a frequency-dependent manner in the absence of IKHT. Without IKHT, the peak negative voltage during low-frequency firing reaches -65 mV (bottom, left), whereas at high frequencies this value rises well above -60 mV (bottom, right). B,IKLT produced from the spikes shown in A. The change in AHP size and general increase in interspike voltage at high frequencies without IKHT (A, bottom right) leads to an increase in IKLT during the interspike interval at high frequencies. C, Whole-cell K+ currents recorded from pyramidal cells (isolated after TEA application) evoked using spike waveforms. All traces are corrected for leak and capacitive current. Spike waveforms consisted of spikes with interspike interval voltages of -60 mV, a half-width of 1 ms, and a spike height of 70 mV (-70 to 0 mV). Spike waveforms were applied at 100 Hz (top) and 200 Hz (bottom). With 100 Hz spike trains, both IKHT and IKLT show little or no current during the interspike interval (top). With 200 Hz, IKHT continues to show no current during the interspike interval, but now IKLT shows a significant increase (bottom) similar to the model (B, bottom right).
Figure 7.
High-threshold K+ current prevents the increased activation of IKLT, contributing to an increase in the gain of the F-I relationship, and stability of high-frequency firing can by analyzed in the firing model. A, To prevent the accumulation of IKLT in the absence of IKHT, the n variable (conductance variable for IKLT) was reset to a value of 0.56 at the beginning of the AHP after each spike. IKLT in the model is shown during spiking at high frequencies with (black line) or without (gray line) the n reset. B, Comparison of the F-I relationship generated from the model using the n reset (▵) and F-I relationships generated with (▪) or without (○) IKHT and no n reset. Incorporating the n reset into the model partially recovered the F-I relationship compared with control (▪). C, Comparison of the F-I relationship generated from the model using both the n and h reset (•) and F-I relationships generated with (▪) or without (○) IKHT and no resets. Combining both resets generated an F-I relationship nearly identical to that with IKHT. D, Comparison of n and h open probabilities during the interspike interval with or without IKHT as a function of firing frequency. The presence of IKHT slows the onset of the n variable accumulation and h variable inactivation in a frequency-dependent manner. E, Time course of the n and h gating variables during the interspike interval in response to a current ramp (cell firing frequency, 120-200 Hz). The time course n and h open probabilities during the interspike interval are affected in a similar manner by the presence of IKHT as in the frequency domain (D).
Figure 8.
Dampening effects of IKLT are mediated through an increase in current that provides a subtractive effect on the F-I relationship. A, Relationship between interspike IKLT and firing frequency with (▪) or without (○) IKHT in the firing model. B, F-I relationships in the presence of different types of frequency-dependent conductances with IKHT and IKLT. With a frequency-dependent outward leak current (▵, _f_-dep. leak), the F-I relationship resembles the firing system without IKHT (○). The use of a frequency-dependent current that is subtracted from the excitatory driving current (•, _f_-dep. sub of IE) also produces an F-I relationship similar to the system without IKHT (○). C, Time course and amplitude of the h variable at different frequencies with or without a frequency-dependent K+ leak current. The presence of leak does not affect the availability of Na+ current.
References
- Baranauskas G, Tkatch T, Nagata K, Yeh JZ, Surmeier DJ (2003) Kv3.4 sub-units enhance the repolarizing efficiency of Kv3.1 channels in fast-spiking neurons. Nat Neurosci 6: 258-266. - PubMed
- Coetzee WA, Amarillo Y, Chiu J, Chow A, Lau D, McCormack T, Moreno H, Nadal MS, Ozaita A, Pountney D, Saganich M, Vega-Saenz de Miera E, Rudy B (1999) Molecular diversity of K+ channels. Ann NY Acad Sci 868: 233-285. - PubMed
- Doiron B, Longtin A, Turner RW, Maler L (2001) Model of gamma frequency burst discharge generated by conditional backpropagation. J Neurophysiol 86: 1523-1545. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases