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Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106
Submitted 6 January 2004; accepted in final form 17 February 2004
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ABSTRACT |
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INTRODUCTION |
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, 1989). Such temporal patterning of spikes has also been shown for projection neurons (analogous to vertebrate mitral cells) of the insect antennal lobe (Laurent 1996; Laurent et al. 1996; Wehr and Laurent 1996). In this system, individual projection neurons were found to fire unique temporal sequences of spikes in response to different odorants. Spike patterns were repeatable across trials of repeated odor presentation and were precisely phase-locked to the odorant evoked local field potential. In response to sensory stimulation, mammalian mitral cells generate spike clusters that are phase-locked to the inspiratory rhythm (Cang and Isaacson 2003; Macrides and Chorover 1972; Margrie and Schaefer 2003; Sobel and Tank 1993). Spike timing is especially precise in repeated odorant applications that generate clusters with the same number of spikes (Margrie and Schaefer 2003). Thus temporal coding of mitral cell spike times may be a critical aspect of the neuronal encoding of odorants.
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; Jahr and Nicoll 1980, 1982) and laterally inhibit neighboring mitral cells (Isaacson and Strowbridge 1998; Yokoi et al. 1995). Recurrent dendrodendritic inhibition also can modulate the pattern of mitral cell activity evoked by phasic stimuli (Halabisky and Strowbridge 2003). In addition, extrasynaptic N-methyl-D-aspartate (NMDA) autoreceptors on mitral cell dendrites (Aroniadou-Anderjaska et al. 1999; Friedman and Strowbridge 2000; Isaacson 1999) may provide feedback excitation during spiking. The interaction of these inhibitory and excitatory mechanisms could modulate the pattern of spikes in single mitral cells to produce temporal codes for odors.
In addition to synaptic mechanisms, mitral cells may possess intrinsic membrane properties that sculpt and pattern their responses evoked by olfactory sensory neuron activation. Previous work has shown that mitral cells fire clusters of spikes interspersed with periods of fast gamma-frequency subthreshold oscillations in response to DC current injection (Desmaisons et al. 1999). Spike clustering is most likely due to intrinsic membrane properties of mitral cells, since it persisted in the presence of ionotropic glutamate and GABA receptor blockers. This intrinsic behavior is strikingly similar to spike clustering in response to DC current injection seen in neurons of other brain areas, including stellate cells of the medial entorhinal cortex (Alonso and Klink 1993; Alonso and Llinas 1989; Klink and Alonso 1993) and inhibitory interneurons of the basal forebrain (Alonso et al. 1996; Wang 2002). This behavior has been proposed to be critical for allowing these cells to serve as pacemakers for the theta rhythm.
Using whole cell recordings, we found that mitral cells generated intermittent, irregularly timed spike clusters at slow theta frequencies (1-5 Hz). In contrast, phasic current stimuli—mimicking the trains of slow excitatory postsynaptic potentials (EPSPs) that occur during sniffing—evoked precisely timed spike clusters. Both spike clustering during step depolarizations and precise timing evoked by phasic stimuli are likely due to the interplay of a 4-aminopyridine (4-AP)–sensitive potassium current and a subthreshold inward current. The ability of mitral cells to fire precisely timed spikes in response to phasic stimuli suggests that their intrinsic membrane properties may allow them to act as filters—converting incoming olfactory sensory neuron activity into precise temporal patterns of spikes that are relayed to higher brain centers.
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METHODS |
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). Olfactory bulb slices were incubated at 30°C for 25 min and maintained submerged at room temperature until needed. Whole cell patch-clamp recordings were made in mitral cells visualized under infrared-differential interference contrast optics (Zeiss Axioskop 1 FS) using an Axopatch 1D amplifier (Axon Instruments). During recordings, olfactory bulb slices were superfused with artificial cerebrospinal fluid (ACSF) that contained (in mM) 124 NaCl, 3 KCl, 1.23 NaH2PO4, 26 NaHCO3, 10 dextrose, 2.5 CaCl2, and 1.2 MgSO4, equilibrated with 95% O2-5% CO2 and warmed to 30°C (flow rate, 1-2 ml/min). A modified ACSF solution was employed when making slices and in the holding chamber that contained reduced CaCl2 (1 mM) and elevated MgSO4 (3 mM). Patch electrodes used for current-clamp recordings (3-5 M
resistance) contained (in mM) 140 K-methylsulfate, 8 NaCl, 10 HEPES, 0.2 EGTA, 4 MgATP, 0.3 Na3GTP, and 10 phosphocreatine. All recording were obtained in the presence of 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium (NBQX, 5 µM) and D-APV (25 µM) in the bath solution to block ionotropic glutamate receptors.
Voltage records were low-pass filtered at 2 kHz and digitized at 5 kHz using a 16-bit A/D converter (ITC-18, Instrutech). In some experiments, a current injection waveform consisting of a train of two to eight temporally overlapping EPSP-like waveforms was injected into mitral cells. Each simulated EPSP in the train was generated using a single alpha function with a decay time constant of 50-100 ms. This stimulus train was modeled after respiration-evoked calcium and voltage oscillations recorded from mitral cell glomerular tufts in vivo (Charpak et al. 2001). In these in vivo experiments, oscillations at the beginning of odor application tended to be larger than those occurring later. For this reason, in many of our experiments, we used simulated EPSP trains where the last three EPSPs were gradually reduced in amplitude (see Fig. 5A).
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). Because mitral cell firing is intrinsically intermittent, these measures were not well suited for our analyses of spike timing. Reproducibility of spike timing has been studied previously both in vitro (Harsch and Robinson 2000; Mainen and Sejnowski 1995; Nowak et al. 1997) and in vivo (Reinagel and Reid 2002) by measuring the precision (SD of spike times) for spikes that occur within repeatable spike events. Repeatable spike events often are defined by analyzing the peristimulus time histogram (PSTH) and identifying peaks in the PSTH that exceed a defined threshold value (e.g., 3 times the mean spike rate). These methods also are less suited to analyze spike timing in mitral cells that generate clusters of near-regular firing intermittently. To separate inter-cluster and within-cluster sources of variability, we choose to focus on the variability (SD) of the latency to the first spike cluster. Membrane potentials indicated are not corrected for the liquid junction potential. All chemicals were obtained from Sigma (St. Louis, MO) except for TTX (Calbiochem). Data are shown as the means ± SE. Statistical significance was determined using paired t-tests except where noted.
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RESULTS |
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; Desmaisons et al. 1999; Friedman and Strowbridge 2000) and other cell types (Alonso and Klink 1993; Alonso and Llinas 1989; Bracci et al. 2003; Gutfreund et al. 1995; Llinas et al. 1991; Pedroarena and Llinas 1997); however, the mechanism underlying this behavior is unclear.
Mitral cells also generate prominent subthreshold membrane potential oscillations near firing threshold (Fig. 1, D and E). Large subthreshold oscillations are often correlated with intermittent firing in a variety of neurons (mitral cells: Desmaisons et al. 1999; entorhinal neurons: Klink and Alonso 1993; thalamocortical projection neurons: Pedroarena and Llinas 1997). Computational models of subthreshold oscillations suggest they are mediated by opposing low-threshold inward and outward currents (Wang 1993, 2002). We first sought to test whether mitral cells generate a sustained Na+ current and whether this current is involved in subthreshold oscillations. We found that bath application of TTX (1 µM) reversibly reduced the steady-state depolarization produced by step current injection by 5.5 ± 0.7 mV (Fig. 1D; n = 5 cells). This effect could be due to blocking either persistent Na+ currents or subthreshold inactivating Na+ currents. TTX also blocked subthreshold oscillations (Fig. 1E; membrane potential variance decreased from 0.57 ± 0.1 mV2 at –41.1 mV to 0.021 ± 0.0004 mV2 at –46.5 mV; P < 0.05), suggesting that these oscillations may result from the interaction between K+ currents and subthreshold Na+ currents. Since TTX also blocks action potentials, it is difficult to determine directly if these Na+ currents are also necessary for intermittent firing.
The timing of spike clusters was highly variable even when mitral cells were activated by constant current steps (1st spike SD = 169 ± 32 ms; n = 11 mitral cells; Fig. 2A). The distribution of interspike intervals shows two distinct peaks: one at <100 ms that reflects intervals within spike clusters and one centered at 470 ms that represents inter-cluster pauses (Fig. 2B; n = 5 cells). Mitral cells typically generated a small afterhyperpolarization (AHP) following each spike cluster. As shown in Fig. 2C, these cluster AHPs decay exponentially with a mean time constant of 202 ± 40 ms (n = 4 cells) and were associated with a transient decrease in input resistance estimated by responses to small hyperpolarizing test pulses (73.9 ± 7.7% of precluster input resistance; n = 3 cells). This decrease in input resistance at the end of a spike discharge suggests that the buildup of an outward current may be responsible for cluster termination and may contribute to low frequency of short inter-cluster pauses (<250 ms).
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; Charpak et al. 2001; Macrides and Chorover 1972; Margrie and Schaefer 2003). We therefore tested whether phasic EPSP-like stimuli evoke reproducible spiking in control mitral cells. In these experiments, we injected a train of six simulated EPSPs at 1-5 Hz; these stimuli were designed to mimic the natural response of mitral cells during respiration (Charpak et al. 2001) and have been used in other in vitro studies (Halabisky and Strowbridge 2003). Trials with phasic waveforms were alternated with simple step depolarizations. As shown in Fig. 5A, phasic stimuli generated precise spike timing (1st spike SD = 1.6 ± 0.33 ms; 2.5 Hz; n = 7 cells) compared with the large variability of spike latencies that resulted from the alternating step trials (1st spike SD = 230 ± 34 ms; n = 18 cells). The first simulated EPSP failed to generate action potentials but decreased the apparent action potential threshold for subsequent sEPSPs. The facilitating effect of the first EPSP on later responses was time dependent; increasing the delay between four identical sEPSPs (Fig. 5B) rapidly diminished the total number of spikes evoked by the sEPSP train. This frequency filtering effect (Fig. 5C) was observed in five of five mitral cells and was not simply due to temporal summation since firing was facilitated at relatively low frequencies (1.3 vs. 1 Hz) in which the membrane potential recovered completely between sEPSP cycles. At higher frequencies, firing occurred at threshold membrane potentials more hyperpolarized than reached during the response to the first sEPSP (at 2 and 2.5 Hz). Higher frequency sEPSP trains also were effective in phase-locking mitral cell spikes (1st spike SD = 1.89 ± 0.43 ms at 4 Hz; n = 3 cells; data not shown).
Our results show that mitral cells, which fire intermittently in response to step stimuli, can generate spikes with reproducible timing in response to phasic stimuli repeated at relatively low frequencies. These properties enable mitral cells to act as high-pass filters, responding selectively to stimuli repeated at >1 Hz and ignoring single simulated EPSP (sEPSP) events (unless they are extremely large amplitude). As shown in Fig. 6, the first sEPSP in a train controls spiking in subsequent sEPSPs. In this experiment, we varied the amplitude of either the first (Fig. 6A) or second (Fig. 6B) sEPSP in a two-sEPSP train stimulus; results from these experiments are summarized in Fig. 6C. Interestingly, the first sEPSP controlled spiking in the subsequent sEPSP in an all-or-none manor. In this neuron, no spikes were evoked by either sEPSP if the first sEPSP amplitude was <17 mV. Increasing the amplitude of the first sEPSP enabled spiking on the second sEPSP; increasing the amplitude of the first sEPSP further did not change the frequency or number of spikes evoked by the second sEPSP appreciably (Fig. 6, B and C; n = 3 cells). By contrast, varying the amplitude of the second sEPSP modulated both firing frequency and spike number. Suprathreshold responses also could be gated by short trains of small-amplitude simulated EPSPs (Fig. 6D; n = 4 cells), similar to those recorded in resting mitral cells in vivo (Cang and Isaacson 2003; Margrie and Schaefer 2003; Spors and Grinvald 2002).
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DISCUSSION |
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We found that mitral cells fire clusters of action potentials at 20-40 Hz interspersed with periods of subthreshold membrane potential oscillations at 30-50 Hz. This spike clustering was dependent on intrinsic membrane properties, since it persisted in the presence of blockers of fast synaptic transmission. This finding is consistent with earlier reports on the intrinsic behavior of mitral cells (Chen and Shepherd 1997; Desmaisons et al. 1999; Friedman and Strowbridge 2000). Spike clustering in response to step depolarizing stimuli or tonic depolarization has been observed in neurons from numerous brain areas, including stellate cells of the medial entorhinal cortex (Alonso and Klink 1993; Alonso and Llinas 1989; Klink and Alonso 1993), noncholinergic inhibitory interneurons of the basal forebrain (Alonso et al. 1996), striatal fast spiking interneurons (Bracci et al. 2003), and layer IV frontal cortex neurons (Gutfreund et al. 1995; Llinas et al. 1991).
The usefulness of temporal coding as a strategy to represent information in the CNS requires that the timing of individual spikes in single neurons be highly reproducible across repeated identical stimuli. The reproducibility of spiking in response to repeated stimuli has generally been quantified by measuring spike precision (Mainen and Sejnowski 1995; Nowak et al. 1997). Precision refers to the temporal "jitter" of spiking across multiple trials and is measured as the SD of spike latency. Previous in vitro studies have suggested that regular spiking cortical neurons have very low intrinsic noise and can respond with high precision to the onset of a step current stimulus (Mainen and Sejnowski 1995; Nowak et al. 1997); noisy stimuli increase the precision of later spikes. In contrast, the intrinsic properties of mitral cells give rise to highly variable, unreliable spiking in response to simple step depolarizations but enable mitral cells to respond reproducibly to phasic stimuli in the theta frequency range.
In many cell types, K+ currents that are sensitive to very low concentrations of 4-AP have relatively slow deactivation and inactivation kinetics and are frequently termed ID-like (Coetzee et al. 1999; Fadool and Levitan 1998; Mitterdorfer and Bean 2002; Saviane et al. 2003; Storm 1988; Wu and Barish 1992). While the subunit composition of ID has not been established, this current may reflect heteromultimers containing Kv1-family subunits (Coetzee et al. 1999). Kv1.3 subunits have been shown to be expressed strongly in the olfactory bulb (Kues and Wunder 1992). A recent study has shown that Kv1.3 protein is initially expressed in all layers of the rat olfactory bulb in early postnatal development (P1–P10), including mitral cell somata, but becomes progressively greater in the external plexiform layer, where the primary and secondary dendrites of mitral cells reside. While this staining pattern could be due in part to channel subunits localized to granule cell dendrites, dendrites terminating in glomeruli (presumably mitral/tufted cell primary dendrites) are especially heavily stained (Fadool et al. 2000). Other studies have shown that Kv1.3-mediated currents constitute the dominant outward conductance in cultured olfactory bulb neurons and that these currents decay with a time constant of several hundreds of milliseconds (Fadool and Levitan 1998). Olfactory bulb cultures contain two morphologically distinct types of neurons: small bipolar neurons that are thought to be granule and periglomerular cells and larger pyramidal shaped neurons with prominent apical and secondary dendrites that are putative mitral/tufted cells (Egan et al. 1992; Fadool and Levitan 1998; Trombley and Westbrook 1990). Both neuronal types express large amounts of Kv1.3 currents; however, there are subtle differences in the rate of inactivation of voltage-dependent currents in these subtypes (Fadool and Levitan 1998). This may reflect different Kv1.3-containing heteromultimeric channels that are present in output versus local interneurons in the olfactory bulb. Fadool et al. (2004) recently investigated Kv1.3 knockout mice and found dramatic alterations in olfactory-mediated behaviors and glomerular anatomy. In addition, cultured neurons from olfactory bulbs of knockout animals show profound alterations in their voltage responses to current steps. These results underscore the potential importance of ID-like currents that involve Kv1.3 subunits in the function of the olfactory bulb. The long initial spike latency (Storm 1988) and the sensitivity of intermittent discharges to specific blockers of slowly inactivating Kv1 family members that we have found in mitral cells suggest that ID-like currents play a critical role in patterning mitral cell responses. Preliminary mitral cell voltage-clamp recordings indicate that mitral cells express at least two 4-AP–sensitive transient potassium currents with decay kinetics that range from 40 to >500 ms (in response to steps from –80 to 0 mV; data not shown). A parallel study is underway in our laboratory with the goal of identifying the molecular basis of the transient K+ currents in mitral cells that enable intermittent firing in response to step stimuli and phase-locking in response to phasic stimuli.
Mechanisms of spike clustering and phase locking
Based on our results, we propose that spike clustering in mitral cells depends on the interplay between slowly inactivating ID-like K+ channels and a subthreshold TTX-sensitive Na+ current. Intermittent firing has been investigated previously using computational (Wang 1993, 2002) and experimental (Klink and Alonso 1993) studies to explain the genesis of fast subthreshold membrane potential oscillations and spike clustering in cells of the medial entorhinal cortex and basal forebrain (Alonso et al. 1996). These studies have proposed that cluster initiation depends on the level of inactivation of outward currents, while cluster termination depends on the buildup of potassium currents during a burst. Our studies support the view that spike cluster termination is controlled by potassium current buildup, since blocking ID-like currents increases cluster duration (and eventually abolishes intermittent firing). In addition, spike threshold increases slightly during the course of a cluster (see Fig. 2C), which suggests that outward currents increase during spike clusters. The first spike in a cluster is always smaller than later spikes; however, there is very little (<3 mV) modulation of spike amplitude during a cluster. This suggests that processes that control Na+ channel availability, such as cumulative inactivation during a train of spikes, may not play a prominent role in cluster termination. While elevated K+ currents are likely to be responsible for cluster termination, the precise biophysical mechanisms involved have not been determined experimentally. Potassium currents may increase during clusters as result of very rapid recovery from inactivation between individual spikes within a cluster (Wang 1993). Alternatively, macroscopic potassium currents may increase throughout each cluster, reflecting the slow deactivation kinetics of individual ID channels (Mitterdorfer and Bean 2002).
The origin of the variability in spike timing across repeated trials of step current is unlikely to reflect subtle changes in membrane properties of mitral cells from trial to trial. We found no correlation between the first spike latency and membrane potential or input resistance immediately preceding the depolarizing stimulus. One possible explanation for spike time variability is spike initiation in mitral cells is controlled by a small number of ion channels, such that spike variability is a reflection of noise from channel gating events. Several studies have addressed this issue using computational (Jones 2003; Schneidman et al. 1998; White et al. 1998) and experimental (Johansson and Arhem 1994) approaches. However, the functional significance of stochastic channel gating in controlling spike timing in mitral cells has not been established and may not apply to neurons as large as mitral cells. Alternatively, variability in discharge times may reflect the complex oscillatory dynamics of opposing inward and outward macroscopic currents active near threshold. Our preliminary voltage-clamp studies indicate that mitral cells express high levels of transient 4-AP–sensitive K+ currents, suggesting that oscillating inward and outward currents may be a more important mechanism for controlling spike timing than stochastic channel gating events. Previous studies on the role of transient 4-AP–sensitive K+ currents in controlling spike timing in neurons have focused on the characteristic delay in the timing of the first spike (Saviane et al. 2003; Storm 1988). Blockade of 4-AP–sensitive K+ currents reduces this delay (McCormick 1998; Saviane et al. 2003; Storm 1988); however, it is not known whether expression of ID-like currents in these neurons leads to variable spike timing.
Precise spike timing evoked by phasic stimuli likely arises because of differences in the kinetics of recovery from inactivation of transient outward currents and voltage-dependent Na+ currents. The initial depolarization from the first simulated EPSP causes a rapid activation of outward currents that inhibit spiking. During the falling phase of the first EPSP, fast transient Na+ currents should recover rapidly from inactivation (Kuo and Bean 1994). By contrast, slowly inactivating ID-like currents will likely de-inactivate at much slower rates (Fadool and Levitan 1998), enabling a subsequent depolarization totrigger a cluster of spikes. Spike clusters are terminated either by repolarization during the falling phase of the EPSP or buildup of outward currents. This scheme is supported by experiments that show that the amplitude of the first EPSP gates the generation of spikes on subsequent EPSPs. Small amplitude simulated EPSPs may not inactivate sufficient K+ currents to allow firing on subsequent simulated EPSPs (as shown in bottom traces in Fig. 6A). Larger initial simulated EPSPs presumably inactivate more ID-like K+ current, thereby facilitating firing following a repolarization/depolarization cycle. Preferential recovery of Na+ versus K+ currents during the repolarization phase is likely to account for the decreased firing threshold following brief repolarizing steps (Fig. 4) and during responses to the trains of simulated EPSPs (Fig. 5).
Functional implications for odor coding
Several theoretical studies have suggested that action potential timing may be important for representing sensory stimuli (Hopfield 1995; Rieke et al. 1997). Temporal coding appears to be especially important in olfactory processing (Laurent et al. 1996; Wehr and Laurent 1996), where single olfactory receptor neurons have broad specificity for many odorants (Araneda et al. 2000; Duchamp-Viret et al. 1999), to increase the number of odorants that can be uniquely identified. Recent studies in insects have shown that downstream neurons that receive information from projection neurons act as coincidence detectors (Perez-Orive et al. 2002). Such a coding scheme requires that incoming spike trains be highly reproducible across repeated trials.
Our study suggests that intrinsic ionic mechanisms in mitral cells promote precise spiking in response to phasic stimuli in the theta frequency range. Prominent 2- to 7-Hz activity coupled to the respiratory rhythm has been observed in mitral cells in vivo using extracellular unit (Belluscio et al. 2002; Macrides and Chorover 1972) and whole cell intracellular (Margrie and Schaefer 2003) recordings, voltage dye imaging (Spors and Grinvald 2002), and calcium imaging in mitral cell apical dendritic tufts (Charpak et al. 2001). The genesis of this respiratory-coupled activity is likely to reflect changes in odorant concentration (and thus activation of olfactory receptor neurons) in the olfactory epithelium during inspiration (Sobel and Tank 1993). Our results suggest that mitral cells are "tuned" to receive synaptic input in the theta band frequency range in which rodents normally sniff. The intrinsic properties of mitral cells allow them to filter olfactory information by controlling the generation of spikes that are evoked by inspiration-induced theta activity. By this mechanism, the activation of a broad subset of olfactory receptor neurons would result in precisely timed trains of spikes in a small subset of mitral cells. Weak or transient stimuli may not evoke spiking at all, whereas sustained stimuli that are not modulated in time might produce spikes that are highly variable from trial to trial, presumably impairing downstream coincidence detection mechanisms. These intrinsic filtering mechanisms might act in concert with synaptic mechanisms that synchronize theta oscillations in adjacent mitral cells (Schoppa and Westbrook 2001; Urban and Sakmann 2002) to ensure that mitral cells which project to the same glomerulus act as distinct functional units.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: B. W. Strowbridge, Dept. of Neurosciences, Case Western Reserve Univ., 10900 Euclid Ave., Cleveland, OH 44106 (E-mail: bens{at}cwru.edu).
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3 trials. D: plot of the effect of TTX (1 µM) on the steady-state depolarization reached during a 200-pA current step (3-s duration). Example traces shown above in control conditions (left) and after exposure to TTX for 2.3 and 3.5 min (right). Arrow marks point during current step where steady-state voltage was measured. Action potentials clipped in example traces. Note that TTX reduces both the depolarizing extent of the step response and amplitude of subthreshold oscillations normally present near firing threshold. E: enlargements of steady-state responses in control, after 2.3- and 3.5-min exposure to TTX, and during washout of TTX.
