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Department of Biomedical Engineering, Georgia Institute of Technology; and Emory University, Atlanta, Georgia
Submitted 19 May 2006; accepted in final form 28 June 2006
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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10 mV more depolarized (P < 0.01). It is concluded that both dynamic and steady inputs can be amplified, but there may be differences in mechanism. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). However, the quest to unveil how synaptic inputs are processed as well as the location of this processing remains in its initial stages (Powers et al. 2002). Central to this issue is whether dendritic active conductances modestly sculpt the synaptic signal or whether they radically transform the input. Previous findings suggest that dendritic conductances are predisposed for the "radical transformer" paradigm with behaviors such as bistability (Hounsgaard et al. 1984) and synaptic amplification (Hultborn et al. 2003; Lee and Heckman 2000; Lee et al. 2003; Powers and Binder 2000; Prather et al. 2001) being prevalent and under neuromodulatory control (Heckman et al. 2003).
The prevailing view is that calcium conductances (Cav 1.3 "L-type") are responsible for these transforming behaviors as they generate dendritic plateau potentials in the presence of neuromodulators (Hounsgaard and Kiehn 1993; Lee and Heckman 1999; Li et al. 2004; Zhang and Harris-Warrick 1995; Zhang et al. 1995). However, a limiting aspect of the calcium current-based dendritic plateaus is the speed of their response, with plateaus taking on the order of 50 ms to form (Lee and Heckman 1998a,b). Given that the majority of input during physiological motor control activities is dynamic (e.g., walking), a "slow" amplification mechanism would further filter out the dynamics beyond those normally associated with passive dendritic integration (Muller and Lux 1993; Rall 1967).
Alternatively, sodium conductances might also be involved in motoneuron dendritic processing. Sodium currents, having much faster kinetics (Hsu et al. 1993), could presumably keep pace with even the fast input transients and so could form the basis of a separate "fast" amplification mechanism. There are indications from step inputs that amplification does extend to these transients (Hultborn et al. 2003; Powers and Binder 2000). However, these studies did not explicitly examine the dynamics, and in the case of Powers et al. (2000), they had observed the amplification under pharmacologically modified conditions that make direct comparison problematic.
Persistent sodium currents have been observed in rat dorsal horn neuron dendrites (Safronov 1999) and in rat and mouse motoneurons (Harvey et al. 2005; Li et al. 2004; Miles et al. 2005; Zeng et al. 2005), but notably, not in turtle motoneurons (Perrier et al. 2000). We have previously observed a fast, persistent inward current that is likely persistent sodium in lumbar motoneurons (Lee and Heckman 2001). Although that current was believed to be located in the initial segment and in and around the soma due to its strong link to spike initiation and firing frequency gain, it is possible that some component of that current was dendritic.
The objective of this investigation was to determine if synaptic amplification does in fact extend to the fastest transients in synaptic input. For this study, we chose a synaptic input (vibration of the Achilles tendon) that generates both a steady component that could be amplified by a mechanism with even the slowest kinetics and a high-frequency component, which, if amplified, would require a mechanism with very fast kinetics. This paper presents data indicating that synaptic amplification does extend to the transient components of the synaptic signal. Furthermore, we believe that the results suggest a mechanism behind this "fast" amplification that is distinct from the mechanism amplifying slower inputs.
Portions of this work have appeared in abstract form.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Standard surgical preparation
Initial surgical preparations were done under deep gaseous anesthesia (1.5–3.0% isoflurane in a 1:3 mixture of O2 and N2O). A tracheotomy was performed and respiratory effort sustained through ventilator support. The right internal carotid artery and the right external jugular vein were cannulated for blood pressure monitoring and intravenous infusion of fluids, respectively. Core temperature was obtained via a probe inserted orally. Radiant heat was used to maintain hindlimb and core temperatures within physiological limits. Electrocardiographic (ECG) electrodes were attached on the chest area. Vital signs (blood pressure, heart rate, core temperature, respiration rate, and expired CO2) were continuously monitored and maintained within physiologic limits for the duration of the experiment.
To gain access to the spinal cord for intracellular recording, a laminectomy was performed to bare the L7 and S1 segments. The dura was opened and the dorsal roots gently retracted. For stimulation purposes, the nerves innervating the medial gastrocnemius (MG) and lateral gastrocnemius-soleus (LGS) muscles in the left hindlimb were carefully isolated and left uninterrupted. The Achilles tendon was fastened to a muscle puller (moving coil DC linear actuator, force at 100% duty = 100 N, peak force = 300 N; H2W Technologies) via a bone chip from the calcaneus to allow manipulation of the tendon for synaptic input. Exposed areas of the hindlimb (including nerves) were prevented from drying out and electrically isolated by drawing the skin flaps of the hindlimb upward to form a pool for mineral oil. A similar mineral oil pool was constructed over the exposed spinal area.
Prior to intracellular recordings, all animals were paralyzed with gallamine triethiodide (Flaxedil; 10 mg initial dose) to prevent recording disruptions due to movement; supplemental doses (1–2 mg) were given as necessary. The isolated nerves of MG and LGS were placed on hook electrodes for antidromic stimulation. Despite multiple vertebral clamps, respiratory motion was routinely visible under low power (x2) magnification. When this motion was too great and mechanical noise was visible in the recordings, a thoracotomy was performed to decouple respiration from the chest wall movements to enhance intracellular recording stability. At the end of the experiments, the animals were killed with a lethal dose (100 mg/kg iv) of sodium pentobarbital (Lee and Heckman 1998a).
Decerebration
To prevent bleeding in the cranial cavity, both the internal carotid arteries were permanently occluded with suture thread after the surgical preparation was complete. Once the animal's vital signs stabilized, a craniotomy was performed to expose the brain rostral to the tentorium. The midbrain was then transected immediately anterior to the superior colliculus with an ophthalmic spatula, and the forebrain rostral to the transection was removed via aspiration. The calvarium was loosely packed with saline-soaked cotton wool to reduce swelling and blood loss. Gaseous anesthesia was then discontinued slowly over 1 h, after which adequate respiratory effort was maintained per ventilator with room air and minimal (0.5–1 l/m) O2 supplement. Decerebrate animals were considered to be under standard neuromodulatory influence.
Pentobarbital anesthesia
Once the surgical preparation was complete, animals were switched from isoflurane to pentobarbital anesthesia via intravenous administration of an initial dose of 6.5 mg/kg. These animals were considered to be under minimal neuromodulatory influence.
Intracellular recording
Electrophysiological assessment is achieved by impaling motoneurons with sharp electrodes made from glass capillary tubes that have been pulled to a fine point and manually broken back under magnification. Because single-electrode voltage-clamp technique was used, resistances of the electrodes were kept low (3–4 M
). The sharp microelectrodes were filled with 0.5 M potassium citrate/1.5 M potassium chloride solution. Although potassium chloride in the pipette improves the electrodes' voltage-clamping ability, it also alters chloride-based inhibitory postsynaptic potentials (IPSPs). However, the tendon vibration response is predominantly excitatory PSPs and therefore should not be affected by this composition. Voltage clamp was performed using the discontinuous, single-electrode voltage-clamp mode of our amplifier (Axoclamp 2B, amplifier; Axon Instruments) (Finkel and Redman 1984). A microdrive advanced the microelectrodes into the spinal cord a distance of 1–2 mm. Motoneurons within the region of the lumbar motor pools (L7–S1) were located and identified antidromically by the field potential evoked from stimulation of the medial and lateral gastrocnemius and soleus nerves.
Synaptic input
Synaptic input provided by activation of muscle spindle Ia afferents resulted in a primarily monosynaptic excitatory synaptic input (Heckman and Binder 1988) and was widely distributed on motoneuron dendrites (Brown and Fyffe 1981; Burke et al. 1979). To provide selective activation of muscle spindle Ia afferents, a high-frequency low-amplitude sinusoidal vibration (180 Hz; 80-µm peak to peak) was delivered to the MG and LGS tendons (Heckman and Binder 1988; Matthews and Stein 1969). Figure 1 illustrates the monosynaptic input resulting from a 5-s tendon vibration. As can be seen, the input generates both a steady input that is stable for long durations, and a high-frequency component at 180 Hz presumably due to the phase locking of the spindle afferents to the vibration. These two components of the synaptic input are readily separated as described in the next section.
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Cell penetration quality and cellular "health" were assessed by measuring the antidromic spike height and resting membrane potential (spike height: >70 mV, resting membrane voltage: < –50 mV). In cells meeting these requirements, recording was switched to discontinuous current clamp (switching frequency from 8.5 to 10 kHz) with capacitance compensation where electrode capacitance and resistance are optimally eliminated. The microelectrodes' current passing capacity was assessed from the slope of the voltage trajectory prior to sampling (i.e., returning to 0 slope prior to the next sampling point). Data from poorly compensated electrodes were discarded. Switching to voltage-clamp mode, slow triangular voltage-clamped ramp commands of 10-s duration were applied to the electrode. In most cells, the amplitude of the triangular-shaped voltage ramp was 30 mV, resulting in a rate of rise of 6 mV/s (Lee and Heckman 2001). By operating the voltage at a slow rate of change, a sufficient approximation of the cell's steady-state I-V function can be obtained (Lee and Heckman 1998b). Concurrent with the voltage ramp, a longitudinal tendon vibration was applied to the Achilles tendon, starting 1 s before the start of ramp command (Matthews and Stein 1969). This provided selective activation of the Ia input and allowed measurement of the Ia effective synaptic input (Binder et al. 2002). Motoneurons were under sufficient clamp control as judged by excursions from clamp command.
Determining the slow and fast components of the effective somatic current
This paper includes measures of currents previously described elsewhere as well as new measures particular to this work. As this has the potential for nomenclature awkwardness, some previously defined measures have been renamed for the clarity of this manuscript. These measures are described here briefly: "IPIC" is a persistent inward current (PIC) due to voltage-sensitive conductances measured at the soma in response to a slow voltage ramp (Lee and Heckman 1998a). This measure of IPIC does not differentiate between PICs of various activation speeds; rather it is a measure of the collective sum of the PICs. As convention, this current was typically smoothed, which effectively eliminated any higher frequency components of the response to the voltage ramp. "Ia IN" is the Ia effective synaptic current ("effective" being defined as the net current reaching the soma) and thus contains the response to both the steady state and the dynamic portions of the synaptic input. For clarity, Ia IN will be referred to as "Isyn" (syn for synaptic) with the steady and dynamic components being "Isyn,slow" and "Isyn,fast," respectively.
Separation of the fast and steady currents measured at the soma in response to the tendon vibration involved several steps, which are illustrated in Figs. 2 and 3. Figure 2A shows the current flux in response to a voltage-clamped ramp (bottom) with and without a tendon vibration applied to the Achilles tendon (top). Figure 2B highlights a small portion of the current flux in expanded time to illustrate the 180-Hz component of current response (bottom compared with top). To calculate the total Ia effective synaptic current (Isyn), the current flux from a slow voltage-ramp protocol with a simultaneous tendon vibration (Fig. 2A, bottom) is subtracted from the response to a slow voltage-ramp protocol without a tendon vibration (Fig. 2A, top). The difference (Isyn; Fig. 2C) is then separated into steady and fast components (i.e., low- and high-frequency components shown in Fig. 2, D and E, respectively). The steady component (Fig. 2D) is extracted simply by low-pass filtering. A moving average window filter was used as it completely removes frequencies that align with the window width. Thus setting the window width to 27.78 ms (exactly 5 intervals of 180 Hz), ensured complete removal of the vibration related component from the filtered signal. This current, referred to as Isyn,slow to emphasize this filtering, is the traditional measure of effective synaptic current used previously to characterize synaptic amplification (Lee and Heckman 2000). The fast component, referred to as Isyn,fast (Fig. 2E), is computed by substracting the low-pass filtered Isyn,slow from the raw Isyn.
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Because the remainder of this paper quantifies only the ascending portion of the triangular ramp response and we are interested in characterizing amplification as a function of somatic voltage rather than time, only the ascending portion of the response will be illustrated, parameterized by voltage (Fig. 3). The raw Isyn,fast (shown in Fig. 2E vs. time and Fig. 3A vs. voltage) is rectified (Fig. 3B) and low-pass filtered (Fig. 3C) with the same moving average window filter (27.78 ms in width). The resulting waveform is a continuous measure of the effective synaptic current oscillation magnitude. Finally, because the synaptic input is excitatory the amplification should be an inward current. Thus the final step is to invert the magnitude (Fig. 3D).
As in our previous publication, an amplification factor was defined as the ratio of the minimum current magnitude at hyperpolarized voltages to the peak current magnitude occurring at more depolarized voltages. For clarity, amplification of the steady component of the input is termed "slow amplification" and is characterized by a slow amplification factor, whereas amplification of the fast component is termed "fast amplification" and is correspondingly characterized by a fast amplification factor. This leaves the term amplification free to refer to amplification of any/all inputs, bearing in mind that overall amplification may not be a constant factor across all input frequencies or paradigms. Because we suspect that there are two mechanisms at work, the fast and slow amplification nomenclature can also double as stand-ins for these mechanisms until the underlying sources are determined.
Voltage-dependent characterization of amplification factors is based on the point of amplification onset (defined as the voltage at the start of the negative slope region of Isyn,fast and Isyn,slow, respectively) and the point of peak amplification (defined as the voltage at the point of most negative Isyn,fast and Isyn,slow, respectively). Given that the true peak may not have occurred in the range of the voltage clamp, these factors are considered as a conservative estimate.
Data acceptance criteria
The main acceptance criteria were that the amplitude of the antidromic spike exceeded 70 mV and the resting membrane potential did not vary by more that ±5 mV during the course of the data collection. A total of 27 cells met the criteria. Acquired data were subsequently filtered and processed as needed off-line. Data with sustained firing patterns generated with the tendon vibration were digitized at 20 kHz.
Statistical analysis
The electrical properties of the cells were compared using paired t-test, assuming unequal sample variances. The exception to t-test assessment was the pentobarbital anesthetized/minimal state data, which had lower N and was therefore more appropriately assessed with the Mann-Whitney U test. In addition, linear regression analyses were used to assess the relationships between variables. All statistical tests were performed using Systat. The significance level in all cases was set at P = 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Schwindt and Crill 1995). Due to poor space-clamp conditions, a voltage-clamped ramp is likely to only activate voltage-dependent conductances of the soma, a fraction of the proximal dendrites and the initial segment (Rall and Segev 1985). Accordingly, the resultant amplification of this synaptic input elicited by a tendon vibration is shown in Fig. 4 for a representative cell. As shown in our previous work (Lee and Heckman 2000), the steady response, Isyn,slow, (Fig. 4B) increased with somatic voltage, resulting in a slow amplification factor of 5.6 with a voltage onset of –67 mV (Note, the PIC is off at hyperpolarized levels, and the synaptic current at this level is used to normalize the current with the PIC. Thus the amplification factor tells how much the PIC increases the synaptic input). The dynamic response, Isyn,fast, (Fig. 4A) also increased with somatic voltage. At hyperpolarized levels (–65 mV), Isyn,fast current was approximately –2.5 nA. As the cell was depolarized to approximately –48 mV, Isyn,fast was enhanced to more than –4.5 nA. Therefore the fast amplification factor was 2.1 with an onset voltage of –60 mV and a voltage at peak of –48 mV. For comparison, Isyn,fast and Isyn,slow are shown together in Fig. 4C with Isyn,fast scaled by the corresponding amplitude Isyn,slow at –60 mV. The currents are of a similar shape but appear to have differing characteristics with the fast amplification occurring at higher voltages and over a somewhat broader voltage range. These differences are examined in the next section.
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Averaged data for amplification factors and voltage ranges (onsets and peaks) were used for a statistical analysis of the population. Overall, there is a strong, voltage-dependent amplification, not only of the steady input but also the dynamic Ia synaptic input. The average fast amplification factor was 2.0 ± 0.7, whereas the average slow amplification factor was 2.4 ± 1.0. This difference is not significant (n = 12; P = 0.078). In contrast to amplification factor, onset voltages for Isyn,fast and Isyn,slow were significantly different with the average onset voltage for fast amplification being 10 mV more depolarized (–58.3 ± 8.5 vs. –68.2 ± 6.4 mV; n = 12; P < 0.01). This difference may indicate that the mechanisms for fast and slow amplification are different (see DISCUSSION). Comparison of the voltages of peak amplification revealed no statistical difference (Isyn,fast: –38.7 ± 6.0 mV; and Isyn,slow: –36.6 ± 18.0 mV; P > 0.5), but this may be due to limitations on the voltage-clamped ramp ranges. The fast amplification factor was also assessed versus input conductance (measured as the slope of the I-V relationship within 5 mV of rest). Although there was a negative trend, with the fast amplification factor varying inversely with input conductance, it was not statistically significant (R = 0.33, n = 14, P 0.1). This finding is consistent with our previous finding regarding slow amplification (Lee and Heckman 2000).
Neuromodulation of fast amplification
Amplification of what we are presently calling Isyn,slow has previously been shown to scale with neuromodulatory drive (Lee and Heckman 2000). Therefore the influence of the neuromodulatory drive of Isyn,fast was assessed as well (Fig. 5) by repeating the synaptic protocols in three pentobarbital-anesthetized animals, referred to as the "minimal state" in Lee and Heckman (2000). As expected, the minimal neuromodulatory state shows little evidence of amplification of Isyn,fast (Fig. 5A). The average fast amplification factor for the minimal state was 1.23 ± 0.25 (n = 7) compared with 2.0 ± 0.7 (n = 12) for the standard decerebrate state (see example in Fig. 5B with factor of 1.9). This difference was significant (P = 0.01; U test). This result is consistent with previous findings that steady inputs were not substantially amplified in the minimal state. Thus it appears that both forms of amplification are similarly subjected to neuromodulatory control.
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In four of seven cells examined in the minimal state, fast amplification was of sufficient size (i.e., >1.0) to permit characterization of the voltage characteristics of fast amplification. The average values for onset voltage and voltage of peak amplification were –54.6 ± 10.2 and –40 ± 6.5 mV, respectively. These values were not significantly different from the standard state values (P > 0.05; U test).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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) and tendon vibration (Powers and Binder 2000) albeit under conditions that made the amplification difficult to assess. The use of voltage clamp in the present study allows for a more direct examination of voltage-sensitive currents in the dendrites and their influence on synaptic integration. The following discussion reflects on the implications of these findings and the origin of fast amplification. Fast amplification via active versus passive means
Studies have suggested that motoneurons with purely passive dendritic structures would be capable of generating only a small fraction of the input needed to drive the cells to their highest firing rates (Powers and Binder 1995; Rose and Cushing 1999). Thus some active intervention is needed to achieve higher firing rates. At issue is the form and characteristics of that intervention. The case for amplification of steady inputs, which we refer to here as "slow" amplification, is reasonably well established (Hultborn et al. 2003; Lee and Heckman 2000; Prather et al. 2001). However, the case for amplification of dynamic inputs still needs to be made. The data presented here indicate that some form of fast amplification does occur. However, the data itself have little to say about the mechanism behind the amplification. Nonetheless, two passive property-related possibilities can be ruled out. First, changes in membrane conductance due to the synaptic input itself cannot be responsible for altering the electrotonic properties of the dendrites. Excitatory inputs generate very little change in conductance under these conditions (Powers and Binder 2000) and any change would cause more, rather than less attenuation. Second, synaptic driving potentials could not directly amplify an input without the dendritic voltage being manipulated by active potentials. That is, excitatory inputs would only appear to be amplified if the dendritic voltage were hyperpolarized (rather substantially) and inhibitory inputs would only appear to be amplified if the dendritic voltage were depolarized. Given that a purely passive dendrite would tend to depolarized as the soma is depolarized during the voltage-clamped ramp protocols, excitatory inputs would be diminished rather than amplified. Thus in either case some type of active conductance is needed to produce amplification even if the effect is only indirect.
Neuromodulatory control of fast amplification
Descending monoaminergic tracts likely function to modulate motoneuron input-output processing. The motoneuron surface, from the soma to the distal dendrites, is covered in serotonergic boutons (Alvarez et al. 1998) and presumably noradrenergic boutons as well but the experimental evidence is less definitive (Schroder and Skagerberg 1985). The opportune proximity of monoaminergic receptors, voltage-dependent conductances, and synaptic input provides a basis for neuromodulatory control of synaptic integration. Lee and Heckman (2000) reported that activation of motoneuron dendritic IPICS can greatly increase the amplitude of the steady component of Ia synaptic input. Here we present evidence that dynamic inputs are amplified as well, albeit differently. In both instances, the level of neuromodulatory drive to motoneurons adjusts the amplification of the input. However, the degree of amplification and the voltages at which amplification occur are distinct. Nonetheless, adjustable amplification of dynamic inputs gives the brain stem a means to regulate synaptic inputs on even the fastest time scales and affect motoneuron excitability across all input scenarios.
Relationship to slow amplification
Our reliance on what might be called a steady dynamic input (i.e., a maintained 180-Hz tendon vibration) helps to bridge amplification of dynamic and steady inputs. There was no indication of slower, voltage-dependent inactivation processes affecting Isyn,fast. Thus one can assume that this fast current is available to amplify slower and even steady inputs in addition to fast transients. It is therefore likely that at least some of the slow amplification is due to fast amplification. Whether it accounts for all of slow amplification remains an open question. That is, could fast and slow amplification be different aspects of the same mechanism. Certainly, the substantial difference (10 mV) in onset voltage refutes the same mechanism scheme. However, it is not inconceivable that dendritic capacitance and resistance preferentially restrict fast amplification in a manner that makes it appear to be voltage shifted. Nonetheless, we believe that this large of a shift is unlikely, and therefore we favor the hypothesis that there are two mechanisms at work.
It was originally assumed that synaptic amplification was due to the same dendritic calcium current-based plateau potentials that caused bistable behavior in motoneurons (Perrier et al. 2000). This assumption was always problematic as it required grading plateau potentials. Given that plateau potentials are virtually defined as "all-or-none" events, grading them would seem to be contradictory from the outset. Despite this fact, the complex geometries of motoneurons do permit several scenarios in which plateaus might appear to be graded when measured as current arriving at the soma. However, if there are two amplifying mechanisms (1 fast and 1 slow), grading of plateaus might no longer be necessary. We propose that the slower amplification is related to the calcium-based conductances underlying the dendritic plateaus (but possibly not the plateaus themselves), whereas the faster mechanism is sodium-conductance-based. This would mean that sodium channels are present in the dendrites, an observation that has only been partially established in adult motoneurons (Larkum et al. 1996).
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GRANTS |
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. H. Lee, Dept. of Biomedical Engineering, Georgia Institute of Technology, Whitaker Bldg., 3103, 313 Ferst Dr., Atlanta, GA 30332 (E-mail: rhlee{at}bme.gatech.edu)
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REFERENCES |
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  K. P. Carlin, T. V. Bui, Y. Dai, and R. M. Brownstone Staircase Currents in Motoneurons: Insight into the Spatial Arrangement of Calcium Channels in the Dendritic Tree J. Neurosci., April 22, 2009; 29(16): 5343 - 5353. [Abstract] [Full Text] [PDF]
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 C.J. Heckman, M. Johnson, C. Mottram, and J. Schuster Persistent Inward Currents in Spinal Motoneurons and Their Influence on Human Motoneuron Firing Patterns Neuroscientist, June 1, 2008; 14(3): 264 - 275. [Abstract] [PDF]
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 C. J. Heckman, A. S. Hyngstrom, and M. D. Johnson Active properties of motoneurone dendrites: diffuse descending neuromodulation, focused local inhibition J. Physiol., March 1, 2008; 586(5): 1225 - 1231. [Abstract] [Full Text] [PDF]
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M. Manuel, C. Meunier, M. Donnet, and D. Zytnicki Resonant or Not, Two Amplification Modes of Proprioceptive Inputs by Persistent Inward Currents in Spinal Motoneurons J. Neurosci., November 21, 2007; 27(47): 12977 - 12988. [Abstract] [Full Text] [PDF]
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 G. Grande, T. V. Bui, and P. K. Rose Estimates of the Location of L-type Ca2+ Channels in Motoneurons of Different Sizes: A Computational Study J Neurophysiol, June 1, 2007; 97(6): 4023 - 4035. [Abstract] [Full Text] [PDF]
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