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1Department of Physiology, 2Department of Physical Medicine and Rehabilitation, and 3Institute for Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611; and 4Department of Biomedical Engineering, Emory University, Atlanta, Georgia 30322
Submitted 30 May 2003; accepted in final form 18 August 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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). However, a background of tonic synaptic activity is often present in vivo (Steriade 2001). Furthermore, much of normal information processing requires the genesis of firing rates that modulate over time. Good examples of this modulation of firing rate occur in the motor system, where firing rates of pyramidal neurons and spinal motoneurons are matched to the smooth progression of many movements (Ashe and Georgopoulos 1994; Holdefer and Miller 2002; Morrow and Miller 2003). Presumably, such firing patterns require integration of many PSPs undergoing both spatial and temporal summation.
In spinal motoneurons, where all motor commands are translated into outputs to muscle fibers, dendritic integration of sustained inputs is under the control of neuromodulatory inputs from the brain stem (Powers and Binder 2001). Perhaps the most important of these neuromodulators are the monoamines serotonin and norepinephrine. Motoneurons have the capacity to generate a large persistent inward current (PIC; Schwindt and Crill 1980), but this capacity can only be realized if monoamines are present (Hounsgaard and Kiehn 1985; Hounsgaard et al. 1988; Perrier and Hounsgaard 2003). Much of the PIC has been shown to originate in dendritic regions (Carlin et al. 2000b; Hounsgaard and Kiehn 1993; Lee and Heckman 1998a, 1999a, 2000; Svirskis and Hounsgaard 1998).
Bistable behavior, in which a brief excitatory input initiates long-lasting self-sustained firing, was the first effect of the PIC to be demonstrated in preparations with monoamines (Hounsgaard and Kiehn 1985; Hounsgaard et al. 1988). However, self-sustained firing in the absence of input only occurs in low threshold motoneurons that are likely to innervate slow twitch muscle fibers (Lee and Heckman 1998b). This does not limit the importance of the dendritic PIC to motor behaviors, such as posture, that are dominated by slow twitch motor units. In every motoneuron, low- or high-threshold, the dendritic PIC markedly alters the response to injected or synaptic currents while they are being applied to the cell.
The PIC imparts a strong acceleration in firing rate during application of injected current (Bennett et al. 1998, 2001; Hornby et al. 2002; Hounsgaard and Kiehn 1989; Hounsgaard et al. 1988; Lee and Heckman 1998b). Excitatory synaptic inputs are enhanced to an even greater degree by the PIC—as much as fivefold (Bennett et al. 1998; Delgado-Lezama et al. 1999; Lee and Heckman 2000; Lee et al. 2003; Prather et al. 2001). Synaptic inhibition, while less studied, has been shown to turn off self-sustained firing (Hounsgaard et al. 1988) and to strongly influence the acceleration in firing rate generated by the PIC (Bennett et al. 1998). In this study, we quantify the interaction between the dendritic PIC and inhibitory synaptic input with single-electrode voltage clamp techniques. All studies were carried out in vivo, with an inhibitory input that was predominated by reciprocal inhibition between antagonist motor pools. Our hypothesis was that inhibition would reduce the dendritic PIC, either by hyperpolarization and by shunting of the active currents (cf. Powers and Binder 2000) or by metabotropic actions (Svirskis and Hounsgaard 1998), resulting in a much more linear current-voltage relation. We found that the degree of reduction of the PIC was approximately linearly related to the amplitude of the inhibition, suggesting that synaptic integration of inhibitory inputs in motoneurons with highly active dendrites could be a linear process.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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; Lee and Heckman 1998b). Briefly, all surgical preparations of the spinal cord and hindlimb were done under deep gaseous anesthesia (1.5–3.0% isoflurane in a 3:1 mixture of O2 and N2O). The preparation included a laminectomy to expose the L7 and S1 segments of the spinal cord for intracellular recording. In the hindlimb, the nerves to the medial gastrocnemius (MG) and lateral gastrocnemius-soleus (LGS) muscles were isolated and placed on hook-shaped bipolar stimulating electrodes. The Achilles tendon was surgically isolated (the plantaris tendon was cut, leaving only the MG and LGS tendons) and attached to a computer-controlled muscle puller. The common peroneal nerve (CP), which contains nerves of several antagonists to MG and LGS, was isolated and placed in a cuff electrode. The gaseous anesthesia was discontinued after a precollicular decerebration in which all forebrain anterior to the superior colliculi was removed. All preparations were then paralyzed with Flaxedil and artificially respired. A bilateral pneumothorax was created to enhance intracellular recording stability. Three experiments were carried out in cats deeply anesthetized with 
-chloralose (initial dose 50 mg/kg; 5-mg/kg supplements given as needed to maintain a stable blood pressure and suppress withdrawal reflexes, which were routinely tested in periods where the animal recovered from the paralysis). Surgical preparations of the spinal cord and hindlimb were identical to those described above for the decerebrate. Levels of monoaminergic input to the cord
The main difference between the two preparations described above is that the decerebrate has tonic activity in the monoaminergic axons originating in the brain stem (Baldissera et al. 1981; Lee and Heckman 1998b). All cells recorded in the decerebrate preparation were thus considered to have a moderate level of monoaminergic input. Anesthesia reduces the PIC (Lee and Heckman 2000), presumably through a reduction in activity of monoaminergic axons. Therefore the cells recorded in the chloralose preparation were considered to have a low level of monoaminergic input. To be consistent with our previous work on PIC effects on excitatory synaptic input (Lee and Heckman 2000), we refer to the decerebrate preparation as providing the "standard" state for monoaminergic input to the cord and the deeply anesthetized preparation as the "minimal" state. The "enhanced" state of the previous study, which depended on the addition of a noradrenergic agonist, was not employed in the present work.
Intracellular recordings
Intracellular recordings of motoneurons were obtained in the lumbar cord with sharp microelectrodes and identified by antidromic stimulation of either the MG or LGS nerves. Microelectrode tips were broken back under microscopic observation and control. Because of the large currents required for successful single-electrode voltage clamp techniques in spinal motoneurons, resistances of the electrodes were kept low—typically around 3–4 M
in saline before entering the cord. In the initial studies in the decerebrate, eight cells were recorded with electrodes filled with a solution combining potassium citrate (1.5 M) and potassium chloride (1.5 M). Most data (19 cells) in the decerebrate and all data in the chloralose preparation (7 cells) were taken with electrodes filled with 2 M potassium citrate to avoid alteration of the reversal potential for the inhibition, which is sensitive to internal chloride concentration (Coombs et al. 1955). The inhibitory reversal potential was not systematically measured, but in two cells in the KCl sample, we noted an approximate 5-mV depolarization of the reversal potential during the 4–5 min required to obtain the measurements presented in this study. In the decerebrate preparation, there were no significant differences in the amplitude of the inhibition or its effect on the PIC in the two samples recorded with different electrode solutions (t-test, P always > 0.3). In all cells, voltage clamp was applied using the single-electrode discontinuous mode (Axoclamp 2A amplifier, Axon Instruments; switching frequency of 8–10 kHz; data with inadequate settling of electrode transients were rejected). Low-frequency gain of the feedback loop (-3 dB of 30 Hz) was enhanced 11-fold by an external circuit, resulting in gains that ranged from about 100 to 300 nA/mV (details in Heckman and Lee 2001; Lee and Heckman 1998a).
Generation of synaptic input
Inhibition of MG and LGS motoneurons was generated by 100-Hz stimulation of the CP nerve. The intensity of the stimulation of the CP nerve was varied in different experiments to allow investigation of different levels of inhibition. Intensities in most experiments stayed within the group I range (1.2–1.8 times motor threshold; assessed before paralysis). In one experiment, intensity was increased to 2.4 times threshold. Repeated trials of different intensities within a single cell were not possible because the PIC tended to decay drastically with more than three or four repeats of the I-V function. The CP innervates all the muscles in the anterior compartment of the lower leg as well as on the dorsum of the foot and also includes cutaneous afferents from the dorsum of the foot. However, the low threshold of the stimulation in most experiments likely restricted the input to group I muscle afferents of antagonist muscles and was probably dominated by Ia reciprocal inhibition (see DISCUSSION for possible roles of other afferents). As in our previous study with reciprocal inhibition (Heckman and Binder 1991a), a modest peak in inhibitory effective synaptic current occurred in the first 0.2 s followed by decay to about 70–80% of this peak amplitude by 0.5–0.6 s. Thereafter, the value decayed by no more than 10–15% for the next 3–4 s. Rate of decay after the first 3–4 s was not systematically studied. However, in about one-half the cells, the inhibition underwent a significant decline 5–6 s after stimulus onset. Consequently, all measurements of inhibition on the PIC were confined to the first 3–4 s.
Experimental protocols
A slow (12–16 mV/s) ramp-shaped voltage command was applied to define the current-voltage (I-V) relationship of the cell (see Fig. 1). Voltage returned to baseline at the same rate, but our analysis focused only on the depolarizing or "up" portion of the ramp to minimize the effect of the time-dependent decay in the synaptic inhibition noted above. We have previously shown that this slow rate of change of voltage provides a good estimate of the cell's steady-state I-V function (Lee and Heckman 1998a). Precisely the same ramp-shaped voltage command was then repeated during a steady background of inhibition, with the most depolarized level for the I-V function being reached within 3 s (Fig. 1). This I-V function plus inhibition was followed by a ramp to repeat the control I-V measurement without inhibition to test for consistency.
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Data analysis
Data were only accepted from cells in which the I-V functions given before and after the function with the inhibitory background exhibited consistent behavior (input conductance changing by <20%; baseline holding current by <5 nA; PIC amplitude changing by <30%). The two control I-V functions (before and after I-V function with CP stimulation) were averaged together. The input conductance of each motoneuron was calculated as the slope of a regression line fit to the I-V function over a 5- to 10-mV range that was 10–15 mV subthreshold to onset of the PIC. This subthreshold range was typically centered around about -70 to -60 mV. The amplitude of the PIC in control conditions and during inhibition was assessed after leak subtraction. The regression line for input conductance was extended through the voltage range in which the PIC reached its maximum amplitude. Subtraction of the regression line from the I-V function gave the leak-subtracted PIC. PIC amplitude was calculated for control conditions from the average of the I-V functions taken before and after the inhibitory plus I-V function to control for small fluctuations in resting potential and PIC amplitude. Statistical analyses relied on linear regression and t-test with a P value of 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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As in our previous studies (Lee and Heckman 1998a, 1999a,b, 2000), the I-V functions in motoneurons in this study exhibited a moderately strong PIC in the preparation with the standard state of monoaminergic input to the cord (i.e., the decerebrate; see METHODS). This PIC was usually evident as a strong downward deflection in the current beginning at about -50 mV, as shown by the example in Fig. 1A (trace labeled "control current"). The same voltage command was repeated during a steady background of inhibition (see METHODS). Because of the high-voltage clamp feedback achieved with our techniques (see METHODS), the addition of inhibition caused virtually no change in the voltage clamp control of the region of the cell near the electrode (which was presumed to be in the soma). Actual voltage traces for the currents with and without inhibition are shown in Fig. 1A. There was never more than a 0.5-mV difference at any point along the voltage ramps either with or without inhibition in any of the cells (in this example the maximum difference was 0.3 mV).
If the inhibitory effects were ionotropic (see DISCUSSION) and were confined to the region of the cell under good clamp control, the inhibition would have simply added an offset and an increase in slope to the control current. This is indeed what occurred at hyperpolarized levels (e.g., -60 to -70 mV; see trace labeled "Current during inhibition" in Fig. 1A). However, at more depolarized levels, the added inhibition nearly eliminated the PIC. Figure 2A shows the results for Fig. 1A with the leak subtracted (see METHODS) and current plotted versus voltage. In control conditions, the amplitude of the PIC reached nearly 25 nA (solid trace). The inhibition reduced the PIC to only about 4 nA (dashed trace). This large reduction in PIC amplitude occurred either by ionotropic actions in portions of the cell outside the region of good clamp control (i.e., in the dendrites) or via metabotropic actions (see DISCUSSION).
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We successfully obtained data similar to that shown in Figs. 1A and 2A in 20 cells in the standard monoaminergic state. In this sample, the steady background of inhibition increased the input conductance of the cell by an average of approximately 38%, from 1.10 ± 0.29 to 1.57 ± 0.29 (SD) µS (this difference was statistically significant, with P < 0.0001 using a paired t-test). Figure 3A illustrates that the change in input conductance due to inhibition ranged widely across this sample of cells, allowing us to analyze the relation between the amplitude of the inhibition and its effect on the PIC (see Scaling of PIC amplitude by inhibition).
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Inhibition had a strong impact on the amplitude of the PIC. On average, the inhibition reduced the PIC by approximately 69%, from 18.8 ± 7.7 to 5.9 ± 8.7 nA (this difference was significant; P < 0.0001; paired t-test). Figure 3B shows that there was considerable variation about this average change, ranging from virtually no effect to three cells in which the PIC was not only reduced but was converted to a net outward current (see the three data points below the zero line). An example of a cell in which the inhibition produced a net outward current is shown in Fig. 2B. The scatter in Fig. 3, A and B, did not appear to be due to inter-animal variability, because the scatter within one particularly successful experiment (symbols identified by diamonds with crosses) was similar to that for the whole sample. Neither the amplitude of the PIC in the control state nor the minimal state were significantly correlated with input conductance (P > 0.3), indicating that there were no differences in inhibitory suppression of PIC in motoneurons innervating slow and fast muscle units. The voltage for the peak amplitude of the PIC did not differ with and without inhibition (paired t-test, P > 0.3), indicating that, unlike the case for excitatory input (Lee and Heckman 2000), the inhibitory effect on the PIC was not accompanied by a shift in the range of PIC activation. This lack of effect of inhibition on PIC activation voltage may imply a metabotropic action for inhibition on the PIC (see DISCUSSION).
Dendritic PICs in the minimal state are small and unaffected by inhibition
In the minimal monoaminergic state (in the chloralose anesthetized preparation; see METHODS), an entirely different result was obtained. In the example shown in Fig. 1B, there was very little PIC in the control condition and the inhibitory background acted mainly to increase the offset and slope of the control current. Figure 2C shows the leak-subtracted PICs for control (thin solid trace) and inhibitory conditions (thin dashed line) for the same cell as Fig. 1B. The PIC was small in the control case and the inhibition had little further impact.
In the minimal state, results for seven cells showed that inhibition increased input conductance by approximately 21%, which was not significantly different from the increase in the standard preparation (t-test, P > 0.3; see the triangular symbols in Fig. 3A). Consistent with our previous work (Lee and Heckman 2000), the average control PIC amplitude in the minimal state (3.4 ± 4.2 nA) was only about 20% as large as the PIC amplitude in the standard preparation (compare x axis values for triangles and diamonds in Fig. 3B). Unlike the case for the standard state, inhibition in the minimal state did not reduce PIC amplitude compared with its control value (3.2 ± 2.4 nA for inhibition, P > 0.8, paired t-test).
Note that the average amplitudes of the control PIC in the minimal state (3.4 nA) and the PIC with inhibition in the standard state (5.9 nA) were not significantly different (t-test, P > 0.3). Thus inhibition can have nearly as powerful an effect on PIC amplitude as anesthesia, which acts to suppress monoaminergic input to the cord. In one important respect, the effect of inhibition was stronger than anesthesia because, as noted above, the inhibition converted the PIC in the standard state to a net outward current in several of the standard state cells (again, see the 3 cells below the 0 line in Fig. 3B), whereas the anesthesia in the minimal state produced small but positive PIC amplitudes (triangles in Fig. 3B).
Inhibitory effective synaptic current is enhanced by the PIC
The large suppression of the PIC in the standard preparation constitutes a considerable enhancement in the efficacy of the inhibitory input. This enhancement can be appreciated from measurements of the inhibitory effective synaptic current [IN; i.e., the net inhibitory current reaching the soma (Lee and Heckman 2000), which includes the effect of the dendritic PIC]. The inhibitory IN is the difference between the cell's I-V function with and without the steady inhibitory background, i.e., the difference between the two current traces in Fig. 1, A and B. The inhibitory INs for the data in Fig. 1, A and B, are plotted as a function of voltage in Fig. 4. In the cell in the standard preparation (thick trace), the inhibitory IN undergoes a marked increase at about -45 mV. This enhancement is due to the inhibitory suppression of the PIC. In contrast, in the minimal preparation (thin trace), inhibition smoothly increases with depolarization but lacks the enhancement due to PIC suppression. On average, the peak inhibitory IN in the standard preparation was -24.6 ± 14.5 nA. The inhibitory IN in the minimal preparation usually lacked a clear peak, as in the example in Fig. 4. Its "peak" value was therefore measured at the same voltage as the peak of the leak-subtracted PIC, giving an average value of -8.6 ± 4.0 nA. This nearly threefold average difference in inhibitory IN between the minimal and standard states was statistically significant (P < 0.001, t-test).
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Scaling of PIC amplitude by inhibition
The peak amplitude of the inhibitory IN for the standard state had a nearly 10-fold range of values (-5.6 to -55.0 nA). The reduction in amplitude of the PIC due to inhibition (i.e., the difference in PIC amplitude with and without the background of inhibition) had a similarly wide range (-0.9 to -28.6 nA). One possibility that is that inhibitory IN and the suppression of the PIC simply scaled proportionally with the magnitude of the inhibition applied to each cell. This magnitude was assessed from the change in input conductance generated by the inhibition (see Fig. 3A; note that this measurement is taken at a hyperpolarized levels to avoid the effects of the PIC). Figure 5A shows that peak inhibitory IN was strongly correlated (r = -0.86, P < 0.001) to inhibition magnitude. In part this correlation is to be expected: the greater the inhibition-induced change in slope of the I-V function, the greater the inhibitory current at depolarized levels where IN is assessed (synaptic current being equal to driving force times conductance change). Therefore we also assessed the relation between the inhibition-induced reduction in PIC amplitude and inhibition magnitude. The resulting correlation was moderate (r = -0.66, P < 0.001). However, the reduction in PIC amplitude was also significantly correlated with the amplitude of the control PIC (r = 0.53, P < 0.01). Thus we normalized the reduction in PIC amplitude by dividing it by the control PIC amplitude. Figure 5B shows the relation between the normalized reduction in PIC amplitude and inhibition magnitude. The three cells in which the inhibition converted the PIC to a net outward current (circles) were clear and obvious outliers and were excluded from the regression analysis, resulting in a strong correlation (r = -0.81). As inhibition magnitude increased, the PIC was reduced to near zero amplitude (the line at -1.0 indicates where PIC amplitude was 0). The results of Figs 5, A and B, suggest that inhibition linearly scales the PIC, so that integration of inhibitory input in motoneurons with highly active dendrites may be a linear process. Figure 5B also suggests that cells with strong outward dendritic currents may behave very differently than cells where the PIC dominates.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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,b; Lee and Heckman 1998a, 1999a; Svirskis and Hounsgaard 1998). These dendritic PICs have previously been shown to enhance ionotropic excitatory synaptic input by as much as much as five- to sixfold, depending on the level of monoaminergic input (Lee and Heckman 2000; Lee et al. 2003). The results of this study showed that a steady background of synaptic inhibition markedly suppressed the dendritic PIC. In fact, the effect of inhibitory suppression on the dendritic PIC was as strong as that of anesthesia (which likely suppresses the monoaminergic drive to the spinal cord). Because the dendritic PIC has a major impact on the net input-output gain of the motoneuron, our results suggest that inhibition can be used to counterbalance descending monoaminergic input in controlling the gain of the motoneuron pool. The linear relation between magnitude of the applied inhibition and the reduction in PIC amplitude suggest that integration of inhibitory input to motoneurons with strong PICs may be remarkably linear. Ionotropic versus metabotropic inhibitory effects on the dendritic PIC
The inhibition used in this study was generated by electrical stimulation of a nerve that innervates muscles that are antagonists to those innervated by the motoneurons studied. Because the stimulation intensity was low (usually well within the group I range), this input was likely to have been dominated by Ia afferents acting via Ia inhibitory interneurons. However, there may have been a modest contribution from other pathways as well. Ia afferents connect to nonreciprocal group I interneurons that can inhibit extensor motoneurons (Jankowska 1992). Furthermore, the common peroneal nerve has cutaneous and joint afferents as well as muscle afferents. Our stimulation could have also activated very low threshold cutaneous afferents with possible inhibitory or excitatory actions. However, any excitation via this source must have been small, as inhibition clearly dominated our results. The relative contribution of the ionotropic inhibitory receptors (glycine and GABAA) compared with metabotropic inhibitory receptors (GABAB) for these various inputs is not clear. Reciprocal inhibition has been considered a classic example of a glycinergic input to motoneurons (Jankowska 1992). However, synaptic boutons in the ventral cord co-release glycine and GABA (Jonas et al. 1998) and glycine and GABAA receptors are co-localized on motoneurons (Fyffe 2001; Geiman et al. 2002; Todd et al. 1996). Consequently, the relative importance of glycine and GABA in reciprocal inhibition is uncertain at present (Fyffe 2001). The key question for interpretation of the inhibitory suppression of the PIC is whether any of these inputs produced significant activation of the postsynaptic GABAB receptors. Curtis and Lacey (1998) suggested that inhibitory actions of the GABAB agonist baclofen on monosynaptic reflexes may not be presynaptic (see also Stuart and Redman 1992), but instead occur via a postsynaptic, dendritic location. Baclofen has been shown to suppress the motoneuron PIC in both turtle (Svirskis and Hounsgaard 1998) and rat motoneurons (D. Bennett, personal communication) as well as in spinal interneurons (Derjean et al. 2003). If GABA was released by any of the interneurons activated by the common peroneal nerve, the high-frequency (100 Hz) and long duration of the stimulation could result in significant spillover of GABA onto GABAB receptors.
Thus both ionotropic and metabotropic actions are possible. Our results appear to suggest involvement of both mechanisms. Inhibitory input invariably increased the input conductance of the cell, which presumably reflects the opening of ion channels. However, the lack of effect of inhibition on the voltage at which the peak of the PIC occurred is not consistent with an ionotropic mechanism. A hyperpolarization of unclamped dendrites would be expected to shift this voltage in a depolarized direction during the voltage ramp applied the soma, just as the depolarization of the dendrites by ionotropic excitatory input shifts PIC activation during the voltage ramp at the soma to a more hyperpolarized level (Lee and Heckman 2000). In contrast, changing PIC amplitude without altering its voltage range is exactly what happens when the level of monoaminergic input to the cord is altered (Lee and Heckman 1999a). Thus we have a paradoxical result: a subthreshold, apparently ionotropic effect (change in input conductance), provides an excellent prediction of a suprathreshold, apparently metabotropic effect (suppression of the PIC). Further work with more specific inhibitory inputs (e.g., recurrent inhibition) and with antagonists for metabotropic receptors are needed to help resolve this issue. An interesting question in this regard is the location of the inhibition, proximal or distal. For example, recurrent inhibition from Renshaw cells is mediated by more distal synapses than is reciprocal inhibition (Fyffe 2001). Recurrent inhibition appears to be highly effective in suppressing the acceleration in firing rate generated by activation of the PIC (H. Hultborn, personal communication).
An interesting point was that the PIC was converted to a net outward current in three cells. The reason why this conversion to outward current occurred in these three cells compared with others was not clear, because these three cells were not unusual with respect to their other parameters (magnitudes of inhibition and amplitudes of PICs were within the midrange of values for all cells). Nonetheless, these results make it clear that the balance of inward and outward currents in the dendrites of motoneurons is likely to have a major impact on synaptic integration.
Control of PIC amplitude
Although the relative roles of ionotropic and metabotropic receptors are uncertain, it is very clear that the inhibition from the common peroneal nerve was very effective in reducing the PIC. On average, the inhibition was as potent as anesthesia in suppressing the PIC. When strong enough, the inhibition can reduce the PIC to zero (Fig. 5B), suggesting that inhibition by local spinal circuits can be used to counterbalance the facilitatory actions of descending monoaminergic inputs on PICs. Our results are consistent with those of Bennett et al. (1998), showing that inhibition increased the frequency and current at which PIC-induced acceleration in firing occurred. This increase might simply reflect a smaller PIC, so that the voltage at which PIC becomes large enough to generate an acceleration in firing is depolarized. Overall, inhibitory actions on the PIC should have a strong influence on the gain of motor outflow because the amplitude of the PIC has a large influence on the net input-output gain of the motoneuron (see Lee et al. 2003) and thus also on the gain of the entire motor pool (see Heckman 1994; Heckman and Binder 1991b). This effect of inhibition on gain is in direct contrast to the classical picture of excitatory and inhibitory interactions, which simply produce net shifts in motoneuron frequency-current relations but do not alter the slope (i.e., gain) (reviewed in Powers and Binder 2001). It should be noted, however, that PIC-dependent gain changes likely only apply to inputs with physiological rates of change (e.g., time courses of 50–100 ms or longer). Transient inputs such as the H-reflex generated by single electrical shocks may not induce strong activation of the PIC. Overall, two points emerge from the present results on inhibition and the previous studies of excitatory inputs (Bennett et al. 1998; Delgado-Lezama et al. 1999; Lee and Heckman 2000; Lee et al. 2003; Prather et al. 2001). The dendritic PIC totally dominates synaptic integration for excitatory inputs and the degree of this effect can be controlled both by descending monoaminergic input and by local inhibitory input within the spinal cord.
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DISCLOSURES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: C. J. Heckman, Physiology, M211, Northwestern Univ. School of Medicine, 303 E. Chicago Ave., Chicago, IL 60611 (E-mail: c-heckman{at}northwestern.edu).
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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Baldissera F, Hultborn H, and Illert M. Integration in spinal neuronal systems. In: Handbook of Physiology. The Nervous System. Motor Control, edited by Brooks VB. Bethesda, MD: American Physiological Society, 1981, p. 509-595.
Bennett DJ, Hultborn H, Fedirchuk B, and Gorassini M. Synaptic activation of plateaus in hindlimb motoneurons of decerebrate cats. J Neurophysiol 80: 2023-2037, 1998.
Bennett DJ, Li Y, and Siu M. Plateau potentials in sacrocaudal motoneurons of chronic spinal rats, recorded in vitro. J Neurophysiol 86: 1955-1971, 2001.
Carlin KP, Jiang Z, and Brownstone RM. Characterization of calcium currents in functionally mature mouse spinal motoneurons. Eur J Neurosci 12: 1624-1634, 2000a.[ISI][Medline]
Carlin KP, Jones KE, Jiang Z, Jordan LM, and Brownstone RM. Dendritic L-type calcium currents in mouse spinal motoneurons: implications for bistability. Eur J Neurosci 12: 1635-1646, 2000b.[ISI][Medline]
Coombs JS, Eccles JC, and Fatt P. The specific ionic conductances and the ionic movements across the motoneuronal membrane that produce the inhibitory post-synaptic potential. J Physiol 130: 326-373, 1955.
Curtis DR and Lacey G. Prolonged GABA(B) receptor-mediated synaptic inhibition in the cat spinal cord: an in vivo study. Exp Brain Res 121: 319-333, 1998.[ISI][Medline]
Delgado-Lezama R, Perrier JF, and Hounsgaard J. Local facilitation of plateau potentials in dendrites of turtle motoneurones by synaptic activation of metabotropic receptors. J Physiol 515: 203-207, 1999.
Derjean D, Bertrand S, Le Masson G, Landry M, Morisset V, and Nagy F. Dynamic balance of metabotropic inputs causes dorsal horn neurons to switch functional states. Nat Neurosci 6: 274-281, 2003.[ISI][Medline]
Fyffe REW. Spinal motoneurons: synaptic inputs and receptor organization. In: Motor Biology of the Spinal Cord, edited by Cope TC. London: CRC Press, 2001, p. 21-46.
Geiman EJ, Zheng W, Fritschy JM, and Alvarez FJ. Glycine and GABA(A) receptor subunits on Renshaw cells: relationship with presynaptic neurotransmitters and postsynaptic gephyrin clusters. J Comp Neurol 444: 275-289, 2002.[ISI][Medline]
Hausser M, Spruston N, and Stuart GJ. Diversity and dynamics of dendritic signaling. Science 290: 739-744, 2000.
Heckman CJ. Computer simulations of the effects of different synaptic input systems on the steady-state input-output structure of the motoneuron pool. J Neurophysiol 71: 1727-1739, 1994.
Heckman CJ and Binder MD. Analysis of Ia-inhibitory synaptic input to cat spinal motoneurons evoked by vibration of antagonist muscles. J Neurophysiol 66: 1888-1893, 1991a.
Heckman CJ and Binder MD. Computer simulation of the steady-state input-output function of the cat medial gastrocnemius motoneuron pool. J Neurophysiol 65: 952-967, 1991b.
Heckman CJ and Lee RH. Advances in measuring active dendritic currents in spinal motoneurons in vivo. In: Motor Neurobiology of the Spinal Cord, edited by Cope TC. London: CRC, 2001, p. 89-106.
Heckman CJ, Miller JF, Munson M, Paul KD, and Rymer WZ. Reduction in postsynaptic inhibition during maintained electrical stimulation of different nerves in the cat hindlimb. J Neurophysiol 71: 2281-2293, 1994.
Holdefer RN and Miller LE. Primary motor cortical neurons encode functional muscle synergies. Exp Brain Res 146: 233-243, 2002.[ISI][Medline]
Hornby TG, McDonagh JC, Reinking RM, and Stuart DG. Effects of excitatory modulation on intrinsic properties of turtle motoneurons. J Neurophysiol 88: 86-97, 2002.
Hounsgaard J, Hultborn H, Jespersen B, and Kiehn O. Bistability of alpha-motoneurones in the decerebrate cat and in the acute spinal cat after intravenous 5-hydroxytryptophan. J Physiol 405: 345-367, 1988.
Hounsgaard J and Kiehn O. Ca++ dependent bistability induced by serotonin in spinal motoneurons. Exp Brain Res 57: 422-425, 1985.[ISI][Medline]
Hounsgaard J and Kiehn O. Serotonin-induced bistability of turtle motoneurones caused by a nifedipine-sensitive calcium plateau potential. J Physiol 414: 265-282, 1989.
Hounsgaard J and Kiehn O. Calcium spikes and calcium plateaux evoked by differential polarization in dendrites of turtle motoneurones in vitro. J Physiol 468: 245-259, 1993.
Jankowska E. Interneuronal relay in spinal pathways from proprioceptors. Prog Neurobiol 38: 335-378, 1992.[ISI][Medline]
Jonas P, Bischofberger J, and Sandkuhler J. Corelease of two fast neurotransmitters at a central synapse. Science 281: 419-424, 1998.
Lee RH and Heckman CJ. Bistability in spinal motoneurons in vivo: systematic variations in persistent inward currents. J Neurophysiol 80: 583-593, 1998a.
Lee RH and Heckman CJ. Bistability in spinal motoneurons in vivo: systematic variations in rhythmic firing patterns. J Neurophysiol 80: 572-582, 1998b.
Lee RH and Heckman CJ. Enhancement of bistability in spinal motoneurons in vivo by the noradrenergic alpha1 agonist methoxamine. J Neurophysiol 81: 2164-2174, 1999a.
Lee RH and Heckman CJ. Paradoxical effect of QX-314 on persistent inward currents and bistable behavior in spinal motoneurons in vivo. J Neurophysiol 82: 2518-2527, 1999b.
Lee RH and Heckman CJ. Adjustable amplification of synaptic input in the dendrites of spinal motoneurons in vivo. J Neurosci 20: 6734-6740, 2000.
Lee RH, Kuo JJ, Jiang MC, and Heckman CJ. Influence of active dendritic currents on input-output processing in spinal motoneurons in vivo. J Neurophysiol 89: 27-39, 2003.
Morrow MM and Miller LE. Prediction of muscle activity by populations of sequentially recorded primary motor cortex neurons. J Neurophysiol 89: 2279-2288, 2003.
Perrier JF and Hounsgaard J. 5-HT(2) Receptors promote plateau potentials in turtle spinal motoneurons by facilitating an L-type calcium current. J Neurophysiol 89: 954-959, 2003.
Powers RK and Binder MD. Summation of effective synaptic currents and firing rate modulation in cat spinal motoneurons. J Neurophysiol 83: 483-500, 2000.
Powers RK and Binder MD. Input-output functions of mammalian motoneurons. Rev Physiol Biochem Pharmacol 143: 137-263, 2001.[ISI][Medline]
Prather JF, Powers RK, and Cope TC. Amplification and linear summation of synaptic effects on motoneuron firing rate. J Neurophysiol 85: 43-53, 2001.
Schwindt PC and Crill WE. Role of a persistent inward current in motoneuron bursting during spinal seizures. J Neurophysiol 43: 1296-1318, 1980.
Steriade M. Impact of network activities on neuronal properties in corticothalamic systems. J Neurophysiol 86: 1-39, 2001.
Stuart GJ and Redman SJ. The role of GABAA and GABAB receptors in presynaptic inhibition of Ia EPSPs in cat spinal motoneurones. J Physiol 447: 675-692, 1992.
Svirskis G and Hounsgaard J. Transmitter regulation of plateau properties in turtle motoneurons. J Neurophysiol 79: 45-50, 1998.
Todd AJ, Watt C, Spike RC, and Sieghart W. Colocalization of GABA, glycine, and their receptors at synapses in the rat spinal cord. J Neurosci 16: 974-982, 1996.
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