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1Centre de Recherche en Sciences Neurologiques and 2Faculté de Médecine Dentaire, Université de Montreal, Montreal, Quebec, Canada; and 3Faculty of Dentistry, McGill University, Montreal, Quebec, Canada
Submitted 5 April 2006; accepted in final form 9 August 2006
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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), the core of which lies between the rostral borders of the Vth and VIIth cranial motor nuclei (Kogo et al. 1996; Nakamura et al. 1999; Tanaka et al. 1999). Several models of the CPG have been proposed (Lund et al. 1998; Nakamura and Katakura 1995; Nozaki et al. 1986), all of which include medial reticular nuclei and last-order interneurons in the lateral reticular formation and spinal trigeminal nucleus.
The trigeminal principal sensory nucleus (NVsnpr) was long regarded as a relay station to thalamus and other regions of the somatosensory system. However, it also contains neurons that project to the motor nuclei that control feeding, the Vth, VIIth, and XIIth cranial motor nuclei (Kolta et al. 2000; Li et al. 1993; Pinganaud et al. 1999; Travers and Norgren 1983; Yoshida et al. 1998). It was recently shown in rabbits that many neurons in the dorso-anterior region of NVsnpr burst rhythmically during fictive mastication (Tsuboi et al. 2003). The same region also expressed c-Fos-like protein, a functional marker of activity, after repeated episodes of fictive mastication (Athanassiadis et al. 2005a). Furthermore, Sandler et al. (1998) have shown that about one-half of NVsnpr neurons recorded in vitro in slices of the gerbil brain stem have plateau properties that allow them to transform a depolarizing input into bursts. Such behavior is more compatible with a role in rhythm generation than with the faithful transmission of sensory information.
The aim of this study was to characterize the firing properties of NVsnpr neurons during postnatal development in the rat. In this species, the transition in ingestive behavior from suckling to mastication occurs at the end of the second postnatal week. The first masticatory movements appear around postnatal day 12, and the adult pattern is attained by 18–21 days of age (Westneat and Hall 1992). We used a brain stem slice preparation to show that the ability of NVsnpr neurons to generate bursts of action potentials during depolarization parallels the maturation of the masticatory motor pattern and that an age-related increase of a persistent sodium current underlies the emergence of rhythmical bursting. We also provide evidence that the extracellular concentration of calcium ([Ca2+]E) could be a determining factor in the initiation and modulation of recurrent bursts. A preliminary report of these findings have been published in abstract form (Brocard et al. 2004).
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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All surgical and experimental procedures conformed to guidelines of the Canadian Institutes of Health Research and were approved by the University Animal Care and Use Committee. Experiments were performed on NVsnpr neurons in slices obtained from 5- to 17-day-old Sprague-Dawley rats. Rats were anesthetized with isoflurane (Abott Laboratories, Saint-Laurent, Quebec, Canada) inhalation and decapitated. The brain was quickly taken out and placed in cold (4°C) sucrose-based artificial cerebrospinal fluid (ACSF, composition in mM: 225 sucrose, 3 KCl, 1.25 KH2PO4, 4 MgSO4, 0.2 CaCl2, 20 NaHCO3, and 10 D-glucose) bubbled with 95% O2-5% CO2, pH 7.4. In the same medium, transverse slices (300 µm thick) through the NVsnpr were prepared using a Vibratome (VT1000 S, Leica). Slices were incubated at room temperature (21–24°C) in the holding chamber filled with normal ACSF (in mM: 125 NaCl, 3 KCl, 1.25 KH2PO4, 1.3 MgSO4, 2.4 CaCl2, 26 NaHCO3, and 25 D-glucose). The slices were transferred to an immersion slice chamber and perfused with normal ACSF at a rate of 
2 ml/min. The slices were allowed 
1 h before the experiment was started.
Electrophysiological recordings
Neurons were visualized using a fixed stage microscope (Eclipse E600FN, Nikon) coupled with a 40x water immersion lens. The image was enhanced with an infrared-sensitive CCD camera and displayed on a video monitor. Whole cell patch-clamp recordings in current-clamp mode were performed from visually identified cells located in the dorsal part of the NVsnpr using an axoclamp 2B amplifier (Axon Instruments, Foster City, CA). Patch electrodes (6–9 M
) were pulled from borosilicate glass capillaries (1.5 mm OD, 1.12 mm ID; World Precision Instruments, Sarasota, FL) on a Sutter P-97 puller (Sutter Instruments, Novato, CA) and filled with a K+-gluconate based solution (in mM: 140 K+-gluconate, 5 NaCl, 2 MgCl2, 10 HEPES, 0.5 EGTA, 2 ATP, and 0.4 GTP).
Drug application
All drugs were purchased from Sigma-Aldrich (Oakville, Ontario, Canada), kept as a concentrated stock solution, and diluted in the bath perfusing ACSF to their final concentration using a syringe pump. The following pharmacological agents were used: TTX (1 µM); tetraethylammonium chloride (TEA, 10 mM); riluzole (20 µM); apamin (100 nM); charybdotoxin (100 nM); and ZD 7288 (10–20 µM). In the experiments examining the role of calcium in burst generation, the amount of CaCl2 removed from the normal ACSF was replaced by an equivalent amount of MgCl2.
Data acquisition and analysis
Electrophysiological data were acquired through a Digidata 1322A interface and analyzed with Clampex 9 software (Axon Instruments). Passive membranes properties of cells were measured by injecting small hyperpolarizing currents pulses to avoid the activation of voltage-sensitive currents. Data are presented in the text and in the tables as mean ± SE. The input resistance is measured by the slope of the linear portion of the I-V relationship. The membrane time constant was determined by fitting an exponential function to the rising phase of the voltage trace used for determining the input resistance. In some cells, there was evidence of inward rectification ("sag") during strong hyperpolarization. The size of the sag was expressed as the ratio of the peak negative voltage to the steady-state membrane potential. The rheobase was defined as the minimum current intensity necessary to fire the cell. Single spike analysis was performed on the first spike elicited near the rheobase. Peak spike amplitude was measured from the threshold potential, and spike duration was defined as the time to fall to half-maximum peak. To study the afterdepolarizations (ADPs) and the afterhyperpolarizations (AHPs), single spikes were evoked by brief intracellular pulses at holding potential. The peak amplitude and duration (to one-half the peak height) of ADPs and AHPs were measured from the same holding potential (–50 mV for the AHP and –70 mV for the ADP). Firing patterns were studied with 1-s-long depolarizing current pulses of varying amplitudes. The average instantaneous firing frequency during the last 500 ms of the 1-s pulse was defined as the steady-state firing frequency. We used one-way ANOVA for age-dependent comparisons with two posttests: Tukey's test was used to compare the means of all pairs of age groups, and the "linear trend post test" was used to evaluate the effect of age on other variables. The pharmacological effects of drugs were evaluated using Student's paired t-test. Values of P < 0.05 were considered significant (GraphPad Prism 4.0, GraphPad Software, San Diego, CA).
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RESULTS |
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NVsnpr neurons displayed four firing patterns
The firing patterns of neurons recorded in normal ACSF were classified as adaptive (25.6%, n = 53), tonic (59.9%, n = 124), or bursting (14.5%, n = 30). Adaptive neurons generated a train of spikes in response to current injection near rheobase (Fig. 1A, bottom), but further depolarization caused a progressive change in spike form; amplitude fell and duration increased (Fig. 1A, top) until sustained depolarization without wavelets remained. Tonic neurons were characterized by a sustained discharge of single spikes that persisted for the entire duration of the depolarization (Fig. 1B), even with large depolarizing current injections. The spike shape remained nearly constant throughout the firing period. Bursting firing patterns were divided into two subtypes: burst-and-tonic (Fig. 1C1) and repetitive bursting (Fig. 1D1). In all bursting cells, an initial burst was elicited at the onset of the current injection (Fig. 1, C2 and D2) followed by either a regular spike train (burst-and-tonic spiking, n = 23) or recurrent bursts (repetitive bursting, n = 7). Adaptive or tonic cells could not be converted into bursting cells by large changes in the holding potential.
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To determine whether these firing patterns constitute distinct neuronal populations in the adult NVsnpr nucleus or represent successive stages in the development of the firing pattern, we compared the proportions of the four groups of cells in animals divided into three age groups: P5–P8 (n = 68), P9–P12 (n = 68), and P13–P17 (n = 73). These three age groups represent key periods of development in the rat in which the pattern of mastication is absent, emerging or of adult form, respectively (Westneat and Hall 1992).
In the youngest age group (P5–P8), only adaptive and tonic neurons were encountered in the proportion of one third and two thirds, respectively (Fig. 2A). From P9 to P12, when the first bursting cells were detected, tonic cells were dominant (85% of the total). In the more mature animals (P13–P17), the proportion of bursting cells increased to nearly 40% of the total, whereas adaptive neurons were very rare (1.4%). After P12, the incidence of bursting cells increased rapidly progressing from 6% at P12, through 25% at P13, to 44% at P14 (Fig. 2B), after which it remained nearly constant. Note that all repetitive bursting neurons were observed in the P13–P17 age group.
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For neurons exhibiting repetitive bursting (n = 7), the bursting frequency increased linearly with current intensity (Fig. 2, D1 and D2), and the F-I relationship was fitted with a linear regression function (Fig. 2D3; mean slope: 113 ± 33 Hz/nA, mean r = 0.987). The mean burst frequency ranged from 3 ± 1 Hz with near-threshold depolarizations to 9 ± 2 Hz with larger currents. The firing pattern switched from recurrent bursting to burst and tonic spiking with further depolarization (see Fig. 8C).
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Age-related changes in electrophysiological properties
An analysis of the voltage responses to hyperpolarizing currents (Fig. 3A) revealed that input resistance and membrane time constant were significantly reduced from P5 to P17 by 40% (Fig. 3B1; P < 0.001, 1-way ANOVA) and 70% (Fig. 3B2; P < 0.0001, 1-way ANOVA), respectively. The largest reduction of the membrane time constant occurred during the second postnatal week. In contrast, the resting membrane potential did not change with age (Fig. 3B3; P = 0.213, 1-way ANOVA). In >90% of the cells, application of large hyperpolarizing current pulse resulted in the appearance of an inward rectifying response (see arrowheads in Fig. 3A). However, the magnitude of this rectification increased twofold over the age range studied (Fig. 3B4; P < 0.0001, 1-way ANOVA).
When depolarized to threshold, NVsnpr neurons produced a single spike (Fig. 4A1). Mean threshold became more negative with age, going from –36 to –43 mV between P5 and P17 (P < 0.01, linear regression r = –0.73). The spike amplitude was unchanged (Fig. 4A2; P = 0.665, 1-way ANOVA) but its duration was shortened by 75% (Fig. 4A3; P < 0.0001, 1-way ANOVA), with the largest reduction occurring during the first 11 postnatal days.
Spikes were followed by a prolonged AHP that also changed with age (Fig. 4B1). Its amplitude increased by 55% (Fig. 4B2; P < 0.001, 1-way ANOVA) between P5 and P17, whereas duration decreased by 65% (Fig. 4B3; P < 0.001, 1-way ANOVA). The decrease in duration mainly occurred between P9 and P14 (P < 0.01; 1-way ANOVA, Tukey post hoc).
An ADP (Fig. 4C1, arrowheads) was observed in a subpopulation of NVsnpr neurons that grew in size during postnatal development. Approximately 30% of neurons exhibited an ADP at P6–P7, but this increased to 70% at P12–P13 and to 87% at P16–P17 (Fig. 4C3). During the same period, ADP amplitude decreased significantly by about 35% (see linear regression in Fig. 4C2; P < 0.05, r = –0.63).
ADP and sag are known to play an important role in activation and maintenance of regenerative bursting in other neurons (Azouz et al. 1996; Pape 1996). Past studies suggest that voltage-dependent Ca2+ currents contribute to the ADP (Kobayashi et al. 1997; Wong and Prince 1981) and that the mixed cation conductance Ih underlies the sag (Pape 1996). We sought to determine if the development of these two specific membrane conductances is related to the emergence of burst firing.
Ionic basis of recurrent bursts
We first examined the effect of decreasing the external Ca2+ concentration ([Ca2+]E) on the firing properties of 19 NVsnpr neurons recorded from P12 to P16. Although spike amplitude and duration did not change, the amplitude of the ADP was significantly increased (Fig. 5A1; Table 2; P < 0.0001, paired t-test), whereas AHP amplitude was significantly reduced (Fig. 5A2; Table 2; P < 0.0001, paired t-test) in Ca2+-free medium. Occasionally, enhancement of the ADP reached threshold and triggered some spikes (Fig. 5A1, right). These reversible changes occurred without significant alteration in input resistance and resting membrane potential (Table 2). However, the most obvious effect of removing Ca2+ was that 80% of tonic and burst and tonic spiking cells recorded in normal ACSF were converted to repetitive bursting in Ca2+-free ACSF (Fig. 5B).
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Persistence of bursting activity in Ca2+-free ACSF suggests that 1) entry of Ca2+ is not essential for the generation of repetitive bursts and 2) that the ability to generate bursts results from intrinsic voltage-dependent properties of the membrane because synaptic transmission is abolished. Furthermore, the increase in the incidence of bursting under Ca2+-free ACSF is likely to be linked to the reciprocal changes in ADP and AHP amplitudes. A reduction of the AHP would allow a larger ADP to occur, which could lead to bursting.
Ca2+-activated K+ current
As in most neurons, Ca2+ activated K+ current probably underlie the AHP in NVsnpr neurons and it is not surprising that elimination of Ca2+ reduces AHP amplitude. The reduction of the AHP amplitude in Ca2+-free saline could constitute a critical factor in the emergence of bursting activities. To test this hypothesis, the effect of specific IKCa blockers on burst generation were studied in older rats (P14–P17). In standard solution, apamin (100 nM), a selective blocker of the small conductance Ca2+-activated K+ (SK) channels, depressed the amplitude of the AHPs (from 3.2 ± 0.4 to 2.1 ± 0.7 mV, n = 4) but did not generate recurrent bursts in response to steady depolarizing current (Fig. 6 A, right). The latter finding did not result from the incapacity of the cells to fire in burst because they generated bursting activity in Ca2+-free saline (Fig. 6A, left). Frequency and duration of burst during Ca2+-free were unchanged by bath application of apamin. On the other hand, when charybdotoxin (100 nM), a selective blocker of the big conductance Ca2+-activated K+ (BK) channels, was bath-applied in standard solution, not only AHP amplitude decreased (from 5.3 ± 1.9 to 1.1 ± 1.1 mV, n = 3), as with apamin, but when depolarized to threshold, NVsnpr neurons produced doublets of spikes rather than single spikes as in control (n = 3; Fig. 6B2), probably caused by enhancement of the ADP. Nevertheless, these cells did not show robust recurrent bursting as observed in calcium-free ACSF (Fig. 6B, left), but they only discharged a doublet or a triplet of spikes at the onset of long depolarizing pulses in two cases while recurrent doublets under steady-state depolarization was only observed in one case. As for apamin, frequency and duration of burst during Ca2+-free were unchanged by bath application of charybdotoxin. Similarly, bath application of TEA (10 mM), a K+ channels blocker, did not prevent bursting in Ca2+-free saline, but it did reduce burst frequency and greatly increase their duration (Fig. 7A; n = 5). Together, these results suggest that TEA-sensitive K+ currents shape the bursting activity, likely by controlling the repolarization.
Ih current
The evidence that the depolarizing sag increases with age led us to assess the role that Ih might play in the emergence of bursting activity. ZD 7288 (10–20 µM), applied at a concentration that blocks the sag in older animals (P14–P17; Fig. 7B, bottom left), did not prevent bursting in Ca2+-free ACSF; instead, it caused an increase of 158 ± 64% in burst frequency (Fig. 7B, bottom right; n = 4). This increase in frequency was associated with a decrease in amplitude (from 5.2 ± 0.7 to 2.5 ± 0.9 mV) and duration (from 2.3 ± 1.6 to 1.7 ± 1.2 s) of the postburst hyperpolarization. Once again, these results suggest that Ih affects the burst characteristics but is not essential for burst generation.
Persistent sodium currents
We then examined the role of sodium influx in burst generation, first by using TTX (1 µM), a specific sodium channel blocker, in Ca2+-free conditions. A brief bath application of TTX (5–10 min) reversibly inhibited the bursting activity of the four neurons tested without abolishing spikes (Fig. 8A). However, continued superfusion of TTX led to a disappearance of spikes (data not shown). These results suggested involvement of a persistent sodium current (INaP) in burst generation. This hypothesis was supported by the observation that riluzole (20 µM), a drug that interferes with INaP, disrupted the generation of repetitive bursts (Fig. 8B, n = 3) without blocking spikes. This effect did not reverse even after 1–2 h of washout. These results confirm a critical role for INaP in burst generation.
Age-related changes in INaP-dependent bursting activity
To define the contribution of INaP in the development of bursting, we compared the effects of injected current on neurons from animals of different ages in absence of [Ca2+]E and in presence of TEA. In two of seven neurons tested in young animals (P5–P7), a brief threshold depolarizing pulse evoked a compound response consisting of a fast spike followed by a train of spikes superimposed on a plateau potential that outlasted the current pulse (Fig. 8C; P6). Addition of TTX to the medium abolished the plateau potential and the spike train before the initial spike was affected (Fig. 8C, insets), indicating again that the plateau depolarization is INaP dependent. In the five other cells recorded, the fast spike was not followed by the plateau potential (data not shown). The incidence of INaP-dependent plateau potentials increased with age and was observed in 80 and 100% of neurons recorded at P9–P12 (Fig. 8C; P11, n = 5) and P14–P17 (Fig. 8C; P16, n = 5), respectively. The mean duration of the plateau potential was 0.3 ± 0.2 s at P5–P7, was unchanged at P9–P12 (0.4 ± 0.1 s), but tended to be longer at P14–P17 (2.5 ± 0.8 s; P = 0.07, 1-way ANOVA). In contrast, peak amplitude tended to increase from P6 to P9–P12 (26.6 ± 3.4 and 38.1 ± 4.9 mV, respectively) but remained stable thereafter (41.7 ± 1.7 mV at P14–P17; P = 0.07, 1-way ANOVA). As a consequence of the increase in peak amplitude, spikes were totally inactivated during plateau potentials. Interestingly, cells that did not generate bursts in Ca2+-free ACSF did not display INaP-dependent plateau potentials (data not shown).
The above results suggest that the emergence of repetitive bursting depends on a concomitant increase in amplitude and duration of the INaP-dependent depolarization.
Characteristics of bursting activity
[CA2+]E DEPENDENCY FOR GENERATION OF BURSTING. An intriguing question is the relationship between INaP and the [Ca2+]E. The proportion of repetitively bursting cells was small (3.4%, n = 7/207) in normal ACSF, but lowering [Ca2+]E increased their incidence. To determine the [Ca2+]E threshold below which most of NVsnpr neurons fire in bursts, the effect of a gradual reduction of [Ca2+]E on firing patterns was studied (Fig. 9A) in six tonic neurons from animals older than P14. Lowering [Ca2+]E from 2.4 to 1.2 mM did not change the tonic firing pattern, but a further reduction to 0.6 mM induced bursting in five of the six cells. Subsequent exposure to Ca2+-free ACSF, increased the amplitude and duration of the plateau potential, but reduced burst frequency (Fig. 9A, right). Lowering [Ca2+]E, also caused a concentration-dependent increase in the amplitude of the ADP (Fig. 5A1) and in the duration of the INaP-dependent plateau potential elicited by a brief depolarizing stimulus (Fig. 9B). Thus the increase in duration of the INaP-dependent plateau observed in low-[Ca2+]E seems to be responsible for the switch from tonic firing to bursting.
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We assessed the voltage dependency of bursting in Ca2+-free ACSF by sustained injection of currents in six neurons from animals older than P14 (Fig. 9C). Bursting was observed at membrane potentials between –59 ± 2 and –41 ± 3 mV. Below –60 mV, most cells were silent; above –41 mV, most were tonically active. The duration and area of the INaP-dependent plateau potential tested in absence of [Ca2+]E and in presence of TEA (n = 5) were also voltage dependent (Fig. 9, D1 and D2). The area of the plateau potential was considerably reduced in a linear manner with hyperpolarized membrane potential (Fig. 9, D1 and D2, circles). This effect was a direct function of the plateau duration that proportionally decreased with holding membrane potential (Fig. 9D2, triangles). No relationship was observed with the plateau amplitude (Fig. 9D2, squares).
Together, these results strongly suggest that the bursts are INaP dependent and are modulated by [Ca2+]E and by the transmembrane potential.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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), but it becomes common later in development. Development of membrane properties
It is likely that the decrease of input resistance and membrane time constant of NVsnpr neurons after birth is caused by a gradual increase in their cell size (Jacquin et al. 1996; Miller and al-Ghoul 1993), accompanied by an increase in density of ionic channels (Cameron et al. 2000). Unlike genioglossal motoneurons (Nunez-Abades et al. 2000), the decrease in input resistance does not result from an increase in synaptic inputs because it is still observed under conditions that prevent synaptic transmission (in Ca2+-free medium).
Surprisingly, there was a decrease of rheobase, which shows that NVsnpr neurons become more excitable with age, even though input resistance and membrane time constant decrease. The negative shift in action potential threshold probably reflects a decrease in activation threshold of Na+ channels (Gao and Ziskind-Conhaim 1998). This and the increase of the INaP during development could contribute to the age-related decrease of the rheobase. Accompanying these changes in excitability, action potential duration shortened as depolarization and repolarization both become faster. This is probably caused by increases in the density of Na+ and K+ channels during development that have been found elsewhere in the rat nervous system (Gao and Ziskind-Conhaim 1998; Martin-Caraballo and Greer 2000; Nerbonne and Gurney 1989).
Both hyperpolarizing (AHP) and depolarizing (ADP) afterpotentials were seen, and the proportion of cells showing an ADP increased with age. Although the ADP is Ca2+ dependent in a variety of vertebrate neurons, it seems to be independent of Ca2+ influx in NVsnpr neurons because removal of extracellular Ca2+ did not block the ADP; instead, it increased its amplitude. Our results suggest that INaP is necessary for the expression of the ADP in these cells because it is abolished by TTX at doses that do not affect the action potential. These results are congruent with what has been found in adult CA1 pyramidal neurons (Azouz et al. 1996; Su et al. 2001). Despite the increase in frequency of ADP, its amplitude decreases after birth, which may be a reflection of increases of K+ currents. This assumption is supported by the recent finding that, in CA1 pyramidal cells, selective blockade of a noninactivating K+ current (M current) increases the amplitude of the ADP (Yue and Yaari 2004). The AHP is dominated by Ca2+-dependent K+ conductances and is abolished by removal of Ca2+ from the medium. We did not study the mechanisms underlying the age-related decrease in AHP duration, but the shorter membrane time constant, associated with larger inward rectification current observed in older animals, may produce a faster recovery from the AHP. The developmental increase in the inward rectification current likely reflects an increase in the density of Ih channels, as has been shown in hypoglossal motoneurons (Bayliss et al. 1994) and mesencephalic trigeminal neurons (Tanaka et al. 2003).
In general, the age-related changes in membrane properties observed in dorsal NVsnpr neurons are similar to those of the "barrelette" region of NVsnpr (Lo and Erzurumlu 2001), the spinal trigeminal nucleus (Guido et al. 1998), and other brain stem regions of the rat (Bao et al. 1995; Berger et al. 1996; Nguyen et al. 2004; Nunez-Abades et al. 1993; Tanaka et al. 2003; Tsuzuki et al. 1995), suggesting that the maturation of many brain stem neurons follows a common time-course.
Development of firing patterns
We classified NVsnpr neurons into three types, based on the firing pattern during depolarization: adaptive, tonic, and bursting. These patterns were strongly linked to some membrane properties. Bursting cells had a lower input resistance than adaptive cells, suggesting that they had a greater membrane area. This assumption is in agreement with previous morphological studies that reported that bursting cells in the neocortex have larger somata than adaptive- or regular-spiking cells (Chagnac-Amitai et al. 1990; Faulkner and Brown 1999; Kasper et al. 1994a; Larkman and Mason 1990; Schubert et al. 2001; Schwindt et al. 1997; Tseng and Prince 1993; Yang et al. 1996). Bursting neurons also exhibit a prominent ADP and have a lower action potential threshold. These characteristics probably reflect differences in sodium channels properties, densities, and/or location between bursting and nonbursting cells. The greater excitability of bursting cells may result from a prominent INaP. Because this current is activated below the action potential threshold (Crill 1996), it will boost depolarization toward the spike threshold. Previous work has shown that firing patterns usually change during postnatal development. Immature cells tend to adapt rapidly, and the ability to fire repetitively usually appears during the first 2 postnatal wk. This change probably results from an increase in the voltage-gated K+ channels that are responsible for repolarization. We found that duration of the action potentials increased with each firing in adaptive neurons during sustained depolarization, which is consistent with the suggestion that a reduction in the inactivation time of Na+ channels is also required for repetitive firing (Wang et al. 1997). The age-related decrease in AHP duration may also facilitate sustained firing and probably correlates with the steeper F-I slopes of mature neurons. However, the most significant developmental change in firing patterns is the emergence of bursting ability. As in the neocortex (Franceschetti et al. 1993, 1998; Kasper et al. 1994b; Kriegstein et al. 1987) and the ventrobasal thalamus (Perez Velazquez and Carlen 1996), burst firing did not appear until the end of the second postnatal week.
Ionic mechanisms underlying the emergence of bursting cells
Bursting was maintained and even enhanced under conditions that reduce synaptic transmission, suggesting that it is an intrinsic property of NVsnpr neurons. It was first shown by Sandler et al. (1998) that NVsnpr neurons have the intrinsic ability to burst. The evidence suggests that NVsnpr bursts are INaP-dependent, as they are in the pre-Bötzinger complex (Butera et al. 1999; Del Negro et al. 2002), cultured spinal cord (Darbon et al. 2004), hippocampus (Jinno et al. 2003; Su et al. 2001), subthalamic nucleus (Beurrier et al. 2000), neocortex (Brumberg et al. 2000; Guatteo et al. 1996; Nishimura et al. 2001), and trigeminal mesencephalic nucleus (Wu et al. 2005). Riluzole, which suppresses INaP predominately (Urbani and Belluzzi 2000; Wu et al. 2005), and TTX inhibited bursts without changing the spike. The ability to burst developed in parallel with a TTX-sensitive plateau potential, and both plateau potentials and bursts were only seen between the activation and steady-state inactivation voltages typical of INaP (Crill 1996). Several of our observations indicate that the ADP is also INaP-dependent and must play an important role in the generation of burst firing. It is prominent in bursting neurons, and its amplitude increases under conditions that facilitate bursting.
Voltage-activated K+ conductances seem to be important for burst termination because burst duration increased substantially under TEA. Big Ca2+-activated K+ conductances may counteract depolarization and indirectly play a role in limiting burst duration because their blockade enhanced the ADP and promoted firing of a second or third spike but was insufficient to induce repetitive bursting in presence of Ca2+. No obvious role could be attributed to small Ca2+-activated K+ conductances. Other factors, such as the slow inactivation of INaP (Del Negro et al. 2002; Ellerkmann et al. 2001; Fleidervish et al. 1996) and the hyperpolarizing action the Na+/K+ electrogenic pump (Ballerini et al. 1997; Darbon et al. 2003) may also contribute to burst termination. Neither was burst generation dependent on Ca2+ currents at all ages examined. This contrasts with the findings of Chen et al. (2005), who reported that bursting in developing CA1 pyramidal neurons is transitionally dependent on calcium currents. With the use of focal application of calcium and sodium channels antagonists, they found that, in animals younger than 25 days, bursting rely on activation of somatic persistent voltage-gated Na+ channels and activation of T/R- and L-type voltage gated Ca2+ channels on the distal dendrites.
Furthermore, repetitive bursting activity was rare at [Ca2+]E > 1.2 mM, and this probably explains the small proportion of repetitive bursting in our standard ACSF (2.4 mM). However, a [Ca2+]E of 2.4 mM may be abnormally high. Under resting conditions, the [Ca2+]E in rat cerebrospinal fluid decreases from 1.6 mM in the fetus to 1.2 mM in the adult (Jones and Keep 1988). Moreover, under both physiological and pathological conditions, neuronal activity decreases [Ca2+]E (Amzica et al. 2002; Nicholson et al. 1978; Somjen 1980). There is even evidence that activation of a single synapse can cause a transient depletion of Ca2+ at that synapse (Rusakov and Fine 2003).
Functional implications
To induce the first cycle of mastication by stimulation of the cortical masticatory area, a train of shocks of moderate frequency (10–100 Hz) and a minimum duration of several hundred milliseconds is usually required in anesthetized or awake animals before mastication starts (Dellow and Lund 1971; Lund and Lamarre 1974). Similarly, sustained activity in sensory afferents is necessary to trigger mastication. This is surprising given the fact that the cortical and sensory afferents project massively and at monosynaptic or very short latency to dorsal NVsnpr (Tsuboi et al. 2003) and to the surrounding areas (Westberg et al. 1998) with which it is strongly interconnected (Athanassiadis et al. 2005b). We propose that repetitive stimulation of these inputs causes massive neuronal activation that is responsible for a drop in [Ca2+]E, that in turn enhances INaP and initiates bursting. Such a relationship has been found in hippocampal pyramidal cells (Yue et al. 2005). The pathway through which [Ca2+]E modulates INaP is not known, but it may involve [Ca2+]E-sensitive second-messenger cascades because INaP can be modulated by a protein kinase C–dependent mechanism (Carr et al. 2002; Franceschetti et al. 2000; Yue et al. 2005).
The transition from suckling to chewing occurs gradually in the course of the second postnatal week in rats. The first masticatory movements appear around P12, and the adult masticatory pattern is established by P18–P21 (Westneat and Hall 1992). In this study, we show that there is a close correspondence between the emergence of bursting in NVsnpr neurons and the development of INaP during the period in which masticatory movements emerge. This adds to recent evidence that suggests that NVsnpr plays a determinant role in the generation of the masticatory pattern. First, neurons of this nucleus project to the facial (Pinganaud et al. 1999; Travers and Norgren 1983), trigeminal (Kolta et al. 2000; Li et al. 1993; Yoshida et al. 1998), and hypoglossal (Pinganaud et al. 1999; Travers and Norgren 1983) motor nuclei, which participate in several coordinate orofacial behaviors. In addition, experiments carried in anesthetized and paralyzed rabbits in which the masticatory pattern was generated by stimulation of the motor cortex show that neurons of the dorsal area of NVsnpr increase expression of c-fos (Athanassiadis et al. 2005a). Extracellular recordings in a similar preparation have shown that a third of the population in this area are rhythmically active in phase with the masticatory cycle (Tsuboi et al. 2003).
NVsnpr is traditionally viewed as a sensory relay to the thalamus. Although there is increasing interest in the roles that bursting may play in sensory encoding (Krahe and Gabbiani 2004; Sandler et al. 1998), it has also been implicated in sensori-motor transformations in simple systems (Viana Di Prisco et al. 2005). We have proposed that NVsnpr neurons may form the core of the masticatory CPG (Tsuboi et al. 2003), because they have both intrinsic burst-generating properties and direct connections to other parts of the CPG and to the three motor nuclei (facial, trigeminal, and hypoglossal) controlling orofacial behaviors (Kolta et al. 2000; Li et al. 1993; Pinganaud et al. 1999; Travers and Norgren 1983; Yoshida et al. 1998). They are capable of generating bursts within the frequency range of natural mastication and the rate of bursting is a direct reflection of the level of tonic depolarization and [Ca2+]E. These neurons also have inputs from muscle spindle, periodontal, and other intraoral mechanoreceptors (Tsuboi et al. 2003), which provide the feedback that is necessary for rapid adaptation of burst parameters and of the motor pattern.
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Present address of F. Brocard: Laboratory Plasticité et Physio-Pathologie de la Motricité, UMR 6196 CNRS, Université de la Méditerranée, 31 Chemin Joseph Aiguier, F-13402 Marseille cx 20, France.
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Address for reprint requests and other correspondence: A. Kolta, Univ. de Montréal, Pavillon Paul Desmarais, C.P. 6128, Succursale Centre Ville, Montreal, Quebec H3C 3J7, Canada (E-mail: arlette.kolta{at}umontreal.ca)
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