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1 Laboratoire de Neurologie et Physiologie du Développement, Institut National de la Santé et de la Recherche Médicale E9935, and Service de Physiologie, Hôpital Robert Debré, 75019 Paris; and 2 Unité de Recherches sur les Adaptations Physiologiques et Comportementales, Faculté de Médecine D'Amiens, 80036 Amiens, France
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Breathing during the
first postnatal hours has not been examined in mice, the preferred
mammalian species for genetic studies. We used whole body
plethysmography to measure ventilation (
E), breath duration (TTOT), and tidal volume (VT)
in mice delivered vaginally (VD) or by cesarean section (CS). In
experiment 1, 101 VD and 100 CS pups aged 1, 6, 12, 24, or
48 h were exposed to 8% CO2 or 10% O2
for 90 s. In experiment 2, 31 VD pups aged 1, 12, or
24 h were exposed to 10% O2 for 5 min. Baseline
breathing maturation was delayed in CS pups, but E
responses to hypercapnia and hypoxia were not significantly different
between VD and CS pups [at postnatal age of 1 h (H1): 48 ± 44 and 18 ± 32%, respectively, in VD and CS pups combined]. The
E increase induced by hypoxia was greater at H12
(46 ± 27%) because of TTOT response maturation. At
all ages, hypoxic decline was ascribable mainly to a VT
decrease, and posthypoxic decline was ascribable to a TTOT
increase with apneas, suggesting different underlying neuronal mechanisms.
development; chemical control of breathing; hypoxic decline
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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POSTNATALLY, RAPID
CHANGES occur in the relative contributions to breathing of
wakefulness, temperature, mechanoreceptor, and chemoreceptor drives,
the ultimate result being predominance of the chemoreceptor drive
(20). Hyperpnea in response to hypoxia increases sharply
after birth because of peripheral chemoreceptor resetting (9,
38). During sustained hypoxia, newborn mammals exhibit a decline
in ventilation (E), i.e., the hypoxic ventilatory decline (HVD), whereas adults can maintain their E
above the baseline level (23, 25). The early maturation of
breathing is of major clinical relevance (14, 15).
Mice are the preferred mammalian species for manipulating genes and
characterizing physiological phenotypes (30). Data
obtained soon after birth are crucial. Null mutants for most genes
investigated in respiratory studies of newborn mice survived only a few
hours (e.g., Refs. 1, 6, 31).
Some of the survivors breathed normally after a period of impaired
breathing at birth (6, 31). Data on breathing maturation
soon after birth are meager. Two studies in mice with the same genetic
background showed a twofold E increase with 8%
CO2 within 1 h of birth (6) and a
fivefold increase with 10% CO2 within 1 day of birth
(1), respectively. Small E increases in
response to 10% O2 have been reported (6, 18,
19), but in one study, mice failed to respond to 10%
O2 24 h after birth (1). Paton and
Richter (27) found that 3-day-old mice increased their
E by 75% when exposed to 10% O2
(5, 6, 36). HVD has been observed within 12 h of
birth (32), but early HVD changes have not been
investigated. These studies suggest that ventilatory control undergoes
rapid maturation during the first 2 days of life in mice but do not provide data on the timing of this process.
Our first experiment investigated E responses to
hypercapnia and hypoxia in mice at several postnatal ages (PNAs) during the first 2 days of life. The breathing of older mice has been characterized in previous studies (27, 32). Our first
hypothesis was that the response to brief (90 s) hypoxia, which is
determined mainly by peripheral excitatory input, would increase
sharply because of peripheral chemoreceptor resetting but that no sharp increase would occur in the response to hypercapnia, which is generally
mature at birth. Because cesarean section (CS) is used to improve
the accuracy of PNA determination (6, 18, 31), we looked for effects of CS on ventilatory maturation by comparing pups delivered vaginally (VD) to pups delivered by CS.
Our second experiment investigated HVD maturation by using a longer period of hypoxia (5 min). Robinson et al. (32) reported that HVD was less marked in juvenile and adult mice than in newborns. Our second hypothesis was that HVD may be present in newborn mice. We made no hypothesis regarding changes in HVD during the 48-h study period.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Mice
In experiment 1, we studied 201 Swiss-IOPS newborn mice of both genders (IFFA-CREDO, L'Arbresle, France), including 101 VD pups and 100 CS pups, divided into five balanced groups with PNAs of 1, 6, 12, 24, or 48 h (H1, H6, H12, H24, and H48, respectively). In experiment 2, 31 Swiss-IOPS VD pups were divided into three balanced age groups, H1, H12, and H24. In both experiments, we used independent age groups to avoid possible effects on ventilatory control maturation of repeated exposure to chemical stimuli (22, 29). Mean group weights are indicated in Table 1.
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The morning after mating was defined as embryonic day 0 (E0). The mice were housed at 24°C with a normal 12:12-h light-dark cycle and food and water ad libitum. Experimental protocols met animal research guidelines established by the Institut National de la Santé et de la Recherche Médicale (National Institute for Health and Medical Research).
CS
Pregnant mice were killed on E18.5 (normal delivery is on E19) by cervical dislocation. Previously described procedures were used to deliver (6) the pups and to stimulate the CS pups (33). All CS pups survived. Those tested at H1 were placed in a box that contained litter from their mother's box and was kept at a constant temperature of 32°C (the mean temperature in 1-h-old litters with the mother). CS newborns tested at H6, H12, H24, and H48 were with foster mothers.Ventilatory Measurements
We used noninvasive, whole body plethysmography based on Drorbaugh and Fenn's principle (7, 10, 11, 24, 26) to measure breath duration (TTOT, ms), tidal volume (VT, µl), andE (calculated as
VT/TTOT, in µl/s). VT and
E were divided by body weight and expressed in
microliters per gram and microliters per gram per second [body
temperature, pressure, and saturation (BTPS)], respectively.
Hereafter, VT and E designate these
weight-normalized variables.
The plethysmograph has been described previously (6, 31). Calibration was done before each test by injecting 2 µl of air into the measurement chamber from a syringe and by introducing the corresponding pressure into Drorbaugh and Fenn's equation. Hypercapnic (8% CO2, 21% O2, and 71% N2) and hypoxic (10% O2, 3% CO2, and 87% N2) mixtures were obtained commercially. The hypoxic mixture contained 3% CO2 to maintain near-normal arterial PCO2 (PaCO2) values during hypoxia (28).
Procedure
Experiment 1. Each animal underwent two hypercapnic or two hypoxic tests. The first test was used to assess responses to hypercapnia and hypoxia. To study repeatability of ventilatory responses, the tests were run in close succession. Each test was started after 1 min of familiarization inside the measurement chamber and consisted of five steps: 1) the chamber was flushed with 60 ml of air, 2) breathing variables were recorded for 90 s, 3) the chamber was flushed with 60 ml of air, 4) the hypercapnic or hypoxic mixture was injected, and 5) breathing variables were recorded for 90 s. Each gas injection took ~45 s. Because of a transient pressure signal disturbance, valid pressure signals became available ~15 s after the end of each gas injection. After the last recording, the mouse was removed from the chamber and subjected to measurements of body weight and mouth temperature. Each animal spent 11-12 min in the chamber.
Experiment 2. Each animal underwent a single hypoxic test (10% O2 with 3% CO2 in N2) with exposure to air for 3 min, to hypoxia for 5 min, and to air again for 3 min. To shorten the pressure signal disturbance caused by the gas injections, we decreased the output resistances of the measurement and reference chambers during the injections. This reduced the injection time to 10 s (45 s in experiment 1). The measurement chamber was too small (30 ml) to allow determination of gas concentrations. However, based on CO2 production by rats aged 7 to 9 days (Ref. 34; corresponding values in newborn mice are unknown), we estimated that CO2 in the chamber remained below 1.6% after 5 min (the longest time between 2 gas changes). Finally, body temperature was recorded continuously throughout the test in three mice (H1, H6, and H12) using a PT100 platinum temperature probe attached to the cervical skin and connected through the wall of the plethysmograph to an external amplifier.
Data Selection
Ventilatory data free from movement artifacts were selected visually by discarding trace segments without individualized breaths or with drifts larger than twice the mean volume signal amplitude. This was done by two investigators, each of whom processed half the VD and CS pups and half the pups within each age group. In experiment 1, TTOT, VT, andE were
averaged over each continuous sequence of valid breaths. The overall
mean of these averaged values weighted for the number of breaths in
each sequence was calculated. The numbers of breaths (and cumulative
duration on 90-s recordings) were 111 ± 56 (56 ± 21 s)
during air breathing and 134 ± 65 (62 ± 21 s) during
hypercapnia or hypoxia. In experiment 2, we averaged valid
data over successive 1-min periods. Sequences of valid breaths were
used after exclusion of apneas (defined as ventilatory pauses longer
than twice the duration of the preceding valid breath). The number of
apneas was calculated in segments free from movement artifacts.
Statistics
Analysis of variance for each stimulus and each variable (TTOT, VT, andE, and apnea
number and duration) was done using Superanova Software (Abacus
Concepts, Berkeley, CA). We used the percentage change from normoxia to
gas stimulus to assess ventilatory responses to hypoxia and hypercapnia
[i.e., 100 × (Estimulus 
Eair)/Eair],
hereafter called the E, VT, and
TTOT responses. Data are summarized as the group means ± SDs in the text and Table 1 and as the means ± SEs in Figs.
1-5.
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In experiment 1, delivery mode and PNA were between-subject factors, and the test (1st vs. 2nd) was a within-subject factor. In experiment 2, PNA was a between-subject factor, and time (5 levels during hypoxia, from minute 1 to minute 5, or 3 levels during air breathing, from minute 1 to minute 3) was a within-subject (repeated) factor. In both experiments, we analyzed HVD by comparing breathing variables during the air periods before and after hypoxia. To take into account the heterogeneous correlations among the repeated time measurements in experiment 2, we adjusted the degrees of freedom using the Huynh and Feldt factor (4). The effects of time at testing (morning, midday, and afternoon) and investigator who performed data selection were found to have no significant effects and are not discussed in this article.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Baseline Breathing in Air
VD and CS pups had similarE at H1, but the
E increase with PNA (P < 0.0001)
was delayed in CS pups (PNA by group interaction: P < 0.0015, Fig. 1A).
TTOT changes mirrored E changes (Fig. 1B). VT was smaller in CS than VD pups
(P < 0.033, Fig. 1C).
Ventilatory Response to Hypercapnia
TheE response to hypercapnia (1st test of
experiment 1), although weaker in CS pups, was not
significantly different between CS and VD pups (for example, 20 ± 31 and 32 ± 27% at H6, 45 ± 32 and 45 ± 31% at H24;
main effect for delivery mode and interaction with PNA not
significant). Therefore, we pooled data from CS and VD pups (Fig.
2A, left).
E response increased with PNA (P < 0.027), mainly because of a VT response increase (Fig.
2C, left; P < 0.003), with no
significant TTOT response change (Fig. 2B, left).
The second hypercapnic test of experiment 1 confirmed
that the E response was independent from delivery
mode and increased with PNA from 26 ± 37% at H1 to 57 ± 37% at H48. E and VT responses were
weaker in the second than in the first test (P < 0.0001) because of higher E levels during the second
air period (P < 0.0001) but not during hypercapnia
(Fig. 3A).
Ventilatory Response to Hypoxia
Hyperpneic response to hypoxia.
The E response to hypoxia (1st test of
experiment 1), although weaker in CS pups, was not
significantly different between CS and VD pups (for example, 13 ± 25% in CS vs. 18 ± 16% in VD at H6; 46 ± 22 vs. 53 ± 22% at H24; main effect for delivery mode and for interaction with
PNA not significant). Therefore, we pooled the data from CS and VD pups
(Fig. 2A, right). Most of the E response
increase occurred around H12 (main effect of PNA: P < 0.0009; H1 and H6 vs. H12: P < 0.014, Fig. 2A,
right) and was ascribable to TTOT response maturation
(Fig. 2B, right; main effect for PNA: P < 0.0003; H1 and H6 vs. H12: P < 0.0050). The
VT response did not change significantly with PNA (Fig.
2C, right).
E response was independent from delivery mode and
increased with PNA (from 38 ± 82% at H1 to 74 ± 35% at
H48). The E and VT responses were larger
in the second than in the first test (P < 0.0001) because of smaller E levels during the second air
period (P < 0.0001) but not during hypoxia (Fig.
3B).
The sharp increase in E responses to hypoxia around
H12 was confirmed in experiment 2 (Fig.
4A). The significant main
effect for PNA (P < 0.013) was accounted for by the
difference between H1 and the other two ages (H12 and H24).
HVD.
E during hypoxia displayed a significant linear
decrease at H12 and H24 (P < 0.0001 and
P < 0.002, respectively, Fig. 4A), indicating an HVD, but was still significantly greater than baseline at
the end of the stimulus (P < 0.001 and
P < 0.005, respectively). E
decreased between the first and second minute of hypoxia
(P < 0.0015, Fig. 4A). TTOT did
not change significantly over time (Fig. 4B), whereas
VT decreased linearly at H12 and H24 (P < 0.001 and P < 0.0001, respectively; Fig.
4C). The additional tests in three animals at H1, H6, and
H12 showed that temperature changes during hypoxia were 0.5, 0.2, and
0.6°C, respectively, producing about 4% error in VT
measurements (11).
Posthypoxic ventilatory decline.
Posthypoxic ventilatory decline (PHVD) was caused mainly by a
longer TTOT after than before hypoxia in experiment
1 (P < 0.0006, Fig. 3B);
VT levels were similar before and after hypoxia. Similarly, in experiment 2, E at H1 and H24 was
significantly below baseline after hypoxia (P < 0.002 and P < 0.005, respectively; nonsignificant difference
at H12; Fig. 4A), and PHVD was driven by TTOT
(P < 0.003, Fig. 4B). The differences for
VT were not significant (Fig. 4C). Another
manifestation of PHVD was a greater number of apneas after vs. before
hypoxia in both experiments (P < 0.002 in
experiment 1, Fig.
5A, and P < 0.0001 in experiment 2, not shown) in all age groups except
for the H48 group in experiment 1, leading to a small PNA by
pre-post factor interaction (P = 0.046; we considered this effect marginal and pooled the PNA groups in Fig. 5A).
Apneas were longer after than before hypoxia (P < 0.002 in experiment 1, Fig. 5B, and
P < 0.004 in experiment 2, not shown). This
effect was present in all age groups in both experiments and was not significantly influenced by PNA. Neither the number nor the duration of
apneas was significantly different after vs. before hypercapnia (Fig.
5).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This is, to our knowledge, the first description of breathing
control maturation during the first 48 h of life in mice. The main
results were as follows: 1) despite normal baseline
E levels at H1, the postnatal E
increase was delayed in CS pups because of a delayed TTOT
decrease; 2) delivery mode had no significant influence on
E responses to hypercapnia or hypoxia during the 48-h study period; 3) a E response to
hypercapnia was present at H1 and ascribable mainly to a VT
response; 4) the E response to hypoxia was small
until H12, then increased sharply as a result of TTOT
response maturation; and 5) HVD and PHVD were present in all age groups.
Plethysmographic Measurements
Contrary to plethysmography in adult mice (10, 26), plethysmography in newborns has not been validated against pneumotachography. Therefore, the validity of absolute VT andE values can be questioned. However, the percent
increases from baseline in response to hypercapnia and hypoxia reliably
assess responsiveness to chemical stimuli. Head-out plethysmography
(1, 32) was not used in this study because it requires
restraining the animals. In adult mice, restraint strongly stimulates
baseline E without significantly affecting the
E increase caused by chemical stimuli
(5). The two studies that used head-out plethysmography in
newborn mice (1, 32) found very strong
E responses to hypercapnia (500% increase in
response to 10% CO2 + 30% O2) or hypoxia
(140% increase in response to 7.4% O2) within 1 day of
birth, compared with the present and previous data. These
differences may be ascribable to E measurement
methods, but no strong interpretation can be offered in the absence of
comparative studies of whole body vs. head-out plethysmography in
newborn mice.
Effects of CS on Ventilatory Control
CS was associated with delayed maturation of the baseline breathing pattern. In VD pups,E increased sharply
as early as H1-H6 and peaked at H12, whereas in CS pups, the
corresponding increase occurred only at H48. The CS pups weighed less
than the VD pups between H6 and H24 but not at H48, suggesting delayed maturation. This was perhaps ascribable to differences in maternal care
and feeding between biological mothers (in VD pups) and foster mothers
(in CS pups). The delayed maturation of baseline breathing pattern and
weight was probably not ascribable to differences in gestational age
between CS and VD pups because E at H1 was nearly
identical in these two groups, and weight was slightly higher in CS pups.
The transition from intrauterine to extrauterine environment, including breathing air after delivery, is associated with profound changes in plasma catecholamines, particularly norepinephrine. This may affect breathing pattern at both the pulmonary and central levels (21). In infants, compared with VD, CS is associated with less of a release of catecholamines, which inhibit secretion and promote absorption of lung fluids, thereby affecting lung mechanics (8, 17). The smaller baseline VT in CS than in VD pups was perhaps an effect of delayed lung fluid absorption, as shown in infants (17). This should translate into greater lung weight and abnormal arterial blood gas values; these variables were not measured here. CS pups had higher TTOT values than VD pups between H6 and H12, a finding not reported previously. Norepinephrine can increase or decrease respiratory frequency in brain stem-spinal cord preparations of newborn rats depending on whether its main action is on the pons or medulla (12). The higher TTOT in CS pups might be ascribable to their presumably smaller norepinephrine release.
Despite these differences in baseline breathing, responses to hypercapnia or hypoxia were similar in CS and VD mice, in line with evidence from infants that CS does not affect the peripheral chemoreflex (39). Thus CS may affect ventilatory function maturation without significantly modifying responsiveness to chemical stimuli.
Maturation of Ventilatory Responses to Hypercapnia
TheE response to hypercapnia was vigorous from
H1 and dependent mainly on a VT increase. At H48, this
response (74 ± 48%) was lower than in previously studied adult
Swiss mice exposed to the same hypercapnic stimulus with or without
restraint [163 ± 100 and 118 ± 40%, respectively
(5)]. Thus the E response to
hypercapnia may continue to increase after 48 h of PNA.
Maturation of Ventilatory Responses to Hypoxia
Hyperpneic response to hypoxia.
The increase in the E response to hypoxia after
12 h was probably caused by postnatal resetting of the
chemoreceptors. Peak responses to hypoxia at H12 and H24 were stronger
in experiment 2. In experiment 1, the longer gas
injection and the subsequent pressure signal instability delayed
occurrence of a valid respiratory signal, so that some of the
movement-free data used for E determination were
collected after the E peak, possibly leading to
underestimation of the response to hypoxia. However, both experiments
showed a sharp hypoxic response increase around H12.
E increases, respectively. In support of this, the E increases were related to VT increases
rather than to TTOT decreases, a pattern characteristic of
the response to hypercapnia. Furthermore, assuming rough
proportionality between inspired CO2 fractions and
E, 3% CO2 would be expected to cause a
E response similar to that with 10% O2
plus 3% CO2, suggesting that the CO2 accounted
fully for this last response. Thus the E increases with hypoxia at H1 and H6 were possibly overestimated. This does not
detract from our finding that this response increased sharply at H12,
attesting to hypoxic response maturation.
HVD.
HVD occurred during the second minute of exposure, as in previous
experiments in newborn rats (13). However, Robinson et al.
(32) reported that E was maintained
during the first 3 min of exposure to 7.4% O2 in mice
within 12 h of birth. Possibly, the excitatory effects of
restriction during head-out plethysmography temporarily counteracted
the HVD in their experiment (32). We found no effect of
age on HVD over the 48-h study period, a finding that does not rule out
such an effect later during development (32). Conceivably,
maturation may be different for the peripheral excitatory response to
hypoxia, which is small at birth but becomes marked after 12 h,
and for the central inhibitory response, which is present at all ages.
This possibility is supported by a recent report that targeted gene
deletion selectively impaired HVD without affecting the hyperpneic
response to hypoxia (16).
PHVD.
E fell below baseline after hypoxia but not after
hypercapnia. Coles and Dick (2) reported that adult
anesthetized, spontaneously breathing or vagotomized paralyzed rats
exposed to 8% O2 for 40 s showed a breathing rate
decrease below baseline after the stimulus. PHVD was not caused by a
metabolic effect on the central drive but rather by a neurally mediated
mechanism susceptible to modulation by 
2-adrenergic
receptors (3). However, in newborn animals, the effects of
hypoxia on metabolism are more marked (25) and may
contribute to PHVD via mechanisms different from those in adults.
E fell mainly because of a VT decrease,
whereas PHVD was ascribable to a TTOT increase. In
addition, HVD and the PHVD showed different time courses: HVD was
minimal at H1 and marked at H12 and H24, whereas PHVD was readily
detectable at H1 and independent from PNA.
Conclusions
The present results have practical implications regarding the analysis of ventilatory control in newborn mice. First, CS delays baselineE maturation but has no significant effect
on ventilatory responses to hypercapnia and hypoxia. Second, the
response to hypercapnia can be assessed at birth, whereas the response
to hypoxia is weak within 12 h of birth and should be evaluated
later. Third, the hyperpneic responses to hypoxia and HVD undergo
different maturation processes within 48 h after birth. Both are
relevant to the development of breathing control and should be
evaluated based on the time course of ventilatory variables
during hypoxia. Fourth, hypercapnia stimulates and hypoxia
inhibits baseline E after stimulus cessation.
Therefore, E measured immediately after the stimulus
may not reflect baseline breathing.
Perspectives
This study acknowledges the growing importance of mice as a model for studying organ physiology (30, 32). Because strain differences may affect breathing pattern in newborn mice, as in adults (35-37), only values from wild-type littermates can serve as reference values for breathing variables in mutant (homozygous or heterozygous) mice of a given strain. However, the developmental milestones of breathing control in outbred mice described in this study provide a basis for designing future experiments in inbred newborn mice. Until now, most work on genetic factors in physiological functions has been conducted in adult mice. However, the phenotypic expression of a given mutation may recover with time, masking the potential role of the mutation. Postnatal physiological function studies designed with maturation profiles in mind can be expected to benefit the search for genotype-phenotype relationships.| |
ACKNOWLEDGEMENTS |
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We thank H. Gautier for thoughtful review of the manuscript.
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FOOTNOTES |
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This study was supported by the Fondation Pour La Recherche Médicale (grant awarded to S. Renolleau) and by the Université Paris VII (Legs Poix).
Address for reprint requests and other correspondence: J. Gallego, Laboratoire de Neurologie et Physiologie du Développement, INSERM E9935, Hôpital Robert Debré, 48 boulevard Sérurier, 75019 Paris, France (E-mail: gallego{at}idf.inserm.fr).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 26 February 2001; accepted in final form 24 July 2001.
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TOP
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METHODS
RESULTS
DISCUSSION
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