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The Journal of Neuroscience, 2000, 20:RC73:1-6
RAPID COMMUNICATION
NMDA Receptor Activity In Utero Averts Respiratory
Depression and Anomalous Long-Term Depression in Newborn
Mice
Chi-Sang
Poon1,
Zhongren
Zhou1, and
Jean
Champagnat2
1 Harvard-MIT Division of Health Sciences and
Technology, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, and 2 Neurobiologie
Génétique et Intégrative, Centre National de la
Recherche Scientifique, 91198 Gif-sur-Yvette, France
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ABSTRACT |
Mutant mice lacking NMDA receptor 1 subunit (NR1) showed marked
depression of respiratory and suckling activities in
vivo and overexpression of synaptic long-term depression (LTD)
in a brainstem cardiorespiratory-related region (nucleus tractus
solitarius) in vitro. Pharmacological blockade of NMDA
receptors in normal newborn mice mimicked the depression in suckling
activity but not respiratory depression in vivo or
brainstem LTD in vitro. Results at the behavioral and
cellular levels demonstrate that NMDA receptor deficiency during
prenatal development may unleash an anomalous form of NMDA
receptor-independent LTD along with life-threatening respiratory
depression consequences in the newborn. These findings raise the
specter of cardiorespiratory dysregulation with increased risks of
morbidity and mortality in the infant as a result of premature births
or genetic or drug-induced NMDA receptor antagonism during pregnancy.
Key words:
NMDA receptor; NR1 knock-out; synaptic long-term
depression; respiratory failure; nucleus tractus solitarius; prenatal
neural development; newborn mice
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INTRODUCTION |
NMDA
receptor plays an important role in many cellular functions or
dysfunctions of the mammalian brain, including synaptic plasticity
(Collingridge and Bliss, 1995 ; Bear, 1996), neural development (Hahm et
al., 1991; Scheetz and Constantine-Paton, 1994), excitotoxicity
(Rothman and Olney, 1995), and antiapoptosis (Ikonomidou et al., 1999).
It has also been implicated at the behavioral level as a key factor in
certain cognitive functions such as learning and memory (Kleinschmidt
et al., 1987; Feldman et al., 1996; Tsien et al., 1996; Manahan-Vaughan
and Braunewell, 1999; Tang et al., 1999) as well as epileptic seizure
(Loscher, 1998) and other neurological disorders (Kornhuber and Weller, 1997; Mohn et al., 1999). By contrast, the role of NMDA receptor activity in prenatal neural development is poorly understood because of
the difficulties of blocking NMDA receptors specifically in the fetus
and not the maternal milieu.
A genetic approach offers a unique opportunity to study the effects of
NMDA receptor malfunctioning in the fetus on prenatal neural
development. Recent advances with molecular cloning have identified two
families of subunits in the NMDA receptor (NMDAR) complex: the NMDAR1
family, which has only one member, NR1, and the NMDAR2 family, which
has four members (for review, see Kutsuwada et al., 1992; Monyer et
al., 1992; Nakanishi, 1992). Of these, NR1 is essential for NMDA
receptor activity and is ubiquitous in the brain, whereas the other
subunits provide functional diversity of the receptor complex and are
more topographic.
In the present investigation, we provide evidence that links the
absence of NMDA receptor activity in the prenatal period to the
postnatal evolution of catastrophic respiratory failure and an
accompanying anomalous long-term depression (LTD) in the nucleus
tractus solitarius (NTS), a brainstem region important for
cardiorespiratory regulation. Thus, NMDA receptor activity during
prenatal development in utero is crucial for subsequent neonatal survival. These findings raise the specter of
cardiorespiratory dysregulation with increased risk of infant morbidity
and mortality (Shannon et al., 1977; Schwartz et al., 1988; Eichenwald
et al., 1997) as a result of premature births or genetic defects and
warrant some cautions on exposure of the fetus to NMDA-antagonistic
anesthetic or analgesic drugs (Orser et al., 1997) and certain
substances of abuse (Spuhler-Phillips et al., 1997; Deutsch et al.,
1998) during pregnancy.
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MATERIALS AND METHODS |
Genotyping.
NR1 / mutant mice were produced
as previously described (Li et al., 1994). Heterozygous females in
BALB/c background were mated overnight with heterozygous males in
either C57BL/6 or 129/Sv background. The parents had been back-crossed
to C57BL/6 or BALB/c for at least six generations to remove most of the
129 strain phenotype. The day after mating the females were checked for
a vaginal plug, and, if present, this would be referred to as embryonic
day 0 (E0). Plugged females were housed individually, and they usually
gave birth between E18.5 and E19.5. Approximately 2-8 hr after birth
the pups were transferred from their nests to an incubator in
preparation for the experiment.
NR1/ mutant mice were initially
identified based on characteristic symptoms such as the absence of milk
in the stomach. After the experiment, all animals were anesthetized on
ice, and a piece of tail was taken from each animal and stored in a
freezer. Tail DNA was extracted and genotyped by PCR analysis with a
set of neo1 primers (5'-GCTTGGGTGGAGAGGCTATTC and
5'-CAAGGTGAGATGACAGGAGATC, 280 bp PCR product) and a set of
primers to the deleted region of the mutant NMDAR1 allele
(5'-TGACCCTGTCCTCTGCCATG and 5'-GCTTCTCCATGTGCCGGTAC, 550 bp
PCR product).
Some normal (wild-type and heterozygous) mice were inadvertently
identified as NR1/ mutants
during the experiment because they apparently had not been fed by the
mothers before the experiment began. The true genotypes of all animals
were verified after the experiment using PCR analysis.
In vivo studies. Normal and
NR1/ mutant mice were incubated
at 34°C in a moist and ventilated chamber before the experiment. Respiration was monitored by means of a miniature plethysmograph (Depledge, 1985). The animal was placed in a two-compartment chamber in
a head-out position, with the head and body compartments being separated by a latex diaphragm sealed around the animal's neck. Pressure changes in the body compartment were detected by a sensitive pressure transducer, and the resulting signal was amplified, digitized at 700 Hz, and continuously displayed on a computer monitor. The pressure (equivalent to volume) signal was calibrated at the beginning and end of the experiment by momentarily injecting into the body compartment 0.1 ml of air from a microsyringe; a good seal between the
two compartments was indicated by a sustained elevated pressure, which
was relieved by opening to the atmosphere through a three-way stopcock.
The effects of changes in temperature and humidity in the chamber
during the relatively brief experimental period were neglected.
Respiratory chemoreflex was assessed by exposing the animal to air
enriched with 5% CO2 for ~10 min and recording
the steady-state respiratory movements for 2 min. Pharmacological
agents were injected subcutaneously by using a Hamilton syringe, and
their effects on suckling and respiration were examined after a
stabilization period of ~30 min. Suckling reflex was induced by a
gentle mechanical stimulation of the oral cavity using a fine catheter
with a blunt tip, which led to a sequence of repetitive jaw
opening-closing reactions. Suckling rhythm was registered as the
number of jaw openings in the sequence induced over a 30 sec
stimulation period.
In vitro studies. Synaptic transmission in rodent NTS was
studied by using a brainstem slice preparation as described previously (Zhou et al., 1997; Zhou and Poon, 2000). Newborn mice were
killed within 10 hr after birth by decapitation under metofane
anesthesia, and their brains were rapidly removed and placed in chilled
artificial CSF (ACSF) saturated with carbogen (95%
O2 and 5% CO2) and
containing (in mM): NaCl, 130; KCl, 5.4;
KH2PO4, 0.8;
NaHCO3, 26; glucose, 30;
MgCl2, 1; and CaCl2, 2. Transverse brainstem slices (400 µm) were cut using a vibratome at a
level around the area postrema. After stabilization at room temperature
(22-25°C) in ACSF for at least 1 hr, the brainstem slice was
transferred to a recording chamber, stabilized under a nylon mesh, and
submerged and continuously superfused with ACSF at 32°C. In all
brainstem slices, bicuculline (10-20 µM, dissolved in
DMSO) was added to the perfusate to suppress possible inhibitory
synaptic transmission through GABAA receptors. A
monopolar tungsten electrode with an ultrafine tip (FHC, Bowdoinham, ME; 5 M , 2-4 µm tip diameter) was positioned by means of a
micromanipulator at the tractus solitarius for discrete electrical
stimulation (pulse width, 0.1 msec; frequency, 5 Hz; intensity, 3-10
V) of the primary afferent fibers. Excitatory postsynaptic response was
elicited by a single electrical impulse. Whole-cell patch recordings of
activity in NTS cells were obtained using a low-noise amplifier
(Axopatch 200A; Axon Instruments, Foster City, CA) with a fluid-filled
micropipette (resistance, 4-10 M) containing (in mM):
KCl, 130, CaCl2, 0.4, EGTA, 1.1;
MgCl2, 1; NaCl, 5; potassium HEPES, 10;
Mg2+-ATP, 2; and
Na2+-GTP, 0.1, pH 7.2-7.3. Neurons were
approached blind, and a gigaohm seal was formed by a gentle suction of
the micropipette. Once in the whole-cell mode, a voltage clamp was
applied (holding potential,  70 mV), and a stabilization period of
~10 min was allowed before recordings began.
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RESULTS |
Relapse of NR1/ mutant mice
after birth
The heterozygous mutants had no phenotypic abnormalities compared
with the wild-type animals (Li et al., 1994). However, physical examination of the NR1/ mutants
revealed two distinct phases in the postnatal period: a latent phase
lasting 10-18 hr after birth, during which the mutant animals appeared
to be healthy with flushed skins as their normal (heterozygous and
wild-type) littermates, and a subsequent morbid phase (0.5-3 hr
duration) of acute respiratory failure characterized by increasing
cyanosis and decreasing motility. All
NR1/ mutants died within 12-20
hr after birth, in contrast to their normal littermates, which survived
under similar environments.
NR1/ mutant neonates suffer from severe
respiratory depression
Plethysmographic measurements (Fig.
1A) during the latent
phase revealed marked depression of the respiratory rhythm in the NR1/ mice compared with normal,
with increased incidence and duration of apnea (Table
1). Thus, the respiratory failure during
the morbid phase was probably the culmination of a sustained
respiratory depression that developed at or soon after birth. Exposure
of the mutants to air enriched with 5% CO2
restored a regular respiratory rhythm (Fig. 1A, Table
1). Both normal and mutant mice showed an increase in respiratory
frequency as well as tidal volume in response to the
CO2 challenge. Despite this, total ventilation of
the NR1/ mutants remained
depressed (compared with normal) after CO2
stimulation (Fig. 1B). The hypopnea is unlikely a
consequence of decreased body metabolism or hypothermia, because both
normal and mutant animals had similar body weights at birth (Li et al.,
1994) and were incubated in a similar manner. Indeed, the mutant
animals appeared to be more motile than the normal animals during
measurement, and their breathing pattern tended to be more irregular
(Table 1). Although arterial CO2 tension could
not be measured directly in these small animals, the hypoventilation
suggests a decreased CO2 chemoreflex in the
mutants, i.e., with decreased CO2 sensitivity and/or threshold (Cunningham et al., 1986).
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Figure 1.
Respiratory depression in NMDAR1 gene knock-out
(NR1/) newborn mice on P0.
A, Tracings of respiratory volume during quiet breathing
with room air (top) and with 5% CO2 in air
(bottom) in normal and
NR1/ mutant mice during the
latent phase after birth. Inspiration is upward. Note
the slow and irregular breathing pattern of the mutant in room air
characterized by frequent coughing (1), sighing
(2), and apnea (3). Also
note the restoration of regular breathing pattern with CO2
stimulation. B, Total ventilation (respiratory frequency × tidal volume) was depressed in
NR1/ mutant mice (mean ± SE; n = 9) compared with normal littermates
(n = 18) breathing room air or 5% CO2
in air. Recordings were obtained in all animals within the first 10 hr
after birth. C, Respiratory frequency was significantly
decreased in mutant mice (n = 6) compared with
normal littermates (n = 16) that were unfed.
Measurements were made at 5 hr intervals until the animal died. All
mutant mice died within 20 hr after birth, whereas the unfed normal
littermates survived longer. Timing for the initial measurement (at the
5th hr) was estimated based on the elapsed time when the newborns were
found and the time needed to prepare the animals for experimental
studies. KO, Knock-out.
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Table 1.
Apneic and body movement episodes in normal and
NR1/ mutant newborn mice on PO breathing
room air or air enriched with 5% CO2
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To examine whether the respiratory depression in the mutant mice was
secondary to feeding disorders, we monitored respiratory activity in a
group of NR1/ mutants and some
littermates that had been misclassified as
NR1/ mutants (because of the
absence of milk in their stomachs) at the time of the experiment but
finally proved otherwise by genotypic analysis. These unfed normal mice
were able to survive beyond the 20 hr maximum life span of their mutant
littermates (Fig. 1C). Moreover, respiratory frequency in
these normal animals remained significantly higher than their mutant
littermates throughout the latent phase. Therefore, the respiratory
depression in the NR1/ mutants
was not caused by malnutrition alone but was probably exacerbated by it
to precipitate the terminal respiratory failure. The significance of
respiratory failure as a primary cause for the early deaths of the
mutants is also supported by the recent finding that
NR1/ mutant mice with artificial
respiration treatment survived significantly longer than those without
(Kolandaivelu and Poon, 1998).
Anomalous LTD in brainstem of
NR1/ neonates
Recent in vitro studies in rat brainstem slices (Zhou
et al., 1997) showed that approximately half of the neurons in the
medial and commissural NTS (type II neurons) exhibited LTD after
low-frequency afferent stimulation, whereas the remaining (type I)
neurons did not. Figure
2A demonstrates such
activity-dependent LTD of NTS neurons in brainstem slices from normal
newborn mice, with similar proportions of type I and type II neurons.
Surprisingly, LTD was found in NTS neurons of all
NR1/ mutants (Fig.
2B), in contrast to the abolition of hippocampal LTD
in mutant animals with similar genetic defects (Kutsuwada et al.,
1996). Indeed, the LTD was expressed even more robustly in NTS of the
NR1/ mutants than normal mice
(100 vs ~50% of the cases; p < 0.01; n = 8, binomial distribution).
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Figure 2.
Long-term synaptic depression in NTS of normal and
NR1/ mice on P0.
A, In brainstem slices (300-400 µm thick) from normal
neonatal mice, low-frequency stimulation (LFS; 5 Hz, 3 min) of afferent
fibers in the tractus solitarius elicited LTD in type II neurons
(means ± SE; n = 4) but not in type I neurons
(n = 5) in NTS. Synaptic strength is indicated by
amplitude of EPSC evoked by an electrical impulse (0.1 msec, 3-10 V)
delivered every 20 sec. Arrows indicate beginning and
end of LFS [the phasic depression of synaptic transmission that
normally occurred during LFS (Zhou et al., 1997; Zhou and Poon, 2000)
is not shown]. Episodic data for each cell were averaged every minute
and were normalized by the average response during the control period
before LFS. Insets, Examples of averaged EPSCs (15 episodes) in the periods before (1) and after the
induction of LTD (2) in each cell type.
B, In NR1/ mutant
mice (n = 8), LFS elicited NMDA
receptor-independent LTD robustly in all NTS cells tested. In
A and B, each neuron was from a different
animal.
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Abnormalities in NR1/ neonates are
absent in normal littermates with acute NMDA receptor blockade
To examine whether the brainstem LTD in the
NR1/ mutants resulted from the
lack of NMDA receptor activity per se, we repeated the experiment in
normal mouse brainstem slices perfused with the NMDA receptor
antagonist D-AP-5 (50 µM). Unlike the NTS of the
NR1/ mutants, NMDA
receptor-independent LTD was not induced in NTS neurons in any of these
pretreated brainstem slices (Fig.
3A). This result is in
agreement with previous studies (Zhou et al., 1997), which showed that
acute pharmacological blockade of NMDA receptors abolished LTD in rat
NTS. Taken together, these findings suggest that the absence of NMDA
receptor activity in the NR1/
mutants during the prenatal period may lead to an NMDA
receptor-independent form of LTD in NTS of the neonate. Furthermore,
the factors responsible for the expression of such NMDA
receptor-independent LTD in NTS are unique to the
NR1/ mutant animals and are
absent in the normal mice.
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Figure 3.
Effects of acute pharmacological blockade of NMDA
receptor activity on physiological functions of newborn mice on P0
studied in vitro and in vivo.
A, Brainstem slices (n = 4) treated
with the NMDA receptor antagonist D-AP-5 did not
demonstrate LTD in NTS when subjected to the same stimuli
[low-frequency stimulation (LFS)] as shown in Figure 2, although the
phasic synaptic accommodation during LFS (10th-13th min) remained
intact. B, Suckling rhythm of normal mice
(n = 16) was markedly depressed by the NMDA
receptor antagonist MK-801 administered subcutaneously. The depressant
effect of MK-801 is similar to that found in
NR1/ mutant mice
(n = 21). Similar application of saline had no
effect in the control group (n = 12).
C, Respiratory rhythm of normal mice at P0 was not
affected by MK-801 (n = 7) or saline
(n = 7). This is in contrast to the depressed
respiratory rhythm in the NR1/
mutant mice (n = 36; also see Fig. 1).
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Because brainstem LTD in normal mice was abolished (instead of
enhanced) by D-AP-5, it is unlikely that the respiratory
depression in the NR1/ mutants
was caused by an absence of NMDA receptor activity per se in the
postnatal period. To confirm this, we injected normal newborn mice with
the noncompetitive NMDA receptor antagonist dizocilpine (MK-801; 3 mg/kg, s.c.) or an equal volume (~10 µl) of saline as control.
Animals treated with MK-801 showed a marked depression of the suckling
rhythm similar to that found in the NR1/ mutants (Fig.
3B) and NMDAR2B mutants (Kutsuwada et al., 1996). By
contrast, respiratory frequency was not significantly different between
the MK-801 group and control group before and after drug administration
(Fig. 3C). Thus, NMDA receptor activity in the postnatal
period is integral to the sucking reflex but not requisite for
respiratory rhythmogenesis in the newborn. The latter finding is in
agreement with previous studies, which showed that MK-801 had little
effect on respiratory rhythm in intact, unanesthetized mice on
postnatal day 0 (P0) (Borday et al., 1998).
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DISCUSSION |
This study demonstrated that abolition of NMDA receptor activity
by genetic disruption of NR1 resulted in overexpression of LTD in NTS
and respiratory depression in the newborn mutant animal. Such
abnormalities at the cellular and behavioral levels were not observed
in normal newborn mice after acute pharmacological blockade of NMDA
receptors, and thus they are most likely to develop prenatally. Because
NMDA receptor-channel binding is not discernible in human fetal
brainstem at midgestation (H. Kinney, personal communication),
it appears that the critical periods for NMDA receptor-dependent
development of normal respiratory rhythm and normal synaptic
transmission in NTS occur late in fetal development. Thus, neonates of
premature births may be particularly at risk of respiratory and
suckling disorders similar to those found in the
NR1/ mutants (Eichenwald et al.,
1997).
Respiratory depression in the
NR1/ mutants could be caused by
multiple factors, potentially including abnormalities in respiratory tract, respiratory rhythmogenesis, and excitatory input to the rhythm
generator. Abnormalities in respiratory tract can be ruled out, because
functional NMDA receptors are requisite for excitotoxicity in the lungs
(Said et al., 1995), and there is no evidence of pulmonary pathology in
NR1/ mutant mice until moments
before they died (Forrest et al., 1994). Because respiratory rhythm is
reportedly the same in the isolated respiratory pattern generators from
normal and NR1/ mutant mice
(Funk et al., 1997), the depressed respiratory rhythm in the
NR1/ mutants is likely to
reflect abnormality in chemoreflex (and possibly baroreflex) rather
than in the pattern generator itself. This conclusion is consistent
with our finding of profound anomalous LTD in NTS, a gateway for
peripheral chemoafferent and other visceral inputs. Glutamatergic
neurotransmission is essential for fetal breathing movements
(Bissonnette et al., 1997), and NMDA receptor mediates peripheral
chemoreceptor afferent input (Ohtake et al., 1998) primarily via the
NTS (Sapru, 1996). In contrast to the slow postnatal maturation of
hypoxic chemosensitivity, peripheral chemoreceptor sensitivity to
CO2 is fully functional from birth (Canet et al.,
1996). In addition, plasticity of afferent transmission plays an
important role in respiratory control (Poon, 1996), and NMDA receptor
has a profound influence on the short-term potentiation of peripheral
chemoreflex (Poon et al., 1999). Thus, the respiratory depression in
the NR1/ mutant neonates may be
ascribable at least in part to a blunting of peripheral chemoreflex
(and/or baroreflex) or its short-term potentiation as a result of the
anomalous LTD in NTS neurons. In the intact animal this deficit may add
to other, as yet unidentified, cardiorespiratory abnormalities
resulting from impairment of NMDA receptor-dependent activities such as
pontine adaptation (Siniaia et al., 2000), neurotransmission in
respiratory neurons (Dogas et al., 1995), or phrenic outflow (Sapru,
1996; McCrimmon et al., 1997). Nevertheless, because
CO2 chemoreflex was not totally abolished by the
mutation (Fig. 1A,B), some chemosensitivity (of
peripheral or central origin) remained in the
NR1/ mutant neonates.
Recently, it has been reported (Ikonomidou et al., 1999) that transient
pharmacological blockade of NMDA receptors during the perinatal period
may trigger widespread apoptotic neurodegeneration in newborn animals
in certain brain regions with high NMDA receptor density such as
dentate gyrus and hippocampal CA1 subfield. However, fetuses exposed to
such pharmacological treatments as late as E17 during gestation did not
show increased apoptosis in any of these brain regions after birth
(Ikonomidou et al., 1999). Indeed, mutant mice with targeted deletion
of the NR1 gene restricted to the CA1 pyramidal cells were able to
survive to adulthood (Tsien et al., 1996). By contrast, the present
study showed that disruption of NMDA receptor function in the fetus
could result in the development of an anomalous form of LTD in a brain
region (NTS) that controls vital functions, where such NMDA
receptor-dependent neurodegenerative effects were not evident
(Ikonomidou et al., 1999). Thus, NMDA receptor activity normally
suppresses the expression of such anomalous LTD during prenatal
development and helps avert postnatal respiratory depression that is
detrimental to neonatal life. Such suppression of abnormal neural
development by NMDA receptor during the prenatal period acts in concert
with its postnatal facilitation of normal suckling activity to foster
the viability of the newborn.
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FOOTNOTES |
Received Nov. 30, 1999; revised Feb. 18, 2000; accepted Feb. 28, 2000.
This work was supported by National Institutes of Health Grants HL52925
and HL60064, Office of Naval Research Grants N00014-95-1-0414 and
N00014-95-1-0863, and the Human Frontier Science Program. We thank Drs.
Y. Li, S. Tonegawa, M. Constantine-Paton, A. Foutz, J. Bissonnette, H. Kinney, and D. Gozal for valuable comments on this manuscript, Drs. Y. Li and S. Tonegawa for providing the NR1/ mutant mice, and K. Kolandaivelu and J. Law for technical assistance.
Correspondence should be addressed to Dr. C.-S. Poon, Harvard-MIT
Division of Health Sciences and Technology, Building E25-501, Massachusetts Institute of Technology, Cambridge, MA 02139. E-mail: cpoon{at}mit.edu.
This article is published in
The Journal of Neuroscience, Rapid Communications Section,
which publishes brief, peer-reviewed papers online, not in print. Rapid
Communications are posted online approximately one month earlier than
they would appear if printed. They are listed in the Table of Contents
of the next open issue of JNeurosci. Cite this article as:
JNeurosci, 2000, 20:RC73 (1-6). The
publication date is the date of posting online at
www.jneurosci.org.
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