Department of Neurology and the Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032
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ABSTRACT |
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Dammerman, R. S., A. C. Flint, S. Noctor, and A. R. Kriegstein. An Excitatory GABAergic Plexus in Developing Neocortical Layer 1. J. Neurophysiol. 84: 428-434, 2000. Layer 1 of the developing rodent somatosensory cortex contains a dense, transient GABAergic fiber plexus. Axons arising from the zona incerta (ZI) of the ventral thalamus contribute to this plexus, as do axons of intrinsic GABAergic cells of layer 1. The function of this early-appearing fiber plexus is not known, but these fibers are positioned to contact the apical dendrites of most postmigratory neurons. Here we show that electrical stimulation of layer 1 results in a GABAA-mediated postsynaptic current (PSC) in pyramidal neurons. Gramicidin perforated patch recording demonstrates that the GABAergic layer 1 synapse is excitatory and can trigger action potentials in cortical neurons. In contrast to electrical stimulation, activation of intrinsic layer 1 neurons with a glutamate agonist fails to produce PSCs in pyramidal cells. In addition, responses can be evoked by stimulation of layer 1 at relatively large distances from the recording site. These findings are consistent with a contribution of the widely projecting incertocortical pathway, the only described GABAergic projection to neonatal cortex. Recording of identified neonatal incertocortical neurons reveals a population of active cells that exhibit high frequencies of spontaneous action potentials and are capable of robustly activating neonatal cortical neurons. Because the fiber plexus is confined to layer 1, this pathway provides a spatially restricted excitatory GABAergic innervation of the distal apical dendrites of pyramidal neurons during the peak period of cortical synaptogenesis.
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INTRODUCTION |
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A prominent feature of the early postnatal
rodent somatosensory cortex is a transient, dense GABAergic fiber
plexus confined to layer 1 (Del Rio et al. 1992;
Lauder et al. 1986
). Neurites of intrinsic GABAergic
cortical neurons, including a subset of Cajal-Retzius (CR) cells and
neurogliaform cells potentially contribute to this plexus (Cobas
et al. 1991
; Hestrin and Armstrong 1996
; Imamoto et al.1994
; Marin-Padilla 1998
).
The only demonstrated extrinsic source of GABA, however, is a
lamina-specific projection from the zona incerta (ZI)
(Castro-Alamancos and Connors 1997
; Lin et al.
1990
). Incertocortical fibers ramify within the upper half of
layer 1 where they make contact with the apical dendrites of pyramidal
neurons (Lin et al. 1997
). This incertocortical pathway develops at the same time as the major thalamocortical pathway from the
dorsal thalamus (Catalano et al. 1991
; Nicolelis
et al. 1995
) and both pathways are driven by sensory input from
the trigeminal system (Carstens et al. 1990
). The layer
1 GABAergic plexus is positioned to provide GABAergic activation during
early stages of synaptogenesis. Whether, or to what degree, these
fibers make functional synapses with developing cortical neurons is
unknown. Additionally, while the incertocortical pathway contributes
fibers to this plexus, the physiological properties of the cells
providing this projection have not been examined.
Unlike the action of GABA in more mature cortex, GABA released from
fibers in layer 1 is likely to have an excitatory effect on developing
cortical neurons. Gramicidin perforated patch recordings have
demonstrated that GABAA receptor activation
produces depolarization of neonatal neurons (Owens et al.
1996). This is due to a high intracellular chloride
concentration in immature neurons maintained by an active chloride
transport mechanism (Clayton et al. 1998
; Rivera
et al. 1999
). Because of the relatively high intracellular chloride concentration in immature neurons, GABAergic activation in
layer 1 would be predicted to depolarize the apical dendrites of
pyramidal neurons. Studies of the developing neocortex have indicated a
role for membrane depolarization as a necessary step in associative
processes including paradigms involving synaptic plasticity and the
conversion of "silent" synapses to functional synapses
(Feldman et al. 1998
; Isaac et al. 1997
).
Given the presumed paucity of AMPA mediated excitatory synapses in
neonatal cortex (Isaac et al. 1997
; Kim et al.
1995
), the synaptic source for depolarization at this age is
unclear. A widespread excitatory GABAergic projection within layer 1 could provide the membrane depolarization necessary to induce long-term
changes in synaptic efficacy.
Here we characterize the postsynaptic current resulting from selective stimulation of layer 1. We find, in all neonatal pyramidal cells examined, a GABAA-mediated depolarizing response that can often initiate action potential firing. This GABAA-mediated postsynaptic current (PSC) could be elicited by electrical but not chemical stimulation of layer 1 and could be elicited by electrical stimulation at relatively large distances from the recorded cells. These observations suggest that the presynaptic source furnishing the excitatory GABAergic response is provided by fibers of passage rather than intrinsic layer 1 cells. The only described extrinsic GABAergic innervation of developing rodent somatosensory cortex is provided by the ZI. We therefore identified incertocortical projection neurons which could contribute to the presynaptic source of the evoked response, and found them to be physiologically mature at neonatal stages and to exhibit high rates of spontaneous activity. The GABAergic plexus in layer 1 therefore provides robust, spatially restricted excitation of pyramidal cells at early stages of development.
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METHODS |
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Whole cell recording
Sprague-Dawley rats were used for all electrophysiological
experiments, and the day of birth was defined as postnatal day 0 (P0).
Standard methods were used for preparation of vibratome slices as
previously described (Blanton et al. 1989). A sapphire blade (Delaware Diamond Knives, Wilmington, DE) was used to maintain the fragile layer 1 in early postnatal slices. The extracellular artificial cerebrospinal fluid (ACSF) solution contained (in mM): 124 NaCl, 2.5 KCl, 1.25 NaH2PO4, 1 MgSO4, 2 CaCl2, 25 NaHCO3, and 20 glucose, pH 7.4 at 25°C, and was
bubbled with 95% O2-5% CO2. Borosilicate glass patch clamp electrodes
(4-8 M
) were filled with (in mM): 130 KCl, 5 NaCl, 10 HEPES, 0.4 CaCl2, 1 MgCl2, and 1.1 EGTA, pH 7.3 at 25°C. In some experiments the sodium channel antagonist QX-314
(2-[Diethlyamino]-N-[2,6-dimethlyphenyl]acetamide) (0.1 mM) was
included in the intracellular solution. Other experiments were
performed using CsCl (130 mM) in place of KCl to block voltage-gated potassium channels. In experiments to test different concentrations of
[Cl
]pipette, gluconate
was substituted for Cl
in the filling solution.
Patch clamp recordings were obtained under infrared differential
interference contrast videomicroscopy (IR-DIC) using an Olympus BX50WI
microscope (Melville, NY). Voltage and current clamp experiments were
performed using an EPC-9 patch-clamp amplifier (Heka Electronic,
Lambrecht, Germany) controlled by a Macintosh computer running Pulse v.
8.0 software (Heka Electronic). Liquid junction potentials were
determined and corrected for using the method of Neher (Neher
1992
). Unless otherwise indicated, pyramidal cells were
recorded as assessed by the presence of the following under IR-DIC:
1) pyramid-shaped soma, 2) apical dendrite extending to the pial surface, and 3) one or more basal
dendrites. Synaptic events were evoked by 200 µs stimulation at
intensities of 100-400 µA applied using a concentric bipolar
stimulating electrode (World Precision Instruments, Sarasota, FL) or by
focal application (pipette diameter
25-35 µm) of 200 µM
L-glutamic acid (Tocris, Ballwin, MO) for 0.5 s. The following
drugs (Research Biochemicals International, Natick, MA) were used at
the indicated concentrations: 50 µM bicuculline, 50 µM
D(-)-2-amino-5-phosphonovalerate (D-AP5), 1 mM
kynurenate, and 10 µM 6,7-dinitroquinoxaline-2,3-dione (DNQX). For
monophasic events, drug effects were measured as changes in average (at
least 3 traces) peak current amplitude. For polyphasic events, evoked
currents were integrated and drug effects were measured as changes in
average charge. In instances where the stimulus artifact obscured the
initial component of an evoked PSC, the latency to onset of the PSC was
estimated by extrapolation of a single exponential fit to the
uncontaminated PSC rising phase.
Perforated patch recording
Perforated patch recordings were obtained as previously
described (Owens et al. 1996). Briefly, patch pipettes
were filled with a KCl-based filling solution (as above), to which
gramicidin (Calbiochem, San Diego, CA) was added on the day of the
experiment (solution kept on ice). The tip of the electrode was filled
with 40 mg/ml gramicidin and the remainder of the electrode was filled with 10 mg/ml gramicidin. Following tight seal formation, access was
allowed to develop for 10-30 min prior to recording.
Retrograde fluorescent microsphere labeling
A solution of rhodamine-conjugated microspheres (FluoSpheres, Molecular Probes, Eugene, OR) was injected (1 µL) onto the surface of the cortex beneath the meninges of P2/3 postnatal rat pups under hypothermic anesthesia. The surgical wound was closed using New Skin (Medtech, Jackson, WY), and the pups were killed at P6/7 to prepare coronal diencephalic slices for patch clamp recording. The zona incerta was identified at low power (4 × objective), and cells containing fluorescent microspheres were identified under high power (60 × objective) prior to patch clamp recording with a filling solution containing 1-2% Lucifer yellow (Sigma, St. Louis, MO). Lucifer yellow and FluoSphere (rhodamine) fluorescence were recorded with a cooled CCD camera (Dage, Stamford, CT) using epifluorescence and appropriate filters during recording.
Calcium imaging
Measurements of relative changes in
[Ca2+]i were made using
epifluorescence microscopy of neocortical slices as previously
described (Flint et al. 1999). Cells were loaded with
the calcium indicator dye fluo-3-AM (Molecular Probes,15 µM) and
imaged under epifluorescent illumination with appropriate filters.
Excitation light exposure was minimized using neutral density filters
and a shutter in the light path. Images were acquired with a cooled CCD
camera (Dage) using NIH Image software on a Macintosh computer. Changes
in fluorescence were converted to
F/F format according to standard
calculations (Owens et al. 1996
).
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RESULTS |
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Whole-cell patch clamp recordings were made from pyramidal neurons
in coronal cortical slices obtained from neonatal rats. Bipolar
stimulation of layer 1 (Fig.
1A) induced fast monophasic PSCs in recordings from pyramidal cells in layers 2-6
(n = 70 cells, 14 cells in each lamina). The layer
1-evoked PSC had a latency to onset of 3.9 ± 0.2 ms (mean ± SE), a latency to peak of 9.0 ± 2 ms, and decay constant = 56.7 ± 4.2 ms. The latency of this response is similar to that
of the well-characterized, monosynaptic thalamocortical synapse at this
early age recorded at room temperature (Kidd and Isaac
1999
). During the first postnatal week (P0-7), the layer
1-evoked PSC was completely and reversibly abolished (>95% reduction
in peak amplitude) by the GABAA receptor antagonist bicuculline (50 µM, n = 35, Fig.
1A), demonstrating that, in developing layer 1, GABAergic
fibers provide the major input to neocortical neurons. We found that
the GABAergic layer 1-evoked PSC could follow repetitive stimulation in
the 0.1-5 Hz range without signs of fatigue including increased
failure frequency or diminished peak amplitude (Fig. 1A).
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In contrast to our findings in neonates, stimulation of layer 1 in the
adult cortex has been reported to produce a predominantly glutamate-mediated response in cortical pyramidal neurons
(Cauller and Connors 1994). We therefore examined
developmental changes in the response to layer 1 stimulation. There was
no glutamatergic contribution to the layer 1-evoked PSC from P0-7, as
the PSC was entirely abolished by bicuculline at these ages
(n = 35, Fig. 1A) and was unaffected by the
glutamatergic antagonists DNQX (10 µM) and D-AP5 (50 µM) (n = 10). By contrast, in recordings made after
P11 (P11-35), we found a consistent contribution to the layer 1-evoked
PSC by ionotropic glutamate receptors (n = 15) as
previously described (Cauller and Connors 1994
).
Detection of a persistent bicuculline-sensitive GABAergic component,
however, was possible at these later ages in the presence of the
nonselective glutamate receptor antagonist, kynurenic acid (1 mM) or
the combination of DNQX and D-AP5 (n = 5 P11 pyramidal cells, n = 5 P35 pyramidal cells). To
determine the relative contribution of ionotropic glutamate and
GABAA receptor activation to the layer 1 evoked
response, the sodium channel antagonist QX-314
(2-[Diethlyamino]-N-[2,6-dimethlyphenyl]acetamide) was added to the
intracellular solution to prevent escape spikes, which were otherwise
often observed even at low stimulus intensities. At P11
(n = 5 pyramidal cells in 3 slices) 82 ± 4% (SD)
of the evoked response was reversibly blocked by a combination of DNQX and D-AP5. The response that persisted in the presence of
these glutamate antagonists was reversibly blocked (>95% reduction in peak amplitude) by bicuculline (Fig. 1A). Thus, during the
second postnatal week, the GABAergic component of the layer 1 response represented approximately 18% of the total response.
Electrical stimulation of cortical lamina other than layer 1 produces
large polysynaptic currents predominantly mediated by glutamate
(Burgard and Hablitz 1993; Flint et al.
1997
; Kim et al. 1995
). This was confirmed in
recordings with the stimulation electrode placed within layer 3/4 (Fig.
1B). Evoked GABA receptor-mediated synaptic responses have
generally not been described during the first postnatal week
(Agmon and O'Dowd 1992
; Burgard and Hablitz 1993
; Kim et al. 1995
; Luhmann and Prince
1991
). Low intensity stimulation in the subcortical white
matter during the first postnatal week produces a purely glutamatergic
synaptic response (Agmon and O'Dowd 1992
;
Burgard and Hablitz 1993
; Kim et al.
1995
); however, more intense white matter stimulation can
recruit a GABAA receptor-mediated polysynaptic
response which fatigues rapidly on repeated stimulation (Agmon
et al. 1996
).
Unlike the inhibitory effect of GABAA receptor
activation in adult cortical neurons, activation of
GABAA receptors depolarizes developing postnatal
pyramidal cells because immature neurons have relatively high
[Cl]i (Owens et
al. 1996
). The reversal potential of the layer 1-evoked PSC
depends on the concentration of chloride in the whole-cell recording
pipette (see Fig. 2A), as
expected for a response mediated by GABAA
receptors. To test whether the GABAergic layer 1-evoked PSC is
excitatory, we used the gramicidin perforated patch recording method
that leaves [Cl
]i
undisturbed (Kyrozis and Reichling 1995
) (Fig.
2B). Focal stimulation of layer 1 in the first postnatal
week produced a depolarizing excitatory postsynaptic potential in all
cells recorded (n = 6/6), and in several cells (4/6)
stimulation of this pathway led to action potential discharge (Fig.
2C). Therefore the GABAergic fiber plexus in layer 1 provides an early excitatory input to pyramidal cells in the developing
neocortex.
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To confirm that we were exclusively stimulating fibers in layer 1, we
employed a slice preparation in which layer 1 was surgically isolated
(Cauller and Connors 1994) (Fig.
3A). In this slice
preparation, where only a band of layer 1 connected the stimulus site
to the region of cortex containing the recorded cell, GABAergic PSCs persisted (n = 5/5, Fig. 3A). Stimulation of
layer 1 at increasing distances from the recording site (up to 5 mm) in
this preparation and in intact slices yielded GABAergic PSCs that were
indistinguishable from those obtained with closer (500 µm)
stimulation (n = 10/10, Fig. 3B). This
indicates that GABAergic fibers project over relatively long distances
in layer 1. Intrinsic GABAergic layer 1 cells, including Cajal-Retzius
and neurogliaform cells, have axons that ramify locally and extend up
to approximately 700 µm within layer 1 (Hestrin and Armstrong
1996
; Zhou and Hablitz 1996a
). Thus intrinsic cortical neurons are unlikely to contribute significantly to the layer
1 response evoked by stimulation at distances of several millimeters.
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In a further attempt to examine the contribution of intrinsic layer 1 neurons to the evoked layer 1 response, we used focal applications of
glutamate to stimulate intrinsic cells of layer 1 but not
incertocortical axons. We have previously demonstrated that focal
application of glutamate in cortical layers other than layer 1 evokes a
barrage of GABAergic PSCs in developing cortical pyramidal neurons
(Owens et al. 1999). As expected, glutamate applied
within 250-500 µm of recorded P5-6 layer 5 pyramidal cells (n = 7/7 from 4 slices) resulted in a barrage of PSCs
(Fig. 3C). In these same cells, glutamate application at
multiple sites in layer 1, however, failed to elicit an increase in PSC
frequency above the baseline frequency of 0.2 PSC/sec, while bipolar
electrical stimulation of these same sites in layer 1 resulted in the
characteristic monophasic PSC (Fig. 3C). This observation,
in conjunction with the ability to evoke a response by distant
electrical stimulation, suggests that the presynaptic source eliciting
this PSC is provided largely by GABAergic fibers of passage in layer 1 rather than by intrinsic layer 1 cells (Chai et al.
1988
; Sandkuhler et al. 1988
).
The GABAergic fiber plexus in developing layer 1 contains axon
projections from GABAergic neurons of the ZI (Imamoto et al. 1994; Lin et al. 1990
). While the physiological
properties of neonatal layer 1 neurons have been examined
(Hestrin and Armstrong 1996
; Kim et al.
1995
; Zhou and Hablitz 1996b
), the properties of
neonatal ZI cells, including incertocortical projection cells, have not
been studied. Cytochrome oxidase staining of the ZI suggests that this
nucleus has high metabolic activity at early developmental stages
(Nicolelis et al. 1995
). We therefore assessed the
physiological maturity of incertocortical projection neurons by patch
clamp recording. Incertocortical projection neurons in the neonatal (P6/7) ZI were identified by two complementary approaches:
1) observation of their characteristic spindle-shaped
morphology (Nicolelis et al. 1995
) by IR-DIC microscopy
and dye-filling with Lucifer yellow, and 2) retrograde
labeling of individual incertocortical projection neurons with
fluorescent microspheres (Figure
4A)
(Katz et al. 1984
). Whole cell recordings from
spindle-shaped and fluorescent microsphere-labeled incertocortical
projection neurons (Fig. 4B) revealed high rates of
spontaneous synaptic events, spontaneous action potential discharge,
and occasional burst firing (n = 22, Fig.
4C). ZI neurons had the following mean physiologic membrane properties: Vm =
48.4 ± 1.9 mV (mean ± SE), Rinput = 595 ± 60 M
,
mem = 73.3 ± 8.9 ms, and dV/dT of the
rising phase of the action potential = 32.4 ± 3.9 mV/ms.
Therefore projection neurons of the ZI, like those of the dorsal
thalamus (Perez Velazquez and Carlen 1996
), are
spontaneously active and functionally well-developed by the first
postnatal week. We used epifluorescence calcium imaging methods in
neonatal brain slices to sample simultaneous activity in large numbers
of incertal cells. Consistent with the high levels of local activity
inferred from our patch clamp recordings, calcium imaging of
fluo-3-loaded slices of the ZI showed high rates of spontaneous calcium
transients (Fig. 4D, n = 200 cells showing multiple calcium transients in 4 slices) and confirmed that the ZI is
metabolically active in the perinatal period. These transients were
completely and reversibly abolished (n = 100 cells in 2 slices) on bath application of the sodium channel antagonist
tetrodotoxin and a combination of agents to prevent extracellular
calcium entry (0 Ca2+, 1 mM
La3+, and 3 mM EGTA) suggesting that these
calcium transients are mediated by extracellular mechanisms rather than
by release from intracellular stores.
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DISCUSSION |
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In the present study, we have shown that the GABAergic plexus in rodent developing layer 1 forms functional synaptic contacts with pyramidal neurons from birth. GABAergic synapses in layer 1 provide localized excitatory GABAergic drive onto the distal apical dendrites of immature cortical neurons. The layer 1 GABAergic plexus is composed of axons from intrinsic layer 1 cells and projecting fibers from the ZI. Because GABAergic layer 1 neurons and GABAergic incertocortical neurons exhibit features of physiological maturity by this stage of development, this excitatory drive may help to sculpt early synaptic connections.
The relative contribution of incertal neurons and cortical layer 1 interneurons to the GABAergic synapse in layer 1 is difficult to
assess. A slice preparation akin to the thalamocortical slice preparation (Agmon and Connors 1991), in which the
intact incertocortical projection was preserved, would simplify this
analysis. Unlike the thalamocortical projection, however, the more
tortuous incertocortical projection cannot be preserved in a 500 µm
acute slice (R.C.S. Lin, personal communication). Nevertheless, the
ability to evoke the layer 1 GABAergic PSC at distances of several
millimeters argues against a contribution of intrinsic layer 1 interneurons whose axons have not been reported to extend that far
(Hestrin and Armstrong 1996
; Zhou and Hablitz
1996a
). Responses evoked at these distances appear to support
an extrinsic source, in particular the incertocortical pathway, which
courses over relatively long distances within layer 1 and is the only
described extrinsic GABAergic projection to the neonatal cortex
(Lin et al. 1990
; Nicolelis et al. 1995
).
Similarly, failure of glutamatergic stimulation of layer 1 to evoke a
PSC in pyramidal cells suggests that the PSC evoked by bipolar
stimulation arises from activation of fibers of passage rather than of
intrinsic layer 1 cells (Chai et al. 1988
;
Sandkuhler et al. 1988
).
Several lines of evidence suggest that the layer 1 GABAergic
synapse may play a role in early stages of cortical development. This
plexus provides an example of synaptically released GABA exciting
neocortical neurons. The excitatory actions of GABA are generally
confined to immature cortical neurons which have a high intracellular
chloride concentration (Owens et al. 1996). A chloride extruding activity develops postnatally, rendering intracellular chloride low and GABA inhibitory (Rivera et al. 1999
).
GABAergic synapses in layer 1 develop during corticogenesis, as
revealed by GABA immunohistochemistry, with a peak density during
neonatal stages and subsequent decrease into adulthood (Lauder
et al. 1986
; Nicolelis et al. 1995
). These
observations suggest a possible functional role of GABA in layer 1 to
provide a depolarizing influence limited to early postnatal stages of
cortical development.
Neuroanatomical studies show that incertocortical axons express
multiple varicosities, presumed presynaptic specializations, as they
course within layer 1 (Lin et al. 1997). Individual
incertocortical fibers can thus contact the apical dendrites of
multiple pyramidal neurons. This is in marked contrast with the
intracortical ramification of specific dorsal thalamic afferents. These
predominantly glutamatergic fibers originate in nuclei of the dorsal
thalamus, course below the cortical plate, arborize within a restricted
radial domain in layers 3 and 4 (Castro-Alamancos and Connors
1997
), and synapse predominantly onto pyramidal neurons
(Elston et al. 1997
). These two pathways develop prior
to birth (Catalano et al. 1991
; Nicolelis et al.
1995
), and their nuclei of origin both receive somatosensory information from the trigeminal nucleus (Carstens et al.
1990
). Thus activity of specific dorsal thalamocortical
afferents will influence local cortical regions, while activity of
incertocortical afferents could influence multiple pyramidal cells
dispersed throughout the developing cortex.
In the somatosensory cortex, the first postnatal week is a
critical period for sensory plasticity in the formation of layer 4 "barrels," the cortical representations of individual whiskers (Woolsey and Wann 1976). Sensory plasticity during the
critical period has been shown to be dependent on the NMDA subtype of
glutamate receptor (Schlaggar et al. 1993
), which can
act as a detector of coincident neuronal activity. Protocols shown to
induce thalamocortical synaptic plasticity in neonates involve pairing
of thalamocortical stimulation with direct experimental depolarization,
presumably to relieve the magnesium blockade of NMDA receptors
(Crair and Malenka 1995
; Feldman et al.
1998
; Isaac et al. 1997
). However, the native
source of depolarization is unknown, as many thalamocortical synapses
at this age lack synaptic non-NMDA-type glutamate receptors and are
therefore functionally silent synapses at negative membrane potentials
(Isaac et al. 1997
). In other brain regions it has been
suggested that synaptic release of GABA in early development provides
the necessary depolarization to induce long-term potentiation at silent
glutamatergic synapses (Ben-Ari et al. 1997
). During the
first postnatal week GABAergic synapses in layer 1 are capable of
depolarizing pyramidal cells. Further, the layer 1 evoked GABAergic excitatory postsynaptic current can sustain stimulation at rates exceeding those commonly used to induce synaptic plasticity at this age
(Crair and Malenka 1995
; Feldman et al.
1998
). The GABAergic depolarization in layer 1 may, therefore,
act in concert with thalamocortical activation during the critical
period for somatosensory plasticity to produce an activity-dependent
refinement of thalamocortical circuitry.
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ACKNOWLEDGMENTS |
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We thank D. Owens for helpful comments.
This work was supported by National Institute of Neurological Disorders and Stroke Grants NS-21223 and NS-35710 and a grant from the Robert Leet and Clara Guthrie Patterson Trust.
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FOOTNOTES |
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Address for reprint requests: A. Kriegstein, Dept. of Neurology, Columbia University College of Physicians and Surgeons, 630 West 168th St., Rm. 4-408, New York, NY 10032 (E-mail: ark17{at}columbia.edu).
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 8 February 2000; accepted in final form 30 March 2000.
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REFERENCES |
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