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The Journal of Neuroscience, December 1, 1998, 18(23):10196-10206
Experience-Dependent Plasticity of Adult Rat S1 Cortex Requires
Local NMDA Receptor Activation
V.
Rema1,
M.
Armstrong-James2, and
F. F.
Ebner1
1 Institute for Developmental Neuroscience, John F. Kennedy Center, Vanderbilt University, Nashville, Tennessee 37203, and
2 Department of Physiology, Queen Mary Westfield
College, London University, London, United Kingdom E1 4NS
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ABSTRACT |
The effect of blocking NMDA glutamate receptors in adult rat
cortex on experience-dependent synaptic plasticity of barrel cortex
neurons was studied by infusing D-AP5 with an osmotic minipump over
barrel cortex for 5 d of novel sensory experience. In acute pilot
studies, 500 µM D-AP5 was shown to specifically suppress NMDA receptor (NMDAR)-dependent responses of single cells in cortical layers I-IV. To induce plasticity, all whiskers except D2 and D1 were
cut close to the face 1 d after pump insertion. The animals were
housed with 2 cage mates before recording 4 d later. This pairing
of two whiskers for several days in awake animals generates highly
significant biases in responses from D2 layer IV (barrel) cells to the
intact D1 whisker as opposed to the cut D3 whisker. D-AP5 completely
prevented the D1/D3 surround whisker bias from occurring in the D2
barrel cells (p > 0.6 for D1 > D3,
Wilcoxon). Fast-spike and slow-spike barrel cells were affected
equally, suggesting parity for inhibitory and excitatory cell
plasticity. D-AP5 only partially suppressed the D1/D3 bias in
supragranular layers (layers II-III) in the same penetrations
(p < 0.042 for D1 > D3). In control
animals, the inactive L-AP5 isomer allowed the bias to develop normally
toward the intact surround whisker (p < 0.001 for D1 > D3) for cells in all layers. We conclude that experience-dependent synaptic plasticity of mature barrel cortex is
cortically dependent and that modification of local cortical NMDARs is
necessary for its expression.
Key words:
cortical plasticity; barrel field cortex; whisker
pairing; glutamate receptors; NMDA receptor; AP5
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INTRODUCTION |
The whisker to barrel cortex pathway
has proven to be a powerful system for studying somatosensory
plasticity since its original description by Woolsey and Van der Loos
(1970) . Many studies on barrel cortex have concerned developmental
modifications of the barrel cell clusters consequent to peripheral
receptor or infraorbital nerve damage (Ryugo et al., 1975; Killackey et
al., 1976, 1978; Woolsey and Wann, 1976; Pidoux et al., 1980; O'Leary
et al., 1995). Recently, however, barrel cortex has been shown to
exhibit activity-dependent plasticity of physiological responses even
in adult rats (Delacour et al., 1987; Diamond et al., 1993;
Armstrong-James et al., 1994; Dykes, 1997). In addition, several
laboratories have shown adult barrel column plasticity using
deoxyglucose (Hand, 1982; McCasland et al., 1991; Kossut et al., 1993;
Siucinska and Kossut, 1994; Jablonska et al., 1996; Melzer and Smith,
1997) and optical imaging (Masino and Frostig, 1995) methods. In our
laboratories we find substantial modifications in response profiles of
barrel cells in all layers of adult cortex after 1-30 d of innocuous
bias in sensory activity by simply trimming all but two whiskers
["whisker-pairing plasticity" (WPP)] (Diamond et al., 1993;
Armstrong-James et al., 1994).
A current question is whether any commonalties exist between mechanisms
supporting long-term potentiation (LTP) and those necessary for WPP. In
CA1 hippocampal slices and rat S1/M1 neocortical neurons, induction of
LTP is heavily dependent on voltage-dependent NMDA receptor (NMDAR)
activation (Ascher and Nowak, 1987), which by contrast is not necessary
for normal synaptic transmission (Artola and Singer, 1987; Bliss and
Collingridge, 1993; Bear, 1996b). Unlike neurons studied in slices of
hippocampus or neocortex, however, both normal sensory cortical
transmission and spontaneous activity in intact neocortex is
substantially NMDAR-dependent in adult rats (Armstrong-James et al.,
1993) and adult cats (Tsumoto et al., 1987; Miller et al., 1989; Hicks
et al., 1991). In previous studies on barrel cortex, we have
established that sensory responses in layers I-III to principal
whisker (PW) stimulation are virtually completely suppressed by D-AP5
iontophoresis at levels specific to NMDAR antagonism. However, as
illustrated in Figure 1, responses of
layer IV cells are partially dependent on NMDAR activation (Armstrong-James et al., 1993). Specifically, activity evoked at  8
msec in layer IV by monosynaptic thalamocortical projections is
entirely unaffected by D-AP5 levels that are adequate to block NMDAR
activity but is suppressed by DNQX or CNQX, which are specific blockers
of AMPA receptors. Spike activity evoked at latencies exceeding 10 msec
is virtually completely suppressed by D-AP5, whereas activity at
intermediate latencies of 8-10 msec is partially suppressed by AP5 and
eliminated by DNQX. These results indicate a shared regulation of spike
discharge through NMDA and AMPA receptors for responses to the PW for
most cells in rat SI cortex. On the other hand, sensory activation of
cortical cells by whiskers forming the surround excitatory receptive
field (SRF) is 80-100% dependent on NMDAR activation (Armstrong-James
et al., 1993) (Fig. 1).
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Figure 1.
Dependence of cortical responses on NMDA
and/or AMPA receptors. Diagram on the left shows the
sensory pathway from the whiskers to their respective barrel in cortex
with synaptic relays in the brainstem (Trigem) and
thalamus. Poststimulus time histograms (right)
illustrate the effect of glutamate receptor blockers on different
components of typical responses of D2 barrel column cells to
stimulation of the principal (D2) or one of the surround
D-row (D1) whiskers (M. Armstrong-James, E. Welker,
C. A. Callahan, unpublished data). Data represent probabilities of
spike discharges and their relative AMPA and NMDA dependence as a
function of time poststimulus. Note that short-latency spikes
(<8 msec poststimulus) are heavily dependent on AMPA receptor
transmission, whereas longer-latency spikes (>10 msec poststimulus)
depend on NMDAR transmission.
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In the present study, we have suppressed NMDAR-dependent neuronal
responses in layers I-IV of barrel cortex for 4 d while leaving
non-NMDAR receptor-dependent discharge largely unaffected in these
layers. We show first that sensory transmission involving NMDARs is
crucial to the manifestation of neocortical experiential plasticity and
second that expression of this plasticity is consequent to
activity-dependent modifications of local cortical circuitry.
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MATERIALS AND METHODS |
Animals. A total of 29 adult male Long-Evans rats
were used in this study. Initial, acute experiments were performed on
16 animals to achieve a satisfactory AP5 delivery protocol. For the final experiments, nine experimental animals and four control animals
were used for analysis of plasticity. All animals were between 2 and 3 months old.
Implantation of osmotic minipumps. Surgery for implanting
the pumps was performed using aseptic procedures under Nembutal anesthesia (50 mg/kg). All experimental and control animals had osmotic
minipumps implanted that contained 200 µl of 500 µM
active D-isomer of 2-amino-5 phosphonopentanoic acid
(D-AP5) or the inactive L-isomer
(L-AP5) of the NMDAR antagonist delivered at the rate of 1 µl/hr. Both D-AP5 and L-AP5 were purchased
from Tocris. Before surgery stock solutions of D-AP5 and
L-AP5 at 10 mM concentration were prepared in
artificial CSF (aCSF) and stored as aliquots at  20°C. One
aliquot was diluted to 500 µM with aCSF and used for one
animal. One to 2 hr before surgery the model 2001 Alzet minipumps were
filled completely with either D- or L-AP5
solution, attached to the tubing and cannula, and immersed in sterile
saline until implantation. The anesthetized rat was placed in a
headholder, the soft tissues were retracted from over the calvarium,
and a small hole was drilled with a fine dental burr at 2 mm posterior and 4 mm lateral to Bregma. This placed the cannula over the dura ~1-2 mm medial to the D2 barrel column. Care was taken to prevent the cannula from puncturing the dura while it was held in place with a
micromanipulator and cemented to the skull. The pump with the tubing
attached was inserted into a subcutaneous cavity created by blunt
dissection of the connective tissue between the scapulae. The
investigators doing the recording were blind to whether a given animal
received the active or inactive isomer. There was no observational
difference in behavior between animals receiving the
D-isomer or L-isomer of AP5.
Whisker pairing. "Whisker pairing" (Armstrong-James et
al., 1994) was initiated ~16 hr after the pump was implanted to allow a sufficient concentration of drug to be present at the onset of
whisker trimming. All whiskers, except D1 and D2, were trimmed close to
the skin. After trimming, the animal was placed in a cage with two
other cage mates for 3 d without further manipulation. Animals
having their whiskers trimmed in this way are defined as
"whisker-paired" animals (Diamond et al., 1993; Armstrong-James et
al., 1994). The spared whiskers are called "paired" or "intact" whiskers, whereas the cut whiskers are called "cut" or
"unpaired" or "trimmed" in the text. After trimming, the
animals appeared to explore and to "whisk" in the normal manner,
and they showed no preference for running against a circular wall in
any particular direction (M. E. Diamond, M. Armstrong-James, and
F. F. Ebner, unpublished observations). On the evening of the
fourth day the pump was removed, and ~14 hr later (on day 5) cortical
responses were recorded.
Anesthesia and surgery. For single-unit neurophysiology, all
animals were anesthetized with urethane (1.5 gm/kg, i.p.; 25% solution
in water). When a surgical level of anesthesia was achieved, the rat's
head was placed in a stereotaxic apparatus. Body temperature was
maintained at 36°C by a rectal thermistor electronically controlling a circulating water heating pad under the animal. Cortex was exposed from 4 to 7 mm lateral to the midline and from 0 to 4 mm posterior to
Bregma to access the D2 barrel. Because anesthetic level profoundly affects response characteristics (Armstrong-James and George, 1988),
anesthesia was maintained by supplementary urethane injections (10%
original dose) to maintain burst rates from layer V neurons at two to
four bursts/sec. This rate has been shown to be characteristic of stage
III slow-wave sleep and light anesthesia (Armstrong-James et al., 1985;
Fox and Armstrong-James, 1986). Under these conditions respiration was
regular (80-110 breaths/min in nearly all animals), and spontaneous
limb and eyelid movements were absent; protraction of whiskers did not
occur and whisking movements were absent. Typically, long-latency and
sluggish hindlimb withdrawal could be induced with very firm,
maintained pressure on the hindfoot.
Electrophysiology and data collection. Responses from
single-unit locations were recorded using carbon fiber microelectrodes (Armstrong-James and Millar, 1979; Armstrong-James et al., 1980). Locations were later identified histologically as being within the D2
barrel column for inclusion in the study. Microelectrodes were advanced
with tri-dimensional microdrives with an accuracy of 5 µm in all
three dimensions. The positions of all penetrations were recorded and
correlated with the subpial depths of neurons. Penetration of the
subarachnoid space was determined optically by observing the black tip
of the microelectrode and additionally by an increase of noise from the
electrode (~50% increase). Minimal dimpling of the cortical surface
occurs with the slender profile of these electrodes; consequently, on
egress of the microelectrodes, cell positions were invariably accurate
to within 25 µm. Penetrations typically were distributed across the
D2 barrel from D1 to D3 barrels. The D2 barrel was located by the
knowledge that barrel cells invariably respond at shortest latency
(<8-10 msec) to their principal (in this case D2) whisker
(Armstrong-James and Fox, 1987; Armstrong-James et al., 1992, 1994).
Receptive fields of neurons from the D2 column were analyzed by
stimulating the D2 (principal) whisker and two immediately adjacent
D-row surround whiskers, D1 and D3. Neurons were selected by clear
isolation of action potentials using a time-amplitude window
discriminator (Bak Instruments). The spike durations of all neurons
were measured and stored for off-line identification of spike duration.
A piezoelectric stimulator was used to deliver standardized 3 msec
duration, 300 µm upward deflections of each whisker. Responses evoked
by each whisker were assessed by averaging poststimulus time histograms (PSTHs) to 50 trials delivered at a rate of one per second.
Discriminated spike logic pulses were collected into 1 msec bins using
a CED 1401 Plus processor (Cambridge Electronic Design 1401 plus)
controlled by a 486 PC (Compaq) and analyzed with the Spike 2 language
(Cambridge Electronic Design) using in-house protocols.
Histology and identification of recording site. Cortical
recording sites were marked in vivo by passing a negative DC
current of 1 µA for 5-8 sec on termination of recordings in a
penetration. This current produced a spherical microlesion, ~50-80
µm in diameter, easily visible in histological sections reacted for
cytochrome oxidase (CO) histochemistry. For two penetrations in each
animal, two lesions per track were made to identify penetration
locations and to correlate in vivo depth with laminae
identification in histology sections. On completion of recordings,
animals were overdosed with Nembutal and perfused transcardially with
saline (0.9% sodium chloride) followed by phosphate-buffered 4%
paraformaldehyde. Brains were saturated in 20% sucrose and then 30%
sucrose, and the cortex was flattened, sectioned tangentially, and
stained for cytochrome oxidase activity (Wong-Riley and Welt, 1980) for locating barrels and microlesion sites. A penetration was considered to
be within the D2 barrel column if the recording sites were judged to be
localized within or above or below the bounds of barrel D2 as defined
by the appropriate patch of high CO activity in layer IV. All
penetrations located in the septa separating barrel columns or within
barrel territories other than D2 were excluded from analysis.
Data analysis. In common with previous studies (e.g.,
Armstrong-James and Fox, 1987; Armstrong-James et al., 1992), neurons collected from depths of 450-800 µm in vivo almost
without exception were within defined barrel territory as observed by
high CO density areas. Above these locations neurons were defined as
layer II-III cells and grouped as a single class. All data were
analyzed according to location either in layers II-III or layer IV as
identified above. Neurons collected below the depth of 850 µm were
considered to be in the infragranular layers, mainly layer V.
Counts of spikes generated 100 msec poststimulus were adjusted for
spontaneous activity, by subtracting the mean count per bin for
spontaneous activity collected in the 50 msec before the stimulus from
each poststimulus bin count. PSTHs for some purposes were grouped into
several intervals or "epochs" for PSTH epoch analysis: namely,
3-10, 10-20, 20-100 msec. Spikes within 3 msec poststimulus were
excluded as being too early to be responses evoked by whisker
stimulation. Latency histograms were constructed from the first spike
poststimulus for each trial, the bin with the highest count of evoked
spikes being registered as the modal latency resolved from 1 msec bins.
Statistical analysis of data were by application of Mann-Whitney
U tests or Wilcoxon tests where appropriate.
Immunocytochemistry. To determine whether there were changes
in the level of NMDAR1 protein at the site of recording, brains from two animals superfused with D-AP5 were
immunoreacted with antibodies to NMDAR1 using the protocol described in
Rema and Ebner (1996a) and compared with controls. Animals were deeply anesthetized with sodium pentobarbital and then perfused transcardially with PBS followed by 4% paraformaldehyde in PBS. The brains were then
removed and cryoprotected in 30% sucrose and sectioned at 40 µm
thickness. Sections were immunoreacted with NMDAR1 antibody (AB59) for
48 hr at 4°C. The reactions were visualized using the diaminobenzidine method.
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RESULTS |
Epidural infusion of AP5
For the present study we needed to determine an optimal
concentration of D-AP5 to be superfused over the cortical
surface with an osmotic minipump (Alzet). To arrive at the most
effective concentration of AP5 to place in the minipump from where it
would be released medial to the barrel field, experiments were
performed using different concentrations of D-AP5 in the
minipump (Fig. 2). It was found that
superfusion of D-AP5 at higher concentrations (2-10
mM), while effective in eliminating long-latency
(NMDA-dependent) responses from layer IV cells, usually caused
significant or total suppression of short-latency (8 msec) spikes
from cells at up to 650 µm depth (middle layer IV), suggesting
inappropriate and nonspecific impairment of AMPA receptor transmission.
Concentrations of D-AP5 at 10 µM were
entirely ineffective in suppressing either late or early responses of
layer IV cells or even cells at 100-200 µm depths (layers I-II).
Concentrations at 100 µM superfused for periods of up to
5 hr also typically left cells at 450-600 µm unaffected, although
these concentrations did reduce evoked activity of layer II cells found
at depths of up to 300 µm below the cortical surface.
D-AP5 superfused epidurally at a concentration of 500 µM was found to satisfy the criteria required.
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Figure 2.
Suppression of whisker-driven responses of cells
in layers I-IV after perfusion of barrel cortex with D-AP5
at concentrations of 0.1-10 mM. Epidural perfusion was
maintained for a minimum of 6 hr. Findings are from 12 animals tested
at concentrations of 0.01 mM (n = 1),
0.1 mM (n = 2), 1.0 mM
(n = 3), 2.0 mM (n = 2), 4 mM (n = 2), and 10 mM (n = 2) D-AP5.
Responsive sites were initially categorized by testing for response to
any whisker at midlayer depths [~300, 400, and 650 µm subpial for
layers II/III and IV (Armstrong-James and Fox, 1987)]. The depth of
the first cell was logged and tested with our standard protocol of 50 deflections of individual whiskers to construct PSTHs.
Top, Responses to deflections of center receptive
whiskers were almost completely suppressed in layer IV by
concentrations of 2, 4, and 10 mM D-AP5, but
only partially by concentrations of 0.1-1.0 mM and not at
all by 0.01 mM. Responses of cells in layer III were also
unaffected by 0.01 mM, but completely suppressed by 1.0 mM D-AP5. Bottom, Responses to
deflection of adjacent in-row surround receptive field whiskers were
completely suppressed in layer IV by concentrations of 2.0-10
mM D-AP5 but only partially by concentrations
of 0.1-1.0 mM D-AP5 and not at all by a
concentration of 0.01 mM. Responses of cells in layer III
were unaffected by 0.01 mM, only partially by 0.1 mM, but completely suppressed by 1.0 mM
D-AP5.
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When the microelectrode was advanced to the thalamic ventral posterior
medial (VPM) nucleus, responses relayed there to principal whisker
stimulation were unaltered after superfusion of D-AP5 as
shown in Figure 3. As judged
independently against previous findings where VPM responses are
exquisitely sensitive to excitatory amino acid antagonists and other
drugs (Salt and Eaton, 1988; Armstrong-James et al., 1991), VPM
responses appeared unaffected.
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Figure 3.
Mean responses of five cells in the
ipsilateral ventral posterior medial (VPM) nucleus of
the thalamus to 50 stimuli applied to each cell's principal whisker
before (stippled) and immediately following 5 hr
(solid black) perfusion of 500 µM
D-AP5 over barrel cortex. Before drug application, VPM
cells were sampled at five sites in one penetration through VPM using
coordinates of Armstrong-James and Callahan (1992). These same sites
(±75 µm) were then retested after D-AP5 application.
Responses of VPM cells to principal whiskers did not differ
significantly before and after 5 hr exposure to 500 µm
D-AP5 to cortex. Surround whisker responses were maintained
in both cases but varied as a function of the recording site in the
nucleus, so they cannot be directly compared.
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In further support of the contention that superfused 500 µM AP5 did not diffuse to the thalamus, we have
found in previous studies that much higher concentrations of depressant
drugs or ions superfused over the barrel cortex cause no diminution of responses from VPM whisker-relay neurons (Diamond et al., 1992). As a
consequence of these findings taken together, all superfusion experiments on D1-D2 whisker-paired animals using the Alzet minipump were performed using 500 µM concentrations of either
D-AP5 (for experimental animals) or the inactive isomer
L-AP5 (for controls).
Figure 4 shows the outcome of a
representative experiment in which 500 µM
D-AP5 was superfused over the dura, and responses from D4
barrel neurons, 1.5 mm away, were followed over a period of 3 hr of
drug exposure. The two examples are from separate penetrations that
were located at subcortical depths of 615 and 680 µm (layer IV). For
the first cell (Cell A), it is evident that substantial suppression of discharges at latencies >10 msec poststimulus develops within a few minutes of D-AP5 superfusion, and that
continued exposure to D-AP5 at this level for 2 hr holds
suppression of NMDAR-dependent discharge at ~60%.
Furthermore, discharges evoked at latencies of <8 msec are entirely
unaffected by D-AP5 for the course of the exposure. Because
earlier studies have shown that all principal whisker-evoked discharges
at latencies <8 msec are entirely dependent on AMPA receptor
activation (Armstrong-James et al., 1993), we conclude that AMPA
receptor-dependent discharges were unaffected.
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Figure 4.
Suppression of long-latency responses by
perfusion of 500 µM D-AP5 onto cortex. Cells
A and B are two neurons analyzed from barrel D4. Cell A
shows changes in mean response magnitudes to center whisker D4 and to
surround whiskers D3 and D5 during application of 500 µm
D-AP5 in a normal adult animal. Sequential trials of
whisker responses were recorded before and after 20, 50, and 180 min of
exposure to D-AP5. Responses were derived from analysis of
PSTH data by accumulating spike numbers into the stacked epochs of
various poststimulus durations (inset key). Note that
short-latency responses (at 3-8 and 8-10 msec) show little change in
magnitude. These responses in previous studies have been shown to be
all (3-8 msec) or mostly (8-10 msec) identifiable with monosynaptic
thalamocortical discharge (see Results) and are generated
through AMPA receptors (Armstrong-James et al., 1993).
Cell B was a recorded some 20 min after Cell A in an
adjacent penetration during a continuation of the perfusion
(D-AP5). A very substantial recovery to normal values for
cells in layer IV occurred 25 min after removal of D-AP5.
The penetration sites in each case were protected from the
superfusate by a small well, constructed from dental cement.
Superfusion was ~1-3 mm distant to the D4 barrel
column.
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D1-D2 whisker-paired animals
In the second phase of this study all experiments were performed
on animals with all whiskers cut except D1 and D2 for a period of
4 d (whisker-paired animals). In normal, untreated animals the
cell population within the D2 barrel column can be expected to exhibit
symmetrical, D-row surround whisker receptive fields such that the mean
response magnitudes to D1 and D3 whiskers are equal. In normal adult
D1-D2 whisker-paired animals, (1) the response to the principal
whisker, D2, becomes significantly larger, and (2) the surround
response to the intact D1 whisker is potentiated, thereby biasing the
SRF (Diamond et al., 1993; Armstrong-James et al., 1994; Rema and
Ebner, 1996b; Sachdev et al., 1998). The findings below compare
receptive field modifications of D2 barrel column cells for
experimental (D-AP5 active isomer) and control (L-AP5 inactive isomer) epidurally superfused animals.
Distribution of cells studied
For these experiments, the loci of penetrations in the D2 barrel
column were regulated to ensure that their positions were not skewed
toward either the D1 or the D3 barrel. Attempts were made to locate
penetrations successively across the width of the D2 barrel between
barrels D1 and D3. This procedure was used to avoid a small inherent
bias of SRF responses to one or other of whiskers D1 or D3, which might
arise from too many penetrations being on one side of the barrel
(Armstrong-James et al., 1994). The spatial distribution of all
penetrations across the D2 barrel column in the two categories of
animals (control and experimental) are shown in Figure
5, and they demonstrate that for control
and experimental animals penetrations were not skewed toward either the
D1 or the D3 barrel.
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Figure 5.
Diagram representing distributions of the
penetrations by segment of the D2 barrel for cells used for analysis in
subsequent figures for D-AP5 (left) and
L-AP5 animals (right). The penetrations in
each group of animals were quite evenly spread through the barrel in
reference to their positions in the horizontal axis.
Arrows point to the positions of the adjacent D1 or D3
barrel in the D-row. Distributions were not significantly different in
left and right barrel halves. It was desirable to obtain an even
distribution with respect to proximity to surrounding barrels because
asymmetrical position of penetrations influence mean neuronal responses
to surround whiskers D1 and D3 (Armstrong-James et al., 1994).
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Typically, in each penetration four to eight cells were studied for
response to brief (3 msec) deflections of the principal whisker (D2)
and the immediately surrounding D-row whiskers (D1 was always the
intact D-row whisker, and D3 always the trimmed D-row whisker). Within
the D2 barrel column we restricted our analysis to responses from cells
located at depths of 0-800 µm spanning the first four cortical
layers (see Materials and Methods). For the bulk of the findings
presented below, cells were grouped for separate analysis by being
designated within supragranular (SG) layers II-III (0-450 µm
depths) or within granular layer IV barrels (>450 to <800 µm).
Effect of D-AP5 on layer IV barrel cell plasticity
The effect of 4 d of epidural perfusion of D-AP5
or L-AP5 over the barrel cortex was computed from PSTH data
for the two groups. Responses from 115 cells from experimental animals
and 51 cells from control animals were analyzed, all of which were
located in the D2 barrel. These cells were located within the same
penetrations as those described below for superficial (layers II-III)
cells. The mean response magnitudes to peripheral stimulation of
the D-row whiskers are compared for the two groups of animals in Figure 6. In control animals L-AP5
failed to prevent whisker-pairing plasticity of D2 barrel cells.
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Figure 6.
Mean response magnitudes for cells in layer IV of
the D2 barrel for control and experimental groups of animals 12-14 hr
after stopping perfusion of cortex with the active NMDAR antagonist
(D-AP5) or the inactive isomer (L-AP5).
Histograms represent mean responses for 115 cells (D-AP5)
and 51 cells (L-AP5). Each cell was sampled and analyzed
from PSTH data to 50 stimuli applied to each of three D-row whiskers.
Error bars represent SEM. Responses to D3 whisker are significantly
different in magnitude to D1 whiskers (****p = 0.002, Wilcoxon matched-pair sample test) for controls. In the
experimental animals (D-AP5), responses to D1 and D3 were
not significantly (n.s.) different. Shortest latency
responses (3-8 msec poststimulus) are indicated by
black within the histograms, which illustrate total
responses during 100 msec poststimulus (gray
stipple = intact whiskers; diagonal
stripes = cut whiskers).
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In those animals a clear bias developed in response to the intact D1
whisker as compared with the cut D3 whisker after 4 d of whisker
pairing (D1 = 31 ± 3.4; D3 = 17.5 ± 2.6; Wilcoxon
matched pair; p = 0.019). For experimental animals the
attainment of difference in mean response magnitudes between D3 and D1
whiskers was eliminated by 4 d of D-AP5 exposure, and
the small difference that was observed (22.5 ± 2.4 and 24.2 ± 2.0 spikes/50 stimuli, D3 and D1, respectively) was not significant
(Wilcoxon matched pair; p = 0.689). No significant differences in mean response magnitude were found between responses to
D3 whiskers for experimental and control animals (Mann-Whitney U test). Differences between responses to D1 whiskers for
experimentals and controls were just significant
(p = 0.05; Mann-Whitney U test). When cells were compared on a cell-by-cell basis the bias to the paired
SRF D1 whisker was prevented completely by D-AP5 exposure (Fig. 7), whereas with control exposure
to L-AP5 a profound bias to the paired D1 whisker
developed, typical of undrugged (normal) animals.
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Figure 7.
Degree of surround whisker bias for cells in the
D2 barrel (layer IV) evaluated on the basis of number of cells
responding at greater or lesser response magnitudes to the D1 whisker
(paired whisker) relative to the D3 whisker. D1=D3
indicates when responses were equal (mean response magnitudes within
±5% of each other). Exposure to the active D-AP5 isomer
eliminated the bias expected after whisker pairing.
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Fast-spike and slow-spike cells
In rodent cortex, fast-spike cells with short action potentials
constitute a different morphological and functional group from cells
with longer action potentials, particularly within layer IV (see
Discussion). Because strong evidence exists that nearly all fast-spike
cells in neocortex are inhibitory interneurons whereas cells with
longer duration spikes are predominantly excitatory cells, plasticity
for the two groups was evaluated.
Action potential durations were measured in the present study for 98 of
the cells in the D2 barrel column (n = 32 layers
II-III; n = 66 layer IV barrel) whose receptivity to
D-row whiskers was tested (Fig. 8).
Spikes were classified as slow spikes when >0.75 msec in duration and
as fast-spikes at durations of 0.75 msec. The distributions of these
cells by action potential duration were compared with durations for a
larger sample of cells from previous studies (M. Armstrong-James,
personal communication). In both studies it is clear that a
bimodal distribution of action potential duration exists with the
anti-mode at 0.75 msec. Figure 9 shows
the effects of D-AP5 compared with controls on
whisker-pairing plasticity of cells in the D2 barrel for fast and slow
spikes separately; data being abstracted from the same database as for layer IV cells in Figure 6 for which spike durations were measured. Two
findings are apparent. First, both classes of cells (slow or fast
spikes) exhibited a similar behavior to whisker pairing in that they
generate similar biases in the receptive field responses toward the
paired surround D1 whisker relative to the D3 whisker. D1 responses in
controls were significantly greater than unpaired D3 responses for both
types of cells (Wilcoxon; p = 0.002 and 0.05 for slow
and fast spikes, respectively). Second, D-AP5 perfusion prevented this bias entirely, with no significant differences in
response to the paired D1 or cut D3 whisker (p > 0.4 and p >0.8 for slow and fast spikes,
respectively).
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Figure 8.
Top, Distribution of spike
durations recorded from D-AP5-perfused animals for the
cells in layers II-III (black bars) and IV
(gray bars) of the D2 barrel column used for this
study. Note the bimodal nature of the histogram with antimode at 0.75 msec. Spike durations were measured on a digital Nicolet storage
oscilloscope; traces were delayed by 1 msec for establishing onset.
Durations were measured from quiescent zero-crossing onset to
repolarization across zero voltage, bandpassed at 0.7-10 kHz.
Bottom, Distribution of spike durations recorded for the
cells in layers II-III (black bars) and IV
(gray bars) of the D2 barrel column. These data
were generated in earlier studies on the D2 barrel column in normal
animals used for unrelated experiments, where no drugs were used, but
conditions were entirely similar. Note the similar bimodal
distributions separated at 0.75 msec in the two studies and similar
modal values.
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Figure 9.
Mean response magnitudes for the cells in the D2
barrel (layer IV) for control and experimental groups of animals
divided into fast-spike and slow-spike categories. Note that both fast-
and slow-spike cells exhibit similar plasticity after treatment with
L-AP5 during pairing and similar total suppression of
plasticity in the presence of the active isomer D-AP5
during pairing. For further details, see Figure 6 from which this data
were reclassified.
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Bias in responses to D1 or D3 by penetration
A further index of plasticity is generated by examining the
proportion of penetrations through the D2 barrel, which exhibited a
bias toward one or other of the D-surround whiskers. For
control animals, only 4.5% of penetrations were biased toward the cut whisker, with 67% being biased toward the paired surround whisker. By
contrast, after treatment with the active isomer D-AP5, the numbers of penetrations biased to one or the other
D-surround whisker were similar with 50% of penetrations
being found to be biased to the cut whisker and 41% to the paired
whisker, D1.
Cells in layers II-III (supragranular cells)
In the supragranular layers of the D2 barrel column, 70 cells in
experimental D-AP5-infused animals and 27 cells in
L-AP5-infused control animals were studied. Because
receptive fields of cells in the upper layers differ somewhat by
laminar location (Armstrong-James and Fox, 1987; Armstrong-James et
al., 1992), it was necessary to establish that laminar distributions
were similar for cells in the two groups included in the analysis. The
distributions of acceptable cells by depth for those located in layers
II-III for experimentals and controls are shown in Figure
10. From this figure it is evident that
there was no difference in bias for laminar distributions of cells
studied between experimental and control animals.
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Figure 10.
Distributions of cells by depth recorded in the
superficial layers of the D2 column, layers II-III (between the
cortical surface and 450 µm). Values 100 to
400 indicate depth ± 50 µm, e.g., 100 = 50-150 µm. Note similarity of distributions for controls and
experimentals, supporting the idea that similar sampling of neurons
occurred in each group.
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Effect of D-AP5 on layers II-III (supragranular)
cell plasticity
The effects of 4 d of epidural superfusion of
D-AP5 and L-AP5 over the barrel cortex on mean
response magnitudes of cells in superficial layers to deflection of the
D-row whiskers are compared for the two groups of animals in Figure
11.
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Figure 11.
Mean response magnitudes for supragranular cells
(layers II-III) of the D2 column for experimental (D-AP5)
and control (L-AP5) animals 12-14 hr after stopping
superfusion of cortex with active NMDAR antagonist (D-AP5)
or inactive isomer (L-AP5). Histograms represent mean
responses for 70 cells (experimentals) and 27 cells (controls). Each
cell was sampled and analyzed from PSTH data to 50 stimuli applied to
each of the D-row whiskers. Error bars represent SEMs. Responses to D3
whisker are significantly different in magnitude as compared with D1
whiskers (*p = 0.05 and **p = 0.02, respectively; Wilcoxon matched-pair sample test). Shortest
latency responses (3-8 msec poststimulus) are indicated by
black regions within the histograms, which include total
responses during 100 msec poststimulus (gray
stipple = intact whiskers; diagonal
stripes = cut whiskers).
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In control animals a clear bias developed in response to the intact D1
whisker compared with the cut whisker D3 after 4 d of whisker
pairing (Wilcoxon matched pair; p = 0.019). The mean response to the intact D1 whisker was close to twice that to the cut D3
whisker in the presence of L-AP5 (19.98 and 10.66 spikes/50 stimuli, respectively), showing a normal development in bias toward the
spared surround whisker. For experimental animals the difference in
mean response magnitudes to D1 and D3 was less (20.68 and 15.32 spikes/50 stimuli, respectively), although this difference was still
just significant (Wilcoxon matched pair; p = 0.048).
However, no significant difference in mean response magnitude was found between like individual D-row whiskers for experimentals and controls. When cells were compared on a cell-by-cell basis, however, a clear bias
to the paired SRF whisker was apparent (Fig.
12). The proportion of cells failing to
exhibit a bias to the paired D1 whisker doubled after treatment with
D-AP5. Overall the exposure to D-AP5 for 4 d had no effect on mean D2 response magnitudes when compared with
controls.
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Figure 12.
Surround whisker bias in supragranular (layers
II-III) cells. Degree of surround whisker bias for cells in layers
II-III of the D2 column evaluated on the basis of numbers of cells
responding at greater or lesser response magnitudes to the D1 whisker
(paired whisker) relative to the D3 whisker (cut whisker).
D1=D3 indicates that responses were equal where mean
response magnitudes fell between ±5% of each other. Exposure to
D-AP5 reduced the bias caused by pairing of whiskers D1 and
D2.
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Spontaneous activity
Infusion of D-AP5 does not alter the spontaneous
activity levels of neurons in layer IV barrels compared with control
(1.189 ± 0.058 Hz and 1.207 ± 0.71 Hz for both
D- and L-AP5; p = 0.2317, Mann-Whitney U). However, in the supragranular layer
II-III neurons there is a reduction in mean spontaneous activity from
1.4 ± 1.368 Hz for control L-AP5 cases compared with
1.0 ± 1.1 Hz for D-AP5 experimental cases.
Effect of D-AP5 on the distribution of
NMDAR1 subunit
One of the questions raised by chronic administration of an NMDAR
blocker is whether the receptors are dramatically upregulated, downregulated, or changed in distribution along the dendrites over the
course of receptor blockade. In three separate cases, after 5 d of
superfusion of 500 µM D-AP5 the cortex was
immunoreacted for the NMDAR1 subunit. When compared with the control
hemisphere, the density of NMDAR1 subunit was not altered, as judged by
inspection of the light microscopic slides in these cases.
| |
DISCUSSION |
The principal objective of this study was to establish whether
innocuous experience-dependent plasticity of adult cortical neurons was
dependent on postsynaptic cortical activity, specifically plasticity
generated through NMDAR activation. We have found that 4 d of
epidural superfusion of 500 µM D-AP5 entirely
prevented experience-dependent plasticity of layer IV barrel neurons.
WPP is seen initially as an upward shift in response level to an intact surround and principal whisker (Armstrong-James et al., 1993; Diamond
et al., 1993). The procedure did not significantly affect overall
spontaneous activity in layer IV neurons and response levels of barrel
neurons, which were similar in controls, experimentals, and in previous
studies on normal animals in our laboratories (Armstrong-James et al.,
1992, 1993; Diamond et al., 1993). D-AP5 was used at a
level that was ineffective in suppressing action potentials generated
at latencies <10 msec poststimulus. Whisker-evoked discharges under
identical conditions at these latencies have been identified with
monosynaptic thalamocortical discharge (Armstrong-James et al., 1991,
1992; Armstrong-James, 1995) and have been found in a previous study
from this laboratory to be dependent for their evocation only on AMPA
receptors (Armstrong-James et al., 1993), in common with intracellular
findings in the cat in vivo (Salt et al., 1995). Recently,
as a first finding it has been shown in the in vitro
thalamocortical slice preparation in the mouse that a monosynaptic
NMDAR component can be generated to electrical stimulation of the
ventrobasal thalamus (Gil and Amitai, 1996). However, those
findings relate to responses of layer V cells, whereas our observations
were confined to cells in layers I-IV. Differences in species,
stimulation conditions, and in vitro as opposed to in
vivo preparations also probably contribute to the different findings.
In one part of this study cells were classified on the basis of
duration of action potentials. This was justified on the basis of a
bimodal distribution being found that was entirely similar to that
found for cells used in previous studies on normal rat cortex. In
vitro studies on cortical neurons in rodents have shown that three
classes of cells exist: regular spiking, bursting, and fast-spike
neurons (McCormick et al., 1985; Agmon and Connors, 1992). Fast-spike
neurons with short action potentials were identified as sparsely spiny
stellate neurons, whereas the other two types were identified as spiny
pyramidal cells. The former have been identified as GABAergic and the
latter as excitatory (McCormick et al., 1985; Keller and White, 1987;
Connors and Gutnik, 1990; Agmon and Connors, 1992). Interestingly,
although we found that fast-spike cells were more responsive than
slow-spike cells in confirmation of other studies (Simons, 1978;
Swadlow, 1989; Armstrong-James et al., 1993), both types of cell
exhibited plasticity that was input specific and suppressed by epidural
D-AP5 administration. The distributions of these cells by
class was unaffected by the infusion procedure, being found to match
distributions for normal animals where no drugs were infused.
For layer II-III cells in the same penetrations, a similar quality and
degree of plasticity were generated by whisker-pairing in control
animals as found for underlying barrel cells. The response bias,
however, was incompletely suppressed by D-AP5
(p <0.042 for D1 vs D3). One possible reason for
this was that the D-AP5 pump was removed about 14 hr before
recording to allow for total recovery from any residual AP5 influence.
Because SG cells, but not barrel cells, have been shown to exhibit
plasticity within 1 d after whisker pairing (Diamond et al.,
1994), 14 hr may be a sufficient time for some plasticity to be newly
generated during the period when D-AP5 was not present.
Alternatively, plasticity in layers II-III might conceivably be more
D-AP5-resistant, although this would seem less likely
because D-AP5 was predicted to be at a higher concentration
locally in SG layers, and transmission in these layers in rat barrel
cortex is dominated by NMDAR transmission, more so than in layer IV
(Armstrong-James et al., 1993) and the concentration of NR1 subunit in
SG layers is higher than in layer IV (Rema and Ebner, 1996a).
Unlike previous studies on NMDAR-dependent plasticity of immature
sensory cortex (Fox et al., 1996; Brooks et al., 1997), our findings
relate to experience-dependent plasticity of fully mature neocortex. As
far as we are aware this is the first study to examine adult synaptic
modification in cortical neurons directly in this way, although
Jablonska and her colleagues (1995) have examined adult mouse barrel
cortex plasticity using the deoxyglucose technique after destruction of
whisker follicles. They found expansion in the cortical activity
patterns corresponding to the "C" row after 7 d of lesioning
all mystacial vibrissa follicles except row C. This plasticity was
prevented by Elvax resin implants containing racemic AP5 (Jablonska et
al., 1995).
Comparison with the findings for suppression of developmental
plasticity suggests that there are at least some common mechanisms for
controlling synaptic modifications in adult and developing neocortex.
In neonatal animals, VPM axons develop a normal pattern of barrel
innervation in rodent cortex, even when cortical activity is completely
suppressed during the first postnatal week (Chiaia et al., 1992;
Schlaggar et al., 1993). This activity independence suggests that axon
arbor distribution is independent of neural activity, in contrast to
the development of ocular dominance (OD) columns. However, some
features of developmental structural plasticity have been found to be
partially dependent on cortical activity over the first week of life in
rodents (Schlaggar et al., 1993). The authors found that rearrangements
of barrel morphology caused by lesioning a row of vibrissae was
prevented by perinatal cortical inactivation by AP5 released from Elvax
resin slabs.
Thus, common mechanisms in adults and neonates are suggested by
findings that cortical activity suppression prevents functional plasticity in the rat barrel cortex as it does for OD columns in kitten
V1 cortex (Reiter and Stryker, 1988). The central feature of most
theories is some form of a correlated firing hypothesis, where frequent
co-activation of weak inputs on cortical cells leads to synaptic
strengthening (Hebb, 1949), which can modify the cortical sensory
representation. Analogies with mechanisms underlying LTP are often
proposed (for review, see Bear, 1996a) that depend in part on the
voltage dependence of the NMDAR. In contrast with the present findings,
it was suggested previously that functional plasticity in sensory
cortex, as measured by NMDAR-dependent LTP, comes to an end after the
second postnatal week in rat barrel cortex (Crair and Malenka, 1995;
Kirkwood et al., 1995). The apparent mismatch with our findings may lie
in fundamental differences in mechanisms or alternatively with
differences in functionality of in vivo and in
vitro preparations. In hippocampal slices, simple synaptic
transmission through NMDARs is normally virtually absent (Collingridge
and Lester, 1989; Madison et al., 1991; Bear and Malenka, 1994).
Similarly, the NMDAR is only activated significantly in neocortical
slices when intense postsynaptic activity occurs to sufficiently
depolarize the cell, and this is typically achieved by partial blockade
of GABA receptors (Artola and Singer, 1987); theoretically the NMDAR
then boosts Ca2+ entry to initiate the cascade of
enzyme activation required for synaptic modification. The major
difference from intact barrel neocortex in vivo is that most
normal neurotransmission between cells in cortex, including sensory
transmission, is expressed through NMDARs (Armstrong-James et al.,
1985, 1993), whereas in untreated slices NMDAR channels are
conventionally closed (Collingridge and Lester, 1989). However, a
graded relationship between postsynaptic activity, much of which is
NMDAR dependent, and plasticity is perfectly reasonable, as suggested
by recent models for sensory cortical plasticity (Bienenstock et al.,
1982; Benuskova et al., 1994; Bear, 1996a).
A major concern was to establish that our findings were not the result
of pathological effects concomitant with our procedures. This
influenced our choice of superfusion methodology over an intact dura
rather than invasive placement of resins or in-dwelling catheters. The
effect of D-AP5 on neuronal plasticity for D2 barrel column
cells was evaluated 14 hr after the removal of the minipump containing
the drug. In regard to preserved physiological function, the findings
show that the neurons studied had an overall response profile and
distribution entirely similar to controls for which superfusion of
inactive isomer of L-AP5 was used. Second, the findings for
receptive field bias exhibited by control neurons matched those
found for previous studies on normal animals in which identical
whisker-pairing experiments were performed, and D2 barrel column cells
were examined without minipump delivery of drugs (Diamond et al., 1993;
Armstrong-James et al., 1994). In addition there were no gross changes
in NMDA receptor density within the D2 column as witnessed by NMDAR1
immunoreactivity. We checked this because of the clustering of NMDA
receptors demonstrated by Rao and Craig (1997) along the dendrites of
hippocampal cells in culture after 7-14 d periods of exposure to
D-AP5. We conclude that our technique had no detectable
deleterious effect on overall excitability or neuronal function.
However, the finding of Rao and Craig (1997) has relevance to our
observation that response magnitudes in animals exposed to
D-AP5 superfusion increase for layer II/III cells. It is
quite possible that NMDAR subsynaptic clustering was induced by the
drug and indiscriminately potentiated all excitatory synapses. However,
in addition we found that spontaneous activity was decreased only in
layers II/III. More research is required to determine whether
such an effect may be unique to NMDARs at particular types of synapses.
The concentration of D-AP5 we used was 10- to 100-fold less
than that used in Elvax resins for several days for examining developmental cortical plasticity in rodents and cats (Schlaggar et
al., 1993; Jablonska et al., 1995; Brooks et al., 1997).
However, the concentration we used was adequate to suppress virtually
all evoked activity of neurons in layers II-III. This was not
surprising because in a previous iontophoretic study on barrel neurons
(Armstrong-James et al., 1993) D-AP5 at concentrations
specific for suppression of NMDAR activity also suppressed virtually
all whisker-evoked responses of neurons in layers II-III. However,
layer IV (barrel) neurons in the same study were found to generate
virtually all of their earliest spikes (<10 msec latency) through AMPA
receptors; later spikes were almost totally NMDAR dependent. Because in
the present study the concentration of AP5 was adjusted to leave
short-latency (AMPAR-dependent) responses unaffected over trials of
several hours, it is reasonable to suggest that the concentration of
D-AP5 was fairly specific for NMDAR suppression within
layer IV.
Even allowing for specificity of D-AP5, however, in this
study the interpretation of the findings can be viewed from the
standpoint of suppression of neuronal responses per se, i.e., activity
suppression rather than an effect that can be interpreted as specific
to NMDAR activity suppression (Miller et al., 1989; Armstrong-James et al., 1993), because transmission of sensory information in both visual
cortex (Tsumoto et al., 1987) and barrel cortex (Armstrong-James et
al., 1993) is substantially NMDAR dependent. This alternative interpretation was given by Miller et al. (1989) for findings by
Kleinschmidt et al. (1987) in which ocular dominance plasticity for
kitten striate cortical neurons was disrupted using intracortical infusion at a point source of 5-50 mM D-AP5 to
achieve target concentrations of ~10-100 µM on sampled
cells showing plasticity suppression. These concentrations are in the
same range as those found to be adequate for NMDAR activity suppression
in this study.
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FOOTNOTES |
Received April 10, 1998; revised Sept. 17, 1998; accepted Sept. 21, 1998.
This work was supported by National Institutes of Health Grants
NS-25907 and NS-13031. We thank Ms. Anita Sankaran for expert assistance with the histology.
Correspondence should be addressed to V. Rema, Institute for
Developmental Neuroscience, Box 152 Peabody Mailroom, Vanderbilt University, Nashville, TN 37203.
| |
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Top
Abstract
Introduction
