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The Journal of Neuroscience, November 1, 2002, 22(21):9171-9175
BRIEF COMMUNICATION
Lesion-Induced Thalamocortical Axonal Plasticity in the S1
Cortex Is Independent of NMDA Receptor Function in Excitatory Cortical
Neurons
Akash
Datwani1, *,
Takuji
Iwasato2, 3, *,
Shigeyoshi
Itohara3, and
Reha S.
Erzurumlu1
1 Department of Cell Biology and Anatomy and
Neuroscience Center, Louisiana State University Health Sciences Center,
New Orleans, Louisiana 70112, 2 PRESTO, Japan Science and
Technology Corporation, and 3 Laboratory for Behavioral
Genetics, Brain Science Institute, RIKEN, Saitama 351-0198, Japan
 |
ABSTRACT |
Neural activity plays an important role in refinement and
plasticity of synaptic connections in developing vertebrate sensory systems. The rodent whisker-barrel pathway is an excellent model system
to investigate the role of activity in formation of patterned neural
connections and their plasticity. When whiskers on the snout or the
sensory nerves innervating them are damaged during a critical period in
development, whisker-specific patterns are altered along the trigeminal
pathway, including the primary somatosensory (S1) cortex. In this
context, NMDA receptor (NMDAR)-mediated activity has been implicated in
patterning and plasticity of somatosensory maps. Using CxNR1KO mice, in
which NMDAR1 (NR1), the essential NMDAR
subunit gene, is disrupted only in excitatory cortical neurons, we
showed that NMDAR-mediated activity is essential for whisker-specific patterning of barrel cells in layer IV of the S1 cortex. In CxNR1KO mice, thalamocortical axons (TCAs) representing the large whiskers segregate into rudimentary patches, but barrels as cellular modules do
not develop. In this study, we examined lesion-induced TCA plasticity
in CxNR1KO mice. TCA patterns underwent normal structural plasticity
when their peripheral inputs were altered after whisker lesions during
the critical period. The extent of the lesion-induced morphological
plasticity and the duration of the critical period were quantitatively
indistinguishable between CxNR1KO and control mice. We conclude that
TCA plasticity in the neocortex is independent of postsynaptic NMDAR
activity in excitatory cortical neurons, and that non-NMDAR-mediated
cortical activity and/or subcortical mechanisms must be operational in
this process.
Key words:
somatosensory cortex; thalamocortical synaptic
plasticity; conditional knock-out; barrels; whiskers; glutamatergic
transmission; Cre/loxP system
| |
INTRODUCTION |
The face representation area of the
rodent primary somatosensory (S1) cortex is characterized by modular
patterns of layer IV granule cells ("barrels") and thalamocortical
axon (TCA) patches that fill these modules (Woolsey and Van der Loos,
1970 ; Killackey, 1973). The distribution of barrels replicates the
spatial arrangement of the whiskers and sinus hairs on the
contralateral snout. These patterns emerge sequentially along the
somatosensory trigeminal neuraxis. They are called "barrelettes" in
the brainstem trigeminal nuclei and "barreloids" in the
ventroposteromedial (VPM) nucleus of the thalamus (Woolsey, 1990;
Erzurumlu and Kind, 2001). The resulting array of presynaptic
whisker-specific inputs and postsynaptic cellular modules confers
neurons with preferential responsiveness to stimulation of individual
whiskers. When nerve or whisker lesions perturb the sensory periphery
during a critical period, there are corresponding alterations in the
physiological and morphological integrity of the barrel map.
Specifically, if a row of whiskers is cauterized during the first few
days after birth, representation of the deprived row shrinks, and that
of neighboring intact barrel rows expands (for review, see Woolsey,
1990). The ratio of this "expansion/shrinkage" (i.e., structural
plasticity) diminishes with age, and no obvious structural changes are
evident when lesions are placed after postnatal day 3 (P3).
Despite a wealth of information at the anatomic, physiological, and
behavioral levels, the mechanisms underlying thalamocortical plasticity
during development and at maturity have been elusive (Goodman and
Shatz, 1993; Cramer and Sur, 1995; Katz and Shatz, 1996; Lebedev et
al., 2000; Pallas, 2001; Wallace et al., 2001). Over the past decade,
glutamatergic neural transmission and its regulation by serotonin
(5-HT) have received significant attention in the sculpting of
connections in the barrel cortex. Several mutations in the genes
encoding NMDA receptors (NMDARs), metabotropic glutamate receptors,
5-HT receptors, 5-HT transporters (5-HTTs), and altered levels of
cortical 5-HT now reveal how presynaptic and postsynaptic
whisker-specific patterns are established in the barrel cortex of mice
(for review, see Erzurumlu and Kind, 2001).
One of these mutant mouse models (CxNR1KO mice) involves selective loss
of functional NMDARs in cortical excitatory neurons (Iwasato et al.,
2000). In these mice, the whiskers on the snout and all subcortical
neural representations of the whiskers are intact. However, in the S1
cortex, layer IV granule cells fail to form barrels, although their
presynaptic inputs from the VPM nucleus of the thalamus develop
whisker-specific patterns that are less distinct than those seen in
control littermates. Thus, the CxNR1KO mouse is an ideal genetic model
to examine the role of cortical excitatory NMDAR function in plasticity
of the TCA terminals during the critical period. We found that CxNR1KO
mice have normal levels of lesion-induced TCA plasticity and duration of the critical period for this plasticity. Thus, NMDAR function in
cortical excitatory neurons is not essential for the lesion-induced TCA plasticity.
| |
MATERIALS AND METHODS |
Experiments and analysis were performed in 208 neonatal mice in
accordance with guidelines of the Institutional Animal Care and Use
Committees of both of our institutes. Of these 208 neonates, 92 were
CxNR1KO
(Emx1Cre/+NR1flox/ )
mice, and 116 were littermate controls. The control mice we used were
not wild-type mice but rather transgenic mice
(Emx1+/+NR1flox/,
Emx1Cre/+NR1
flox/+, or
Emx1+/+NR1
flox/+ mice) derived from the crossing of
Emx1Cre/+NR1+/
or
Emx1Cre/CreNR1+/
mice with NR1flox/flox mice as described
previously (Iwasato et al., 2000). For each age group, 10-59 mice were
used. P0-P6 neonatal mice were anesthetized by hypothermia, the center
row (row C) whisker follicles were electrocauterized (Fig.
1A), and damaged
follicles were removed with forceps. The pups were allowed to recover
and returned to their home cages. Between P7 and P9, the pups were
killed by intraperitoneal overdose injection of sodium pentobarbital.
The effectiveness of row C lesions was verified by two independent
techniques: hematoxylin-eosin (HE) staining of 50 µm tangential
sections through the whisker pads and cytochrome oxidase (CO)
histochemistry on coronal sections through brainstem trigeminal nuclei
and the VPM nucleus of the thalamus.
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Figure 1.
Peripheral and central effects of row C whisker
lesions. A, Diagram of the whisker-barrel pathway
illustrating row C lesion in the whisker pad (WP) and
effects in the principal sensory nucleus (PrV)
and the S1 cortex. TG, Trigeminal ganglion. B,
C, HE-stained tangential sections through the whisker pad of a
normal mouse (B) and a row C follicle
electrocauterized control mouse (C).
Arrows indicate damaged row C whisker follicles, whereas
other rows are uncompromised. D, E, CO histochemistry
reveals normal representation of whiskers and whisker rows (i.e.,
barrelettes) in the principal sensory nucleus (D)
and the absence of row C representation after electrocautery
(E). Lesions were placed at P1, and the whisker
pads and brainstem were examined at P8. Scale bar: B, C,
200 µm; D, E, 500 µm.
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For 5-HTT immunohistochemistry, 60 µm tangential sections of the
cerebral cortex were incubated in anti-5-HTT rabbit polyclonal antibody
(1:10,000; DiaSorin, Stillwater, MN) overnight in PBS with 0.3% Triton
X-100. Sections were rinsed in PBS and then incubated in a secondary
biotinylated goat anti-rabbit antibody (1:200; Sigma, St. Louis, MO),
followed by processing with ABC (Vector Laboratories; Burlingame, CA)
and DAB (Sigma) for light microscopy visualization. Sections were
mounted on gelatin-coated slides, dehydrated, cleared in xylene, and
coverslipped in DePeX mounting medium (BDH Laboratory Supplies, Poole,
UK). In some instances, 5-HTT-immunostained sections were
counterstained with cresyl violet (Nissl stain). For quantitative
analysis, 5-HTT-immunostained tangential cortex sections were
visualized under the light microscope, and images of the barrel field
were acquired by a CoolSnap digital camera (Media Cybernetics,
Carlsbad, CA). Measurements of the entire large whisker-representation
areas (LWAs) and surface areas devoted to each 5-HTT-immunopositive
barrel row (rows B-D) within the LWA were made using the Metaview
Image Analysis Program (Universal Imaging Corp, Downingtown,
PA). The barrel septa were included in the row area
measurements, because these areas are also susceptible to encroachment
by the TCAs from intact neighboring rows. We adopted the measurement
scheme referred to as the D/C ratio that was used previously (Schlaggar
et al., 1993). For each hemisphere, the areas of rows B-D were
normalized for the LWA and expressed as a percentage. Subsequently, the
D/C ratio was calculated by dividing the normalized row D percentage by
the normalized row C percentage for control and CxNR1KO cortices. The
D/C ratio provides a numerical value to the relative cortical territory
devoted to rows D and C and the relative expansion in row D and
reduction of row C in each hemisphere after peripheral lesion. The
standardization corrects for flattening artifacts, normalizes for
overall LWA, and provides a numerical index for the plasticity in both
deprived and nondeprived rows. Consequently, one can effectively
examine the degree of variation of plasticity after row C vibrissa
follicle cauterization across different ages in control and CxNR1KO
barrel cortices.
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RESULTS |
Electrocautery was performed on the center-row (row C) whisker
follicles of CxNR1KO mice and littermate controls
(Emx1+/+ NR1
flox/,
Emx1Cre/+NR1
flox/+, or
Emx1+/+NR1
flox/+) between P0 and P6. Pups were killed by
intraperitoneal overdose injection of sodium pentobarbital between P7
and P9, and the effects of electrocautery were clearly identified in
tangential sections through the whisker pad (Fig. 1, compare
B with C).
Mitochondrial enzyme CO is used routinely as a histochemical marker for
whisker-specific patterns along the rodent trigeminal pathway. We
confirmed the whisker lesion effects in the brainstem trigeminal nuclei
(Fig. 1D,E) and in the VPM nucleus of the thalamus (data not shown). In CxNR1KO and control mice, clear effects of row C
lesions could be detected in the brainstem and thalamus when lesions
were placed during the first 3 d after birth. In the principal
sensory nucleus of the trigeminal nerve, CO patches corresponding to
the row C whiskers were absent (Fig. 1E,
arrow), and in the VPM nucleus, these patches fused into a
narrow band (data not shown), as has been reported previously by others
(for review, see Woolsey, 1990).
We visualized TCA patterns in layer IV of flattened cortices by
immunohistochemistry for 5-HTT. The expression and localization of
5-HTT has been studied extensively in the developing rodent brain.
Developing primary sensory neurons of the somatosensory, auditory, and
visual relay nuclei of the dorsal thalamus express the 5-HTT
gene, and their cortical projections can be identified reliably
by 5-HTT immunohistochemistry (Lebrand et al., 1996, 1998). We found
that in both CxNR1KO and control mice, TCAs corresponding to the
damaged row C whiskers fused into a band. TCA patches corresponding to
the neighboring row B and row D whiskers enlarged when row C whisker
follicles were cauterized during the critical period that lasts through
P3 (Fig. 2). Analysis of row C and row D
areas normalized to LWA by means of ANOVA show that at all ages
examined, the control row areas are always greater than corresponding
row areas of CxNR1KO (Fig.
3A,B)
(p < 0.05). These results are consistent with
our previous report that in the absence of functional NMDARs in
excitatory cortical neurons, the amount of territory occupied by each
TCA terminal patch decreases (Iwasato et al., 2000). Yet the overall
shapes of the curves are similar, indicating that the relative
reductions and expansions of row C (Fig. 3A) and row D (Fig.
3B), respectively, over various ages examined are comparable
between CxNR1KO and control mice.
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Figure 2.
5-HTT immunoreacted tangential sections through
layer IV of the S1 cortex in both control and CxNR1KO pups demonstrate
normal critical-period plasticity. Whisker lesions
(WL) at P0 resulted in robust alterations of TCAs
in both control and CxNR1KO cases. Damaged row C representation areas
were reduced dramatically, and flanking rows B and D areas were
expanded. Lesions placed at subsequent ages P2 and P3 resulted in
progressively less dramatic alterations in TCAs. Arrows
indicate compromised row C as a fused band of TCAs in both control and
CxNR1KO barrel cortex. Lesions placed at P4 or later were ineffective
in imparting plastic changes in TCA patterning in both control and
CxNR1KO mice. Scale bar, 500 µm.
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Figure 3.
Quantification of lesion-induced critical-period
plasticity in control and CxNR1KO barrel cortex. A, B,
Analyses of normalized percentage row C and percentage row D areas at
various ages of whisker lesions indicate that, despite the reduced
areas of overall barrel rows in CxNR1KO S1 cortex (solid
line), the shapes of the curves are similar, indicating that
the TCAs respond similarly to the effects of peripheral lesions.
C, The D/C ratios are indistinguishable for both
genotypes and at different ages of row C lesion and follow a graded
diminution until P3. Lesions placed after P3 are not effective in
reorganizing TCAs, because the critical period of barrel plasticity has
lapsed. n indicates number of animals. Error bars
indicate SEM. Comparisons were made using ANOVA. For D/C ratios, there
were no significant differences across all ages. Analysis of row D
revealed significant differences between control (dashed
line) and CxNR1KO cortices at all ages: P0,
p < 0.000008; P1, p < 0.01;
P2, p < 0.0003; P3, p < 0.04;
P4, p < 0.0004; P5, p < 0.02;
and P6, p < 0.002. Comparisons of row C between
CxNR1KO and control cortices revealed significant differences for all
ages except for P1, P2, and P3, probably because of significant
contraction in row C area at these early ages. p values
for other ages are as follows: P0, p < 0.0001; P4,
p < 0.001; P5, p < 0.02; and
P6, p < 0.001.
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The effects of row C whisker lesions on the D/C ratio at different
postnatal days in control and CxNR1KO S1 cortex were not significantly
different (Fig. 3C). After lesions at progressively older
ages, the overall D/C index of plasticity was diminished comparably for
both groups. Qualitatively, we could discern slightly more plastic
changes in the CxNR1KO animals at P3 (Fig. 2); however, this was not
statistically significant when quantitative areal measurement and
statistical analyses were performed. In some cases, 5-HTT immunostained
sections were counterstained with Nissl stain to reveal cellular
organization in barrel cortex (data not shown). As expected, there were
no cellular patterns in the barrel cortex of experimental (with whisker
lesions) or CxNR1KO animals without whisker lesions, indicating that
even in the absence of postsynaptic cellular patterning, TCAs can
undergo dramatic reorganization. This is significant because it has
been suggested that the modular organization of layer IV barrel cells
and expression of high levels of extracellular matrix proteins such as
tenascin in barrel septa play a role in "cordoning off" TCA
terminals and maintaining their patterned organization (Cooper
and Steindler, 1986; Steindler et al., 1990; but see Jhaveri et al.,
1991). Our results document that the whisker-specific pattern
information is still relayed to the neocortex and maintained by the
TCAs, even when there are no barrels or barrel boundaries in the
neocortex and extracellular matrix distribution is uniform (Iwasato et
al., 2000). In addition, structural plasticity of TCAs occurs
regardless of patterning of postsynaptic elements and NMDAR function in
excitatory cortical neurons.
| |
DISCUSSION |
Our results show that TCA plasticity and the extent of the
critical period for this plasticity in the S1 cortex of CxNR1KO mice
are similar to control transgenic and normal mice. Thus, it is apparent
that NMDAR function in the cortical excitatory neurons is not essential
for the TCA plasticity. These results are in contrast to those of a
previous pharmacological blockade study (Schlaggar et al., 1993), in
which subdural application of Elvax implants loaded with the NMDAR
antagonist APV over the postnatal rat S1 cortex blocked row C
lesion-induced TCA plasticity. A number of possibilities may account
for these different results. Interference with non-NMDA glutamatergic
receptor systems of the APV doses used, action on the presynaptic
thalamic neurons, and action on cortical neurons are among these
possibilities. A later study by the same group showed significant
alterations in single-whisker responsiveness of barrel neurons and
functional organization of cortical columns in postnatal rats treated
with APV-loaded Elvax implants over the barrel cortex (Fox et al.,
1996). The results of this electrophysiological study are in agreement
with our current findings. On the basis of the functional properties of
barrel cortex neurons, Fox et al. (1996) inferred that topographic
refinement of TCAs might be perturbed or intracortical connectivity
might be altered. Our most recent findings in the CxNR1KO mice show that both TCA terminal fields and dendritic differentiation and orientation of barrel cortex cells are compromised (Datwani et al.,
2002). Finally, in the barrel cortex, GABAergic elements also
show patterns and alterations after peripheral lesions during the
critical period (Lin et al., 1985; Akhtar and Land, 1991; Kiser et al.,
1998). Thus, residual NMDAR function in the GABAergic barrel-field
neurons might contribute to the TCA plasticity observed in the CxNR1KO mice.
TCA plasticity in CxNR1KO mice provides insights into the instructive
role of neural activity. We propose that critical-period plasticity and
its duration are set by the levels of afferent activity that start in
the sensory periphery and propagate to the barrel cortex via the
subcortical trigeminal centers. Lesion-induced alterations in TCA
patterning may be a simple transfer of these effects from the brainstem
to the thalamus and consequently to the S1 cortex. This may explain the
recovery of barrel patterns after nerve lesion and cortical NMDAR
blockade (Boylan et al., 2001). In this study, nerve lesions were
placed after the brainstem patterns have already formed and at the
onset of patterning in the VPM nucleus of the thalamus. Thus, the
afferents projecting from one station to the next may already possess
the necessary patterning information to enable their appropriate clustering.
In CxNR1KO mice, barrels as cellular modules do not form, and although
TCAs representing the large whiskers on the snout segregate and develop
patterns, these patterns are smaller than those seen in normal
mice. It is noteworthy that the anterior sinus hair representation was generally absent in CxNR1KO S1 cortex, suggesting that relative levels of activity transmitted by different size vibrissas may be critical in determining the amount of cortical territory occupied by each whisker-related afferent. A recent study in
the developing visual system indicates that relative levels of activity
between competing sets of inputs are crucial for activity-dependent
refinement of sensory connections. Stellwagen and Shatz (2002) showed
that when the afferent input from one eye is made more active by use of
agents that elevate cAMP, corresponding eye-specific layers in the
lateral geniculate nucleus enlarge. If activity levels in both eyes are
elevated, then eye-specific lamination develops normally. These
findings provide strong support for the idea that the relative levels
of activity rather than absolute levels are critical in regulating the
amounts of target territories claimed by competing sets of afferents. A
similar type of differential neural activity along elements
representing large versus small whiskers and damaged versus intact
whiskers may underlie the patterning and plasticity of TCAs in the
barrel cortex, independent of NMDAR function in excitatory postsynaptic cells.
In conclusion, region-specific genetic perturbations of the NMDARs
allow us to differentiate between the presynaptic and postsynaptic elements in patterning of the mammalian sensory cortex. Similar approaches for other receptor systems of glutamatergic transmission would allow dissection of their role in cortical patterning. Likewise, region-specific gene deletions in subcortical sensory pathways will
yield important information about the role of a variety of gene
products in pattern formation and neural plasticity and molecular switches that control the duration of critical periods.
| |
FOOTNOTES |
Received May 21, 2002; revised Aug. 8, 2002; accepted Aug. 16, 2002.
*
A.D and T.I. contributed equally to this work.
This work was supported by a grant-in-aid for Scientific Research from
the Ministry of Education, Culture, Sports, Science, and Technology of
Japan (T.I.) and by National Institutes of Health/National Institute of
Neurological Disorders and Stroke Grant NS-39050 (R.S.E.). We thank R. Ando and Y. Taguchi for technical assistance.
Correspondence should be addressed to either of the following: Dr. Reha
S. Erzurumlu, Department of Cell Biology and Anatomy, Louisiana State
University Health Sciences Center, 1901 Perdido Street, New Orleans, LA
70112, E-mail: rerzur{at}lsuhsc.edu; or Dr. Takuji Iwasato, Behavioral
Genetics Laboratory, Brain Science Institute, The Institute of Physical
and Chemical Research (RIKEN), 2-1, Hirosawa, Wako-shi, Saitama
351-0198, Japan, E-mail: iwasato{at}brain.riken.go.jp.
| |
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[Abstract]
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M. J. Albright, M. C. Weston, M. Inan, C. Rosenmund, and M. C. Crair
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J Neurophysiol,
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[Abstract]
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M. Inan and M. C. Crair
Development of Cortical Maps: Perspectives From the Barrel Cortex
Neuroscientist,
February 1, 2007;
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49 - 61.
[Abstract]
[PDF]
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A. Rebsam, I. Seif, and P. Gaspar
Dissociating Barrel Development and Lesion-Induced Plasticity in the Mouse Somatosensory Cortex
J. Neurosci.,
January 19, 2005;
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706 - 710.
[Abstract]
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TOP
ABSTRACT
INTRODUCTION
