 |
 Previous Article | Next Article 
The Journal of Neuroscience, August 1, 2002, 22(15):6650-6658
Axon Sprouting in a Model of Temporal Lobe Epilepsy Creates a
Predominantly Excitatory Feedback Circuit
Paul S.
Buckmaster1, 2,
Guo Feng
Zhang1, and
Ruth
Yamawaki1
Departments of 1 Comparative Medicine and
2 Neurology and Neurological Sciences, Stanford University
School of Medicine, Stanford, California 94305
 |
ABSTRACT |
The most common type of epilepsy in adults is temporal lobe
epilepsy. After epileptogenic injuries, dentate granule cell axons (mossy fibers) sprout and form new synaptic connections. Whether this
synaptic reorganization strengthens recurrent inhibitory circuits or
forms a novel recurrent excitatory circuit is unresolved. We labeled
individual granule cells in vivo, reconstructed sprouted mossy fibers at the EM level, and identified postsynaptic targets with
GABA immunocytochemistry in the pilocarpine model of temporal lobe
epilepsy. Granule cells projected an average of 1.0 and 1.1 mm of axon
into the granule cell and molecular layers, respectively. Axons formed
an average of one synapse every 7 µm in the granule cell layer and
every 3 µm in the molecular layer. Most synapses were with spines (76 and 98% in the granule cell and molecular layers, respectively).
Almost all of the synapses were with GABA-negative structures (93 and
96% in the granule cell and molecular layers, respectively). By
integrating light microscopic and EM data, we estimate that sprouted
mossy fibers form an average of over 500 new synapses per granule cell,
but <25 of the new synapses are with GABAergic interneurons. These
findings suggest that almost all of the synapses formed by mossy fibers
in the granule cell and molecular layers are with other granule cells.
Therefore, after epileptogenic treatments that kill hilar mossy cells,
mossy fiber sprouting does not simply replace one recurrent excitatory circuit with another. Rather, it replaces a distally distributed and
disynaptic excitatory feedback circuit with one that is local and monosynaptic.
Key words:
temporal lobe epilepsy; mossy fibers; axon sprouting; electron microscopy; granule cell; GABA
| |
INTRODUCTION |
Temporal lobe epilepsy is the most
common type of epilepsy in adults (Engel et al., 1997 ). The recurrent
excitation hypothesis of temporal lobe epilepsy proposes that, after
epileptogenic injuries, granule cell axons (mossy fibers) reorganize
and establish an abnormal recurrent excitatory circuit that generates
seizure activity through positive feedback between granule cells
(Nadler et al., 1980; Tauck and Nadler, 1985). Data supporting the
recurrent excitation hypothesis include evidence that mossy fibers
invade the granule cell layer and molecular layer of the dentate gyrus
(regions mossy fibers normally avoid) in tissue from patients (de
Lanerolle et al., 1989; Sutula et al., 1989; Houser et al., 1990; Babb
et al., 1991; Isokawa et al., 1993; Franck et al., 1995; Masukawa et
al., 1995; Zhang and Houser, 1999) and models of temporal lobe epilepsy (Cronin and Dudek, 1988; Sutula et al., 1988, 1998; Mello et al., 1993;
Represa et al., 1993; Okazaki et al., 1995; Buckmaster and Dudek,
1997b; Kotti et al., 1997; Wenzel et al., 2000). Electron microscopic
analyses suggest that at least some of the new synaptic contacts formed
by sprouted mossy fibers are with granule cell dendrites (Frotscher and
Zimmer, 1983; Babb et al., 1991; Represa et al., 1993; Franck et al.,
1995; Okazaki et al., 1995; Zhang and Houser, 1999; Wenzel et al.,
2000).
In contrast to the recurrent excitation hypothesis, the recurrent
inhibition hypothesis proposes that sprouted mossy fibers preferentially synapse with inhibitory interneurons rather than with
granule cells. The cell bodies and dendrites of inhibitory interneurons
appear to be contacted by more mossy fiber terminals after axon
reorganization (Sloviter, 1992; Kotti et al., 1997). If this hypothesis
is correct, mossy fiber sprouting may be a homeostatic mechanism to
control hyperexcitability by enhancing recurrent inhibition in the
dentate gyrus.
Thus, currently available data are consistent with both the recurrent
excitation and recurrent inhibition hypotheses. The net effect of mossy
fiber sprouting will depend on the number of synapses made with each
cell type: granule cells versus GABAergic interneurons. To address this
issue, we measured the axon length and synaptic density and examined
the ultrastructure and neurochemistry of the postsynaptic targets of
sprouted mossy fibers in a model of temporal lobe epilepsy.
| |
MATERIALS AND METHODS |
Animals. All experiments were approved by the
Stanford University Institutional Animal Care and Use Committee and
performed in accordance with the National Institute of Health
Guide for the Care and Use of Laboratory Animals. Sprague
Dawley male rats (2 months old) were treated with pilocarpine (380 mg/kg, i.p.) 20 min after atropine methylbromide (5 mg/kg, i.p.).
Diazepam (10 mg/kg, i.p.) was administered 2-3 hr after the onset of
status epilepticus and repeated as needed. Rats were video monitored for seizure activity 40 hr/week. Their first observed spontaneous seizure occurred 45 ± 7 d (mean ± SEM) after status
epilepticus, and they were used in an experiment 45 ± 19 d
after their first observed seizure.
Intracellular labeling. We chose to intracellularly label
granule cells in vivo rather than in hippocampal slices,
because the in vivo technique permits labeling of the entire
axon arbor of the cell, and it provides superior tissue
preservation for ultrastructural analyses and immunocytochemical
labeling. The methods used for in vivo intracellular
labeling of granule cells have been described previously (Buckmaster
and Dudek, 1999). Cells were labeled with biocytin by passing 300 msec
pulses of 0.1-0.3 nA hyperpolarizing current, 50% duty cycle, for an
average of 16 min. The rat was then killed by urethane overdose (2.5 gm/kg, i.p.) and perfused through the ascending aorta at 30 ml/min with 0.9% NaCl for 1 min and 2.5% paraformaldehyde and 1% glutaraldehyde in 0.1 M phosphate buffer (PB), pH 7.4, for 30 min. The brain was removed, hemisected, postfixed overnight, and then
cryoprotected in 30% sucrose in 0.1 M PB.
Tissue processing. The hippocampus was isolated,
straightened, frozen, and sectioned perpendicular to the septotemporal
axis with a microtome set at 40 µm. The methods used for the Timm's stain were similar to those described previously (Buckmaster and Dudek,
1997b). For biocytin processing, serial sections were collected in 0.1 M Tris buffer (TB), pH 7.4, and treated with 1%
sodium borohydride for 30 min and 1% hydrogen peroxide for 2 hr. After rinsing, sections were placed in blocking solution consisting of 2%
bovine serum albumin (BSA), 0.25% DMSO, and 0.05 M Tris-buffered saline (TBS), pH 7.4, for 1 hr.
Sections incubated in avidin-biotin-horseradish peroxidase complex
(1:250; Vector Laboratories, Burlingame, CA) in 0.5% BSA, 0.25% DMSO,
and 0.05 M TBS at 4°C for 86 hr. After thorough
washing in TB, sections were exposed to 0.04% diaminobenzidine and
0.05% NiCl for 15 min. Hydrogen peroxide was added to result in a
0.0025% solution, and sections were reacted for 1 hr. The reaction was
stopped in washes of TB. Sections were postfixed with 1%
OsO4 in sodium cacodylate buffer for 1 hr,
dehydrated in a series of ethanols, placed in propylene oxide,
gradually transferred to pure Araldite/Eponate-12 (Ted Pella, Redding,
CA), and flat embedded between sheets of ACLAR at 60°C for 24 hr.
The axon arbors of nine granule cells were drawn with a camera lucida,
and two-dimensional axon lengths were measured from the drawings with
respect to position within strata of the dentate gyrus. Axon arbors of
two of the nine cells were also reconstructed three-dimensionally with
a Neurolucida system (MicroBrightField, Colchester, VT). Axon lengths
measured two-dimensionally were adjusted for three-dimensionality by a
correction factor (1.25), which was determined using values from the
cells analyzed both ways. Axon lengths were adjusted for tissue
shrinkage using previously determined shrinkage factors (1.06× in the
transverse plane and 1.96× in the z-axis) (Buckmaster and
Dudek, 1999).
Electron microscopy. After light microscopic analysis,
biocytin-labeled axon segments in the granule cell layer and molecular layer were selected for ultrastructural analysis. Selected regions were
remounted on a blank Araldite/Eponate-12 block. From each thick
section, ~500 serial ultrathin sections (80 nm) were made (Reichert
Ultracut S; Leica, Vienna, Austria) and collected on single-slot
nickel grids coated with support film. For postembedding GABA
immunocytochemistry, sections were etched with 0.5% periodic acid for
30 min and 7% sodium metaperiodate for 30 min. Sections were exposed
to blocking solution consisting of 0.8% ovalbumin and 5% fetal calf
serum in 0.05 M TBS, pH 7.6, for 1 hr. After sections were incubated overnight in rabbit anti-GABA serum (1:80) in
blocking solution, they were gently rinsed and then incubated in
anti-rabbit colloidal gold (10 nm diameter, 1:80; Ted Pella) in 0.1%
Triton X-100 and 0.05 M TB, pH 8.2, for 90 min.
After rinsing, sections were stained with 2% uranyl acetate for 6 min and Sato's lead stain for 4 min. All chemicals and reagents were from
Sigma (St. Louis, MO) unless specified otherwise.
Using a transmission electron microscope (Jeol 100CX; Jeol, Peabody,
MA), the biocytin-labeled axon collateral and surrounding structures
were photographed. Sections processed for postembedding GABA
immunocytochemistry were checked for positive controls on a
batch-by-batch basis. A batch of sections was included for
immunocytochemical analysis only if specifically GABA-labeled aspiny
dendrites were found in the molecular layer.
Axon segments were three-dimensionally reconstructed from electron
micrographs using Neurolucida software (MicroBrightField) and a data
tablet (Summagraphics, Seymour, CT). Low-magnification (1800-18,500×)
prints at intervals of <50 sections were used to align
biocytin-labeled profiles with surrounding landmarks, such as granule
cell nuclei. Serial high-magnification (39,600-58,300×) prints were
used to reconstruct axon segments. The number of high-magnification prints greatly exceeded the number of sections, because axon segments snaked up and down and sometimes extended longitudinally within a
section so that montages of multiple prints had to be assembled. Axon
length was measured only from reconstructed segments; gaps in the
reconstruction were not included.
The criteria used to identify ultrastructural profiles have been
described previously (Gray, 1959; Peters et al., 1991; Buckmaster et
al., 1996, 2002). Briefly, synapses were identified by cleft material
between parallel membranes of a vesicle-filled biocytin-labeled presynaptic element and a postsynaptic element with a postsynaptic density. Sometimes it was difficult to determine whether or not a
synaptic contact was present, because the plane of section was not
always perpendicular to the plane of the apposed cell membranes. In
those cases, the specimen holder of the electron microscope was tilted
to check suspected synapses, and ~30% of them were synaptic
contacts. Dendritic shafts were identified by morphological features of
dendrites, including microtubules and mitochondria. Dendritic spines
were identified by morphological features of spines, including a spine
apparatus and continuity with a dendritic shaft.
| |
RESULTS |
Sprouted mossy fiber length
In control tissue, mossy fibers are confined to the hilus and CA3
region, but, in epileptic tissue, mossy fibers project into the granule
cell layer and inner one-third of the molecular layer. This axon
reorganization is revealed by the Timm's stain, which labels black the
zinc-rich mossy fiber terminals (Fig. 1).
Previous studies have shown that, in rat models of temporal lobe
epilepsy, individual granule cells have sprouted mossy fiber
collaterals that extend an average summed length of ~1 mm in the
granule cell layer and ~1 mm in the molecular layer (Sutula et al.,
1998; Buckmaster and Dudek, 1999). Our findings confirm these results.
In six epileptic rats, nine granule cells were labeled: two in the
superior blade, two at the apex, and five in the inferior blade of the
granule cell layer. In the granule cell layer, the average axon length per cell was 1.01 ± 0.41 mm (mean ± SEM), and, in the
molecular layer, it was 1.12 ± 0.59 mm. All of the labeled
granule cells had only one primary axon arising from the soma.
Therefore, all of the sprouted axons that projected into the granule
cell layer and molecular layer were collaterals and not new primary
axons. We cannot exclude the possibility that axon arbors were
incompletely labeled with biocytin, but this seems unlikely. All of the
cells had darkly labeled dendrites, dendritic spines, and axons,
including fine collaterals and a primary branch that projected to the
distal CA3 region.
View larger version (117K):
[in this window]
[in a new window]
|
Figure 1.
Timm's-stained sections of the hippocampus in a
control (a, c) and a pilocarpine-induced
epileptic rat (b, d). Boxed
regions in a and b are shown at
higher magnification in c and d,
respectively. Black mossy fiber terminals are evident in the granule
cell layer (gcl) and inner one-third of
the molecular layer (ml) in the epileptic but not
the control rat.
|
|
Sprouted mossy fibers preferentially synapse with
dendritic spines
Granule cells have spiny dendrites unlike many inhibitory
interneurons in the dentate gyrus (Ramón y Cajal, 1995). If
sprouted mossy fibers preferentially synapse with granule cells, one
would expect to find a high proportion of synapses with dendritic
spines. On the other hand, if sprouted mossy fibers preferentially
synapse with inhibitory interneurons, one would expect to find a high proportion of synapses with dendritic shafts. To identify synapses and
postsynaptic ultrastructure, segments of sprouted mossy fibers were
reconstructed at the EM level (Fig. 2).
Many synaptic contacts were found along the reconstructed axon
segments. Although there was variability in the size of the
postsynaptic densities, the vast majority of synapses formed by
sprouted mossy fibers were clearly asymmetric (type 1) synaptic
contacts (Fig. 3a). From six
epileptic rats, eight sprouted mossy fibers were reconstructed for a
summed length of 312 µm in the granule cell layer and 973 µm in the
molecular layer (Fig. 4). In addition,
three axon segments were examined for synaptic contacts but were not
reconstructed. The proportion of synapses formed with dendritic spines
versus dendritic shafts was measured (Table
1). In the granule cell layer, 45 synaptic contacts were identified: 76% with dendritic spines and 24%
with dendritic shafts. In the molecular layer, 471 synaptic contacts
were identified: 93% with dendritic spines and 7% with dendritic
shafts. The proportion of synapses formed with dendritic spines was
significantly higher in the molecular layer than in the granule cell
layer (p < 0.005;
 2 test). These findings suggest that
sprouted mossy fibers preferentially synapse with spiny granule cells.
However, some classes of inhibitory interneurons in the dentate gyrus
do have spines (Halasy and Somogyi, 1993; Sik et al., 1996;
Acsády et al., 1998; Buckmaster et al., 2002). Therefore, some of
the synapses with spines might have been with inhibitory interneurons
and not granule cells. In addition, granule cells could receive
excitatory synaptic contacts on their dendritic shafts. Therefore, some
of the synapses with shafts (Fig. 3b) might have been with
spiny granule cells and not interneurons. To address these issues, we
used postembedding GABA immunocytochemistry to evaluate the
neurochemical identity of the synaptic targets of sprouted mossy
fibers.
View larger version (39K):
[in this window]
[in a new window]
|
Figure 2.
EM reconstruction of a sprouted mossy fiber in an
epileptic rat. a, A granule cell labeled with biocytin
in vivo in an epileptic rat. Photograph of section
containing the soma (a1) and a light-microscopic
reconstruction (a2) of the cell. Dendrites are thick;
axon is thin. All of the axon shown in this reconstruction is within
the dentate gyrus, and most is within the hilus. Several sections away
from the soma, an axon collateral projected from the hilus through the
granule cell layer and into the molecular layer. A segment of that axon collateral
(box) was selected for reconstruction at the EM level.
h, Hilus; gcl, granule cell layer;
ml, molecular layer. b, Photograph of the
selected axon segment. c1, EM reconstruction of the
selected axon segment (black). Gray
contours indicate cell nuclei that were used as landmarks. The
area in the box is shown at high
magnification in d. c2, Side view of
three-dimensionally reconstructed axon segment demonstrating how the
axon projected through the thickness of the section. d1,
Magnified view of boxed region in c1
demonstrates that the reconstructed axon segment consists of aligned
serial contours (gray) that outlined
biocytin-labeled axon profiles in serial electron micrographs. The
black contour outlined the biocytin-labeled axon
(black) in d2, which forms a synapse
(arrowhead) with a dendritic spine.
|
|
View larger version (95K):
[in this window]
[in a new window]
|
Figure 3.
Sprouted mossy fibers synapsed with dendritic
spines and dendritic shafts. a, A biocytin-labeled axon
(black) in the molecular layer formed synapses
(arrowheads) with a large and a small spine.
b, A biocytin-labeled axon (black) in the
molecular layer formed a synapse (arrowhead) with the
shaft of a spiny (arrows) dendrite.
|
|
View larger version (16K):
[in this window]
[in a new window]
|
Figure 4.
Sprouted mossy fibers synapsed preferentially with
dendritic spines. Reconstructed sprouted mossy fibers with synaptic
contacts indicated by markers. Squares
indicate that the postsynaptic target was a dendritic spine;
circles indicate a dendritic shaft. The identity of each
reconstruction (rat and segment) corresponds to Table 1. Borders
between strata (h, hilus; gcl, granule
cell layer; ml, molecular layer) are indicated by
lines.
|
|
Sprouted mossy fibers preferentially synapse with GABA-negative
dendritic spines
Inhibitory interneurons synthesize and express the
neurotransmitter GABA (Ribak et al., 1978; Sloviter and Nilaver, 1987), and their cell bodies and dendrites are GABA-positive (Halasy and
Somogyi, 1993). Granule cells usually are not GABA positive (Sloviter
and Nilaver, 1987), but, under special circumstances, they may be
(Sloviter et al., 1996). In our material, all granule cells appeared to
be GABA-negative. However, if some did have GABA-positive dendrites, we
would have overestimated the number of synapses formed by sprouted
mossy fibers with interneurons. Specifically GABA-labeled aspiny
dendrites were identified in the molecular layer of each batch of
immunolabeled sections. In addition, whenever GABA-negative
postsynaptic targets were identified, other GABA-positive structures
were evident in the same section (Fig.
5a). Adjacent sections were
examined to verify neurochemical identity of postsynaptic targets.
These positive controls reduced the likelihood of false-negative
results.
View larger version (95K):
[in this window]
[in a new window]
|
Figure 5.
Sprouted mossy fibers synapsed with GABA-negative
and GABA-positive targets. a, A biocytin-labeled axon
(black) formed synaptic contacts
(arrowheads) with two GABA-negative spines. Nearby
GABA-positive structures were labeled with 10-nm-diameter colloidal
gold particles, and a GABA-positive axon terminal formed a symmetric
synapse (arrow) with a granule cell body.
b, A biocytin-labeled axon (black) in the
molecular layer formed a synaptic contact (arrowhead)
with a GABA-positive dendritic shaft.
|
|
Sprouted mossy fibers formed asymmetric synaptic contacts with
GABA-negative and GABA-positive postsynaptic targets (Fig. 5). The
proportion of synapses formed with GABA-negative versus GABA-positive
targets was measured from a subset of the reconstructed sprouted mossy
fibers described above (Table 1). From three epileptic rats, four
reconstructed sprouted mossy fibers had a summed length of 173 µm in
the granule cell layer and 585 µm in the molecular layer (Fig.
6). In addition, another three axon
segments from three different rats were examined for synaptic contacts
but were not reconstructed. In the granule cell layer, 30 synaptic
contacts were identified: 93% with GABA-negative targets and 7% with
GABA-positive targets. In the molecular layer, 366 synaptic contacts
were identified: 96% with GABA-negative targets and 4% with
GABA-positive targets. These findings indicate that sprouted mossy
fibers preferentially synapse with GABA-negative dendritic spines. For
sprouted mossy fibers in both the granule cell layer and molecular
layer, 67% of the postsynaptic dendritic shafts and 98% of the
postsynaptic dendritic spines were GABA-negative.
View larger version (29K):
[in this window]
[in a new window]
|
Figure 6.
Sprouted mossy fibers synapsed preferentially with
GABA-negative dendritic spines. Reconstructed sprouted mossy fibers
with synaptic contacts indicated by markers.
Squares indicate that the postsynaptic target was a
dendritic spine; circles indicate a dendritic shaft.
Open markers indicate that the postsynaptic target was
GABA-negative; filled markers indicate GABA-positive.
The identity of each reconstruction (rat and segment) corresponds to
Table 1. Borders between strata (h, hilus;
gcl, granule cell layer; ml, molecular
layer) are indicated by lines.
|
|
Number of new synapses
Synaptic density was measured from the EM reconstructions of
sprouted mossy fibers (Figs. 4, 6). For the eight reconstructed axon
segments in the molecular layer, an average of one synapse was formed
per 3 µm (0.17-0.43 synapses/µm). For the five reconstructed axon
segments in the granule cell layer, an average of one synapse was
formed every 7 µm (0.10-0.22 synapses/µm). Synaptic density was
significantly higher in the molecular layer than in the granule cell
layer (p < 0.002; t test). Most
presynaptic profiles formed only one synapse, but it was not uncommon
to find a large presynaptic bouton that formed multiple synapses. Only
very rarely could we verify multiple synaptic contacts between a
sprouted mossy fiber and a postsynaptic neuron. However, this was
difficult to determine, because postsynaptic neurons were not labeled individually.
Integrating our light microscopic data on sprouted mossy fiber length
per granule cell with our EM data on synaptic density, we estimate that
the average granule cell formed 140 new synapses in the granule cell
layer and 370 new synapses in the molecular layer. Furthermore, we
estimate that >88% of the new synapses were with dendritic spines and
>95% were with GABA-negative targets.
| |
DISCUSSION |
Previous studies provide evidence that sprouted mossy fibers
synapse with spines of excitatory granule cells (Frotscher and Zimmer,
1983; Represa et al., 1993; Franck et al., 1995; Okazaki et al., 1995;
Zhang and Houser, 1999; Wenzel et al., 2000). However, other studies
suggest that sprouted mossy fibers preferentially synapse with
inhibitory interneurons (Sloviter, 1992; Kotti et al., 1997). We
addressed this unsettled issue by intracellularly labeling granule
cells in epileptic rats in vivo, reconstructing sprouted
axon segments at the EM level, identifying postsynaptic targets with
GABA immunocytochemistry, and quantifying the number of new synapses
formed by sprouted mossy fibers. We found that sprouted mossy fibers
synapse almost exclusively with GABA-negative dendritic spines.
Granule cells are the predominant synaptic target of sprouted
mossy fibers
It is highly likely that sprouted mossy fibers synapsed with the
GABA-negative dendritic spines of granule cells. Granule cells are the
predominant GABA-negative neurons in the dentate gyrus, and their spiny
dendrites project through the granule cell layer and into the molecular
layer in which they extend and ramify (Ramón y Cajal, 1995).
Hilar mossy cells, like granule cells, are GABA-negative (Soriano and
Frotscher, 1994), but, in rats, mossy cell dendrites are mostly
confined to the hilus and only occasionally extend into the molecular
layer (Amaral, 1978). There are GABA-negative cholinergic neurons in
the dentate gyrus, but they are extremely rare (Frotscher et al.,
2000). Therefore, granule cells account for the vast majority of
GABA-negative neuronal structures in the granule cell layer and
molecular layer.
Only 4% of the synaptic contacts examined were with
GABA-immunoreactive neurons. This finding suggests that sprouted mossy fibers only occasionally synapsed with inhibitory interneurons. The
Timm's stain has been used to demonstrate appositions and synaptic
contacts between mossy fiber terminals and basket cells in the granule
cell layer of control (Ribak and Peterson, 1991) and epileptic
(Sloviter, 1992; Kotti et al., 1997) rats. Qualitatively, it appears
that basket cells receive more synaptic input from Timm's-positive
terminals after mossy fiber sprouting (Sloviter, 1992; Kotti et al.,
1997). Quantitative analyses are needed, but this finding suggests that
basket cells may receive more direct synaptic input from granule cells
after mossy fiber sprouting. However, it does not necessarily follow
that basket cells receive more excitatory synaptic contacts, because
Timm's-positive inputs may have only replaced Timm's-negative
excitatory inputs that were lost during epileptogenic injuries.
Regardless of the changes in excitatory synaptic input to basket cells,
our findings suggest that, for each new synapse formed by a sprouted
mossy fiber with a GABA-positive neuron, >20 new synapses are formed
with granule cells.
Functional implications
Our findings support the hypothesis that granule cell axon
reorganization produces a novel recurrent excitatory network that might
generate seizures in patients and models of temporal lobe epilepsy
(Nadler et al., 1980; Tauck and Nadler, 1985). According to that
hypothesis, sprouted mossy fibers replace the excitatory synaptic input
to granule cell proximal dendrites that is lost after hilar mossy cells
are killed by epileptogenic injuries. Mossy cells are the predominant
neuron in the hilus (Amaral, 1978; Buckmaster and Jongen-Rêlo,
1999). In patients and models of temporal lobe epilepsy, the loss of
hilar neurons is correlated with the extent of mossy fiber sprouting
(Babb et al., 1991; Masukawa et al., 1995; Buckmaster and Dudek, 1997b;
Nissinen et al., 2001). Like sprouted mossy fibers, axons of mossy
cells are glutamatergic, and they synapse almost exclusively with
GABA-negative dendritic spines in the granule cell layer and molecular
layer (Buckmaster et al., 1996; Wenzel et al., 1997). However, sprouted
mossy fibers project locally (within 400 µm of the parent cell body)
(Sutula et al., 1998; Buckmaster and Dudek, 1999), whereas mossy cell axons project distally (beyond 600 µm of the parent cell body) before
making the vast majority of their synaptic contacts (Buckmaster et al.,
1996). Therefore, the loss of mossy cells and the sprouting of mossy
fibers does not simply replace one recurrent excitatory network with
another. Rather, it replaces a distally distributed and disynaptic
excitatory feedback circuit with one that is local and monosynaptic.
Previous slice experiments provide functional evidence of recurrent
excitation between granule cells after mossy fiber sprouting in models
of temporal lobe epilepsy (Wuarin and Dudek, 1996, 2001; Molnár
and Nadler, 1999; Lynch and Sutula, 2000). In addition, mossy fiber
sprouting brings synaptically releasable zinc into the granule cell
layer and molecular layer where it might diffuse to inhibitory synapses
and impair GABAA receptor-mediated inhibition
(Buhl et al., 1996; Shumate et al., 1998).
The consequences of synaptic reorganization in the dentate gyrus may be
especially dire. It has been proposed that normally the dentate gyrus
acts like a gate and prevents seizures by filtering neuronal activity
between highly seizurogenic regions in the hippocampus and entorhinal
cortex (Stringer et al., 1989; Lothman et al., 1991). In
kainate-induced epileptic rats, however, the threshold for maximal
dentate activation is increased, not decreased (Buckmaster and Dudek,
1997a). Nevertheless, the formation of a novel excitatory feedback
circuit between granule cells may reduce the filtering capability of
the dentate and increase its propensity to amplify neuronal activity
and propagate seizures through the hippocampus and to other limbic structures.
Our findings support the recurrent excitation hypothesis, but many
questions persist. Mossy fiber sprouting apparent as aberrant Timm's
staining in the granule cell layer and molecular layer is a common
finding in patients and models of temporal lobe epilepsy. The extent of
aberrant Timm's staining, however, does not correlate with seizure
frequency (Buckmaster and Dudek, 1997b; Timofeeva and Peterson, 1999;
Nissinen et al., 2001). Longo and Mello (1997, 1998) reported that, in
models of temporal lobe epilepsy, treatment with cycloheximide blocks
mossy fiber sprouting, but the rats develop epilepsy nevertheless.
However, other investigators have not been able to replicate that
controversial result (Williams et al., 2002). Mossy fiber sprouting is
likely to be one of many factors that contribute to temporal lobe
epileptogenesis. Some other likely contributors include changes in
neurotransmitter expression by granule cells (Shumate et al., 1998),
altered patterns of synaptic input from the entorhinal cortex after
layer III neuron loss (Du et al., 1993), and the loss of GABAergic
interneurons in the dentate gyrus (de Lanerolle et al., 1989; Sloviter
et al., 1991; Mathern et al., 1995; Zhu et al., 1997; Maglóczky
et al., 2000).
Another persistent question is the effect of mossy fiber sprouting
within the hilus. The summed length per granule cell of mossy fiber
collaterals within the hilus is greater in epileptic versus control
rats (Sutula et al., 1998; Buckmaster and Dudek, 1999; Wenzel et al.,
2000). Within the hilus of control rats, there are a variety of
different cell types that mossy fibers might synapse with (Amaral,
1978). In patients (de Lanerolle et al., 1989; Sloviter et al., 1991;
Mathern et al., 1995; Zhu et al., 1997; Maglóczky et al., 2000)
and models of temporal lobe epilepsy (Sloviter, 1987; Obenaus et al.,
1993; Buckmaster and Dudek, 1997b; Buckmaster and Jongen-Rêlo,
1999), hilar neuron loss changes the number and proportion of synaptic
targets available to mossy fibers within the hilus. The formation of
novel basal dendrites by granule cells (Spigelman et al., 1998;
Buckmaster and Dudek, 1999) provides another synaptic target within the
hilus and another avenue for excitatory feedback between granule cells (Ribak et al., 2000). Future studies could address these issues by
reconstructing mossy fibers in the hilus and identifying their postsynaptic targets.
The present study shows that sprouting mossy fibers synapse
almost exclusively with excitatory neurons in the granule cell layer
and molecular layer of the dentate gyrus. Lesioning the synaptic input
from the entorhinal cortex to granule cells also triggers mossy fiber
sprouting and synaptogenesis in adult rats (Laurberg and Zimmer, 1981;
Frotscher and Zimmer, 1983). A variety of experimental treatments that
produce epilepsy also induce axon sprouting in other brain regions
(Salin et al., 1995; Perez et al., 1996; McKinney et al., 1997;
Esclapez et al., 1999). These findings highlight the remarkable
plasticity of the adult CNS and suggest that the formation of
novel recurrent excitatory circuits may be a common contributing factor
to epileptogenesis.
| |
FOOTNOTES |
Received April 23, 2002; revised May 29, 2002; accepted May 31, 2002.
This work was supported by National Institutes of Health/National
Institute of Neurological Disorders and Stroke Grants NS40276 and NS39110.
Correspondence should be addressed to Paul Buckmaster, 300 Pasteur
Drive, R102 Edwards Building, Department of Comparative Medicine,
Stanford University, Stanford, CA 94305-5330. E-mail: psb{at}stanford.edu.
| |
REFERENCES |
-
Acsády L,
Kamondi A,
Sik A,
Freund T,
Buzsáki G
(1998)
GABAergic cells are the major postsynaptic target of mossy fibers in the rat hippocampus.
J Neurosci
18:3386-3403[Abstract/Free Full Text].
-
Amaral DG
(1978)
A Golgi study of cell types in the hilar region of the hippocampus in the rat.
J Comp Neurol
182:851-914[Web of Science][Medline].
-
Babb TL,
Kupfer WR,
Pretorius JK,
Crandall PH,
Levesque MF
(1991)
Synaptic reorganization by mossy fibers in human epileptic fascia dentata.
Neuroscience
42:351-363[Web of Science][Medline].
-
Buckmaster PS,
Dudek FE
(1997a)
Network properties of the dentate gyrus in epileptic rats with hilar neuron loss and granule cell axon reorganization.
J Neurophysiol
77:2685-2696[Abstract/Free Full Text].
-
Buckmaster PS,
Dudek FE
(1997b)
Neuron loss, granule cell axon reorganization, and functional changes in the dentate gyrus of epileptic kainate-treated rats.
J Comp Neurol
385:385-404[Web of Science][Medline].
-
Buckmaster PS,
Dudek FE
(1999)
In vivo intracellular analysis of granule cell axon reorganization in epileptic rats.
J Neurophysiol
81:712-721[Abstract/Free Full Text].
-
Buckmaster PS,
Jongen-Rêlo AL
(1999)
Highly specific neuron loss preserves lateral inhibitory circuits in the dentate gyrus of kainate-induced epileptic rats.
J Neurosci
19:9519-9529[Abstract/Free Full Text].
-
Buckmaster PS,
Wenzel HJ,
Kunkel DD,
Schwartzkroin PA
(1996)
Axon arbors and synaptic connections of hippocampal mossy cells in the rat in vivo.
J Comp Neurol
366:270-292.
-
Buckmaster PS,
Yamawaki R,
Zhang GF
(2002)
Axon arbors and synaptic connections of a vulnerable population of interneurons in the dentate gyrus in vivo.
J Comp Neurol
445:360-373[Web of Science][Medline].
-
Buhl EH,
Otis TS,
Mody I
(1996)
Zinc-induced collapse of augmented inhibition by GABA in a temporal lobe epilepsy model.
Science
271:369-373[Abstract].
-
Cronin J,
Dudek FE
(1988)
Chronic seizures and collateral sprouting of dentate mossy fibers after kainic acid treatment in rats.
Brain Res
474:181-184[Web of Science][Medline].
-
de Lanerolle NC,
Kim JH,
Robbins RJ,
Spencer DD
(1989)
Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy.
Brain Res
495:387-395[Web of Science][Medline].
-
Du F,
Whetsell Jr WO,
Abou-Khalil B,
Blumenkopf B,
Lothman EW,
Schwarcz R
(1993)
Preferential neuronal loss in layer III of the entorhinal cortex in patients with temporal lobe epilepsy.
Epilepsy Res
16:223-233[Web of Science][Medline].
-
Engel Jr J,
Williamson PD,
Wieser H-G
(1997)
Mesial temporal lobe epilepsy.
In: Epilepsy: a comprehensive textbook (Engel Jr J,
Pedley TA,
eds), pp 2417-2426. Philadelphia: Lippincott-Raven.
-
Esclapez M,
Hirsch JC,
Ben-Ari Y,
Bernard C
(1999)
Newly formed excitatory pathways provide a substrate for hyperexcitability in experimental temporal lobe epilepsy.
J Comp Neurol
408:449-460[Web of Science][Medline].
-
Franck JE,
Pokorny J,
Kunkel DD,
Schwartzkroin PA
(1995)
Physiologic and morphologic characteristics of granule cell circuitry in human epileptic hippocampus.
Epilepsia
36:543-558[Web of Science][Medline].
-
Frotscher M,
Zimmer J
(1983)
Lesion-induced mossy fibers to the molecular layer of the rat fascia dentata: identification of postsynaptic granule cells by the Golgi-EM technique.
J Comp Neurol
215:299-311[Web of Science][Medline].
-
Frotscher M,
Vida I,
Bender R
(2000)
Evidence for the existence of non-GABAergic, cholinergic interneurons in the rodent hippocampus.
Neuroscience
96:27-31[Web of Science][Medline].
-
Gray EG
(1959)
Axo-somatic and axo-dendritic synapses of the cerebral cortex.
J Anat
93:420-433[Web of Science][Medline].
-
Halasy K,
Somogyi P
(1993)
Subdivisions in the multiple GABAergic innervation of granule cells in the dentate gyrus of the rat hippocampus.
Eur J Neurosci
5:411-429[Web of Science][Medline].
-
Houser CR,
Miyashiro JE,
Swartz BE,
Walsh GO,
Rich JR,
Delgado-Escueta AV
(1990)
Altered patterns of dynorphin immunoreactivity suggest mossy fiber reorganization in human hippocampal epilepsy.
J Neurosci
10:267-282[Abstract].
-
Isokawa M,
Levesque MF,
Babb TL,
Engel Jr J
(1993)
Single mossy fiber axonal systems of human dentate granule cells studied in hippocampal slices from patients with temporal lobe epilepsy.
J Neurosci
13:1511-1522[Abstract].
-
Kotti T,
Riekkinen PJ,
Miettinen R
(1997)
Characterization of target cells for aberrant mossy fiber collaterals in the dentate gyrus of epileptic rat.
Exp Neurol
146:323-330[Web of Science][Medline].
-
Laurberg S,
Zimmer J
(1981)
Lesion-induced sprouting of hippocampal mossy fiber collaterals to the fascia dentata in developing and adult rats.
J Comp Neurol
200:433-459[Web of Science][Medline].
-
Longo BM,
Mello LEAM
(1997)
Blockade of pilocarpine- or kainate-induced mossy fiber sprouting by cycloheximide does not prevent subsequent epileptogenesis in rats.
Neurosci Lett
226:163-166[Web of Science][Medline].
-
Longo BM,
Mello LEAM
(1998)
Supragranular mossy fiber sprouting is not necessary for spontaneous seizures in the intrahippocampal kainate model of epilepsy in the rat.
Epilepsy Res
32:172-182[Web of Science][Medline].
-
Lothman EW,
Bertram III EH,
Stringer JL
(1991)
Functional anatomy of hippocampal seizures.
Prog Neurobiol
37:1-82[Web of Science][Medline].
-
Lynch M,
Sutula T
(2000)
Recurrent excitatory connectivity in the dentate gyrus of kindled and kainic acid-treated rats.
J Neurophysiol
83:693-704[Abstract/Free Full Text].
-
Maglóczky ZS,
Wittner L,
Borhegyi ZS,
Halász P,
Vajda J,
Czirják S,
Freund TF
(2000)
Changes in the distribution and connectivity of interneurons in the epileptic human dentate gyrus.
Neuroscience
96:7-25[Web of Science][Medline].
-
Masukawa LM,
O'Connor WM,
Lynott J,
Burdette LJ,
Uruno K,
McGonigle P,
O'Connor MJ
(1995)
Longitudinal variation in cell density and mossy fiber reorganization in the dentate gyrus from temporal lobe epileptic patients.
Brain Res
678:65-75[Web of Science][Medline].
-
Mathern GW,
Babb TL,
Pretorius JK,
Leite JP
(1995)
Reactive synaptogenesis and neuron densities for neuropeptide Y, somatostatin, and glutamate decarboxylase immunoreactivity in the epileptogenic human fascia dentata.
J Neurosci
15:3990-4004[Abstract].
-
McKinney RA,
Debanne D,
Gähwiler BH,
Thompson SM
(1997)
Lesion-induced axonal sprouting and hyperexcitability in the hippocampus in vitro: implications for the genesis of posttraumatic epilepsy.
Nat Med
3:990-996[Web of Science][Medline].
-
Mello LEAM,
Cavalheiro EA,
Tan AM,
Kupfer WR,
Pretorius JK,
Babb TL,
Finch DM
(1993)
Circuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: cell loss and mossy fiber sprouting.
Epilepsia
34:985-995[Web of Science][Medline].
-
Molnár P,
Nadler JV
(1999)
Mossy fiber-granule cell synapses in the normal and epileptic rat dentate gyrus studied with minimal laser photostimulation.
J Neurophysiol
82:1883-1894[Abstract/Free Full Text].
-
Nadler JV,
Perry BW,
Cotman CW
(1980)
Selective reinnervation of hippocampal area CA1 and the fascia dentata after destruction of CA3-CA4 afferents with kainic acid.
Brain Res
182:1-9[Web of Science][Medline].
-
Nissinen J,
Lukasiuk K,
Pitkänen A
(2001)
Is mossy fiber sprouting present at the time of the first spontaneous seizures in rat experimental temporal lobe epilepsy?
Hippocampus
11:299-310[Web of Science][Medline].
-
Obenaus A,
Esclapez M,
Houser CR
(1993)
Loss of glutamate decarboxylase mRNA-containing neurons in the rat dentate gyrus following pilocarpine-induced seizures.
J Neurosci
13:4470-4485[Abstract].
-
Okazaki MM,
Evenson DA,
Nadler JV
(1995)
Hippocampal mossy fiber sprouting and synapse formation after status epilepticus in rats: visualization after retrograde transport of biocytin.
J Comp Neurol
352:515-534[Web of Science][Medline].
-
Perez Y,
Morin F,
Beaulieu C,
Lacaille J-C
(1996)
Axonal sprouting of CA1 pyramidal cells in hyperexcitable hippocampal slices of kainate-treated rats.
Eur J Neurosci
8:736-748[Web of Science][Medline].
-
Peters A,
Palay S,
Webster HD
(1991)
In: The fine structure of the nervous system, Ed 3, pp 138-211. New York: Oxford UP.
-
Ramón y Cajal S
(1995)
In: Histology of the nervous system of man and vertebrates, Vol 2 (Swanson N, Swanson LW, translators), pp 614-625. New York: Oxford UP.
-
Represa A,
Jorquera I,
Le Gal La Salle G,
Ben-Ari Y
(1993)
Epilepsy induced collateral sprouting of hippocampal mossy fibers: does it induce the development of ectopic synapses with granule cell dendrites?
Hippocampus
3:257-268[Web of Science][Medline].
-
Ribak CE,
Peterson GM
(1991)
Intragranular mossy fibers in rats and gerbils form synapses with the somata and proximal dendrites of basket cells in the dentate gyrus.
Hippocampus
1:355-364[Medline].
-
Ribak CE,
Vaughn JE,
Saito K
(1978)
Immunocytochemical localization of glutamic acid decarboxylase in neuronal somata following colchicine inhibition of axonal transport.
Brain Res
140:315-332[Web of Science][Medline].
-
Ribak CE,
Tran PH,
Spigelman I,
Okazaki MM,
Nadler JV
(2000)
Status epilepticus-induced hilar basal dendrites on rodent granule cells contribute to recurrent excitatory circuitry.
J Comp Neurol
428:240-253[Web of Science][Medline].
-
Salin P,
Tseng G-F,
Hoffman S,
Parada I,
Prince DA
(1995)
Axonal sprouting in layer V pyramidal neurons of chronically injured cerebral cortex.
J Neurosci
15:8234-8245[Abstract].
-
Shumate MD,
Lin DD,
Gibbs III JW,
Holloway KL,
Coulter DA
(1998)
GABAA receptor function in epileptic human dentate granule cells: comparison to epileptic and control rat.
Epilepsy Res
32:114-128[Web of Science][Medline].
-
Sik A,
Penttonen M,
Buzsáki G
(1996)
Interneurons in the hippocampal dentate gyrus: an in vivo intracellular study.
Eur J Neurosci
9:573-588.
-
Sloviter RS
(1987)
Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy.
Science
235:73-76[Abstract/Free Full Text].
-
Sloviter RS
(1992)
Possible functional consequences of synaptic reorganization in the dentate gyrus of kainate-treated rats.
Neurosci Lett
137:91-96[Web of Science][Medline].
-
Sloviter RS,
Nilaver G
(1987)
Immunocytochemical localization of GABA-, cholecystokinin-, vasoactive intestinal polypeptide-, and somatostatin-like immunoreactivity in the area dentata and hippocampus of the rat.
J Comp Neurol
256:42-60[Web of Science][Medline].
-
Sloviter RS,
Sollas AL,
Barbaro NM,
Laxer KD
(1991)
Calcium-binding protein (calbindin-D28K) and parvalbumin immunocytochemistry in the normal and epileptic human hippocampus.
J Comp Neurol
308:381-396[Web of Science][Medline].
-
Sloviter RS,
Dichter MA,
Rachinsky TL,
Dean E,
Goodman JH,
Sollas AL,
Martin DL
(1996)
Basal expression and induction of glutamate decarboxylase and GABA in excitatory granule cells of the rat and monkey hippocampal dentate gyrus.
J Comp Neurol
373:593-618[Web of Science][Medline].
-
Soriano E,
Frotscher M
(1994)
Mossy cells of the rat fascia dentata are glutamate-immunoreactive.
Hippocampus
4:65-69[Web of Science][Medline].
-
Spigelman I,
Yan X-X,
Obenaus A,
Lee Y-S,
Wasterlain CG,
Ribak CE
(1998)
Dentate granule cells form novel basal dendrites in a rat model of temporal lobe epilepsy.
Neuroscience
86:109-120[Web of Science][Medline].
-
Stringer JL,
Williamson JM,
Lothman EW
(1989)
Induction of paroxysmal discharges in the dentate gyrus: frequency dependence and relationship to afterdischarge production.
J Neurophysiol
62:126-135[Abstract/Free Full Text].
-
Sutula T,
Xiao-Xian H,
Cavazos J,
Scott G
(1988)
Synaptic reorganization in the hippocampus induced by abnormal functional activity.
Science
239:1147-1150[Abstract/Free Full Text].
-
Sutula T,
Cascino G,
Cavazos J,
Parada I,
Ramirez L
(1989)
Mossy fiber synaptic reorganization in the epileptic human temporal lobe.
Ann Neurol
26:321-330[Web of Science][Medline].
-
Sutula T,
Zhang P,
Lynch M,
Sayin U,
Golarai G,
Rod R
(1998)
Synaptic and axonal remodeling of mossy fibers in the hilus and supragranular region of the dentate gyrus in kainate-treated rats.
J Comp Neurol
390:578-594[Web of Science][Medline].
-
Tauck DL,
Nadler JV
(1985)
Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats.
J Neurosci
5:1016-1022[Abstract].
-
Timofeeva OA,
Peterson GM
(1999)
Dissociation of mossy fiber sprouting and electrically-induced seizure sensitivity: rapid kindling versus adaptation.
Epilepsy Res
33:99-115[Web of Science][Medline].
-
Wenzel HJ,
Buckmaster PS,
Anderson NL,
Wenzel ME,
Schwartzkroin PA
(1997)
Ultrastructural localization of neurotransmitter immunoreactivity in mossy cell axons and their synaptic targets in the rat dentate gyrus.
Hippocampus
7:559-570[Web of Science][Medline].
-
Wenzel HJ,
Woolley CS,
Robbins CA,
Schwartzkroin PA
(2000)
Kainic acid-induced mossy fiber sprouting and synapse formation in the dentate gyrus of rats.
Hippocampus
10:244-260[Web of Science][Medline].
-
Williams PA, Wuarin JP, Dou P, Ferraro DJ, Dudek FE (2002) A
reassessment of the effects of cycloheximide on mossy fiber sprouting
and epileptogenesis in the pilocorpine model of temporal lobe epilepsy.
J Neurophysiol, in press.
-
Wuarin J-P,
Dudek FE
(1996)
Electrographic seizures and new recurrent excitatory circuits in the dentate gyrus of hippocampal slices from kainate-treated epileptic rats.
J Neurosci
16:4438-4448[Abstract/Free Full Text].
-
Wuarin J-P,
Dudek FE
(2001)
Excitatory synaptic input to granule cells increases with time after kainate treatment.
J Neurophysiol
85:1067-1077[Abstract/Free Full Text].
-
Zhang N,
Houser CR
(1999)
Ultrastructural localization of dynorphin in the dentate gyrus in human temporal lobe epilepsy: a study of reorganized mossy fiber synapses.
J Comp Neurol
405:472-490[Web of Science][Medline].
-
Zhu Z-Q,
Armstrong DL,
Hamilton WJ,
Grossman RG
(1997)
Disproportionate loss of CA4 parvalbumin-immunoreactive interneurons in patients with Ammon's horn sclerosis.
J Neuropathol Exp Neurol
56:988-998[Web of Science][Medline].
Copyright © 2002 Society for Neuroscience 0270-6474/02/22156650-09$05.00/0
This article has been cited by other articles:
|
|
|
|
 
R. Muramatsu, S. Nakahara, J. Ichikawa, K. Watanabe, N. Matsuki, and R. Koyama
The ratio of 'deleted in colorectal cancer' to 'uncoordinated-5A' netrin-1 receptors on the growth cone regulates mossy fibre directionality
Brain,
October 25, 2009;
(2009)
awp266v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. S. Buckmaster, E. A. Ingram, and X. Wen
Inhibition of the Mammalian Target of Rapamycin Signaling Pathway Suppresses Dentate Granule Cell Axon Sprouting in a Rodent Model of Temporal Lobe Epilepsy
J. Neurosci.,
June 24, 2009;
29(25):
8259 - 8269.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. K. Sharma, W. H. Jordan, R. Y. Reams, D. G. Hall, and P. W. Snyder
Temporal Profile of Clinical Signs and Histopathologic Changes in an F-344 Rat Model of Kainic Acid-induced Mesial Temporal Lobe Epilepsy
Toxicol Pathol,
December 1, 2008;
36(7):
932 - 943.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. J. Morgan and I. Soltesz
From the Cover: Nonrandom connectivity of the epileptic dentate gyrus predicts a major role for neuronal hubs in seizures
PNAS,
April 22, 2008;
105(16):
6179 - 6184.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. K. Sharma, R. Y. Reams, W. H. Jordan, M. A. Miller, H. L. Thacker, and P. W. Snyder
Mesial Temporal Lobe Epilepsy: Pathogenesis, Induced Rodent Models and Lesions
Toxicol Pathol,
December 1, 2007;
35(7):
984 - 999.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. L. Howard, A. Neu, R. J. Morgan, J. C. Echegoyen, and I. Soltesz
Opposing Modifications in Intrinsic Currents and Synaptic Inputs in Post-Traumatic Mossy Cells: Evidence for Single-Cell Homeostasis in a Hyperexcitable Network
J Neurophysiol,
March 1, 2007;
97(3):
2394 - 2409.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Dyhrfjeld-Johnsen, V. Santhakumar, R. J. Morgan, R. Huerta, L. Tsimring, and I. Soltesz
Topological Determinants of Epileptogenesis in Large-Scale Structural and Functional Models of the Dentate Gyrus Derived From Experimental Data
J Neurophysiol,
February 1, 2007;
97(2):
1566 - 1587.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Jin, D. A. Prince, and J. R. Huguenard
Enhanced excitatory synaptic connectivity in layer v pyramidal neurons of chronically injured epileptogenic neocortex in rats.
J. Neurosci.,
May 3, 2006;
26(18):
4891 - 4900.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. S. Overstreet-Wadiche, D. A. Bromberg, A. L. Bensen, and G. L. Westbrook
Seizures Accelerate Functional Integration of Adult-Generated Granule Cells
J. Neurosci.,
April 12, 2006;
26(15):
4095 - 4103.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. K. Shetty, V. Zaman, and B. Hattiangady
Repair of the Injured Adult Hippocampus through Graft-Mediated Modulation of the Plasticity of the Dentate Gyrus in a Rat Model of Temporal Lobe Epilepsy
J. Neurosci.,
September 14, 2005;
25(37):
8391 - 8401.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Epsztein, A. Represa, I. Jorquera, Y. Ben-Ari, and V. Crepel
Recurrent Mossy Fibers Establish Aberrant Kainate Receptor-Operated Synapses on Granule Cells from Epileptic Rats
J. Neurosci.,
September 7, 2005;
25(36):
8229 - 8239.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Zhang, Y. Kanaho, M. A. Frohman, and S. E. Tsirka
Phospholipase D1-Promoted Release of Tissue Plasminogen Activator Facilitates Neurite Outgrowth
J. Neurosci.,
February 16, 2005;
25(7):
1797 - 1805.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Santhakumar, I. Aradi, and I. Soltesz
Role of Mossy Fiber Sprouting and Mossy Cell Loss in Hyperexcitability: A Network Model of the Dentate Gyrus Incorporating Cell Types and Axonal Topography
J Neurophysiol,
January 1, 2005;
93(1):
437 - 453.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. B. Bausch and J. O. McNamara
Contributions of Mossy Fiber and CA1 Pyramidal Cell Sprouting to Dentate Granule Cell Hyperexcitability in Kainic Acid-Treated Hippocampal Slice Cultures
J Neurophysiol,
December 1, 2004;
92(6):
3582 - 3595.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Gabriel, M. Njunting, J. K. Pomper, M. Merschhemke, E. R. G. Sanabria, A. Eilers, A. Kivi, M. Zeller, H.-J. Meencke, E. A. Cavalheiro, et al.
Stimulus and Potassium-Induced Epileptiform Activity in the Human Dentate Gyrus from Patients with and without Hippocampal Sclerosis
J. Neurosci.,
November 17, 2004;
24(46):
10416 - 10430.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Koyama, M. K. Yamada, S. Fujisawa, R. Katoh-Semba, N. Matsuki, and Y. Ikegaya
Brain-Derived Neurotrophic Factor Induces Hyperexcitable Reentrant Circuits in the Dentate Gyrus
J. Neurosci.,
August 18, 2004;
24(33):
7215 - 7224.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Rigoulot, E. Koning, A. Ferrandon, and A. Nehlig
Neuroprotective Properties of Topiramate in the Lithium-Pilocarpine Model of Epilepsy
J. Pharmacol. Exp. Ther.,
February 1, 2004;
308(2):
787 - 795.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Kobayashi, X. Wen, and P. S. Buckmaster
Reduced Inhibition and Increased Output of Layer II Neurons in the Medial Entorhinal Cortex in a Model of Temporal Lobe Epilepsy
J. Neurosci.,
September 17, 2003;
23(24):
8471 - 8479.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. A. Bender, S. V. Soleymani, A. L. Brewster, S. T. Nguyen, H. Beck, G. W. Mathern, and T. Z. Baram
Enhanced Expression of a Specific Hyperpolarization-Activated Cyclic Nucleotide-Gated Cation Channel (HCN) in Surviving Dentate Gyrus Granule Cells of Human and Experimental Epileptic Hippocampus
J. Neurosci.,
July 30, 2003;
23(17):
6826 - 6836.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Feng, P. Molnar, and J. V. Nadler
Short-Term Frequency-Dependent Plasticity at Recurrent Mossy Fiber Synapses of the Epileptic Brain
J. Neurosci.,
June 15, 2003;
23(12):
5381 - 5390.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Kobayashi and P. S. Buckmaster
Reduced Inhibition of Dentate Granule Cells in a Model of Temporal Lobe Epilepsy
J. Neurosci.,
March 15, 2003;
23(6):
2440 - 2452.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
