Possible Role of Protein CPG15 in Hippocampal Mossy Fiber Sprouting Under Conditions of Pentylenetetrazole Kindling
We examined changes in expression of the candidate plasticity-related gene 15 (CPG15) in the dentate gyrus (DG) and hippocampal CA3 region in the pentylenetetrazole (PTZ) kindling model and investigated the role of this gene in the phenomenon of mossy fiber sprouting (MFS). Experimental rats were...
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Інститут фізіології ім. О.О. Богомольця НАН України
2015
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| Cite this: | Possible Role of Protein CPG15 in Hippocampal Mossy Fiber Sprouting under Conditions of Pentylenetetrazole Kindling / M.Y. Song, F.F. Tian, J. Dang, W.J. Huang, J.L. Guo // Нейрофизиология. — 2015. — Т. 47, № 4. — С. 325-330. — Бібліогр.: 25 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1859948998812499968 |
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| author | Song, M.Y. Tian, F.F. Dang, J. Huang, W.J. Guo, J.L. |
| author_facet | Song, M.Y. Tian, F.F. Dang, J. Huang, W.J. Guo, J.L. |
| citation_txt | Possible Role of Protein CPG15 in Hippocampal Mossy Fiber Sprouting under Conditions of Pentylenetetrazole Kindling / M.Y. Song, F.F. Tian, J. Dang, W.J. Huang, J.L. Guo // Нейрофизиология. — 2015. — Т. 47, № 4. — С. 325-330. — Бібліогр.: 25 назв. — англ. |
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| description | We examined changes in expression of the candidate plasticity-related gene 15 (CPG15) in
the dentate gyrus (DG) and hippocampal CA3 region in the pentylenetetrazole (PTZ) kindling
model and investigated the role of this gene in the phenomenon of mossy fiber sprouting
(MFS). Experimental rats were divided into the control and PTZ groups. The epileptic model
was created by intraperitoneal PTZ injection, while control rats were injected with saline.
At days 3, 7, 14, 28, and 42 after the first PTZ injection, Timm staining was scored in the
CA3 hippocampal area, and a product of CPG15 (protein CPG15) was labeled in the DG
stratum granulosum and in the CA3 area using immunohistochemistry. The Timm scores in
the CA3 region increased gradually from day 3 and were significantly higher than those in
the control within the subsequent period. The level of CPG15 protein in the DG and CA3
area decreased gradually until day 14 and returned to the normal level at day 28. The results
obtained indicate, for the first time, that CPG15 may be involved in the process of MFS.
Understanding the molecular mechanisms underlying this phenomenon may lead to successful
therapeutic interventions that limit epileptogenesis.
Ми досліджували зміни експресії продукту гена CPG15
у зубчастій звивині (ЗЗ) та зоні CA3 гіпокампа в моделі
пентилентетразолового (ПТЗ-) кіндлінгу та можливу роль цього гена у феномені спрутингу моховитих волокон
(СМВ). Піддослідні щури були поділені на групи контролю та ПТЗ-кіндлінгу. Модель епілепсії створювали за допомогою внутрішньоочеревинних ін’єкцій пентилентетразолу
(ПТЗ); контрольним щурам ін’єкували фізіологічний
розчин. На третю, сьому, 14-ту, 28-му та 42-гу добу після
першої ін’єкції ПТЗ оцінювали забарвлення, за Тіммом, у
зоні CA3. Локалізацію протеїну CPG15 у stratum granulosum ЗЗ та зоні CA3 гіпокампа визначали з використанням
імуногістохімічної методики. Інтенсивність забарвлення, за
Тіммом, у зоні CA3 поступово збільшувалася починаючи з
третьої доби та була вірогідно вищою, ніж така в контролі,
протягом усього наступного періоду. Рівень протеїну CPG15
у ЗЗ та полі CA3 поступово зменшувався до 14-ї доби та
повертався до нормальних значень на 28-му добу. Отримані
результати вперше вказують на те, що CPG15 може бути
залученим у процес СМВ. Зрозуміння молекулярних механізмів, на яких базується цей феномен, може призвести до розробки успішних терапевтичних заходів, котрі обмежували б епілептогенез.
|
| first_indexed | 2025-12-07T16:15:51Z |
| format | Article |
| fulltext |
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 4 325
UDC 577.218:612.825.3
M.-Y. SONG,1 F.-F. TIAN,1 J. DANG,1 W.-J. HUANG,1 and J.-L. GUO1
POSSIBLE ROLE OF PROTEIN CPG15 IN HIPPOCAMPAL MOSSY FIBER
SPROUTING UNDER CONDITIONS OF PENTYLENETETRAZOLE KINDLING
Received March 13, 2014
We examined changes in expression of the candidate plasticity-related gene 15 (CPG15) in
the dentate gyrus (DG) and hippocampal CA3 region in the pentylenetetrazole (PTZ) kindling
model and investigated the role of this gene in the phenomenon of mossy fiber sprouting
(MFS). Experimental rats were divided into the control and PTZ groups. The epileptic model
was created by intraperitoneal PTZ injection, while control rats were injected with saline.
At days 3, 7, 14, 28, and 42 after the first PTZ injection, Timm staining was scored in the
CA3 hippocampal area, and a product of CPG15 (protein CPG15) was labeled in the DG
stratum granulosum and in the CA3 area using immunohistochemistry. The Timm scores in
the CA3 region increased gradually from day 3 and were significantly higher than those in
the control within the subsequent period. The level of CPG15 protein in the DG and CA3
area decreased gradually until day 14 and returned to the normal level at day 28. The results
obtained indicate, for the first time, that CPG15 may be involved in the process of MFS.
Understanding the molecular mechanisms underlying this phenomenon may lead to successful
therapeutic interventions that limit epileptogenesis.
Keywords: protein CPG15, mossy fiber sprouting, temporal lobe epilepsy, dentate gyrus,
hippocampus.
1Department of Neurology, Xiangya Hospital, Central South University,
Changsha, China.
Correspondence should be addressed to F.-F. Tian
(E-mail: tianfafa@gmail.com).
INTRODUCTION
Epilepsy is a widespread chronic neurological
disorder. Although the exact pathogenetic mechanisms
of this disease remain unclear to a great extent, mossy
fiber sprouting (MFS) is a pathological phenomenon
observed in both animal models of temporal lobe
epilepsy (TLE) and brain sections of epileptic patients
[1–3]. Most studies supported the hypothesis that
MFS contributes to increased seizure susceptibility
by forming recurrent excitatory neuronal circuits.
However, the mechanisms underlying these structural
changes are not fully understood.
The hippocampal mossy fibers, axons of dentate
granule cells, are normally guided to the CA3 area
of the hippocampal area and form synapses with
pyramidal cells. However, mossy fibers in the epileptic
hippocampus abnormally innervate, due to MFS,
granule cells and the molecular layer, establishing
hyperexcitable recurrent circuits in the dentate gyrus
(DG) [4]. Based on recent findings [5–7], MFS can
be regarded as a result of the disruption of molecular
mechanisms underlying axonal growth and axonal
guidance.
The candidate plasticity-related gene (CPG15) is the
first isolated one in a screen for activity-regulated genes
mediating synaptic plasticity in the rat hippocampus
[8]. This gene encodes a small protein attached to the
plasma membrane by its glycosylphosphatidylinositol
(GPI) anchor. Protein CPG15 is a downstream target of
the classic synaptic plasticity signaling cascade, which
regulates axonal and dendritic arbor growth, as well as
synapse maturation and neuronal survival in the CNS [9–
11]. Since mossy fibers are axons of granule cells, it is
possible that CPG15 is related to MFS in epileptogenesis
via regulation of the axonal growth and synaptic plasticity.
We investigated the correctness of this hypothesis
using the pentylenetetrazole (PTZ) kindling model,
widely adopted as a model of synaptic rearrangement
and neuronal plasticity in the epileptic brain.
METHODS
Animals and the PTZ Model. One hundred twenty
adult male Sprague-Dawley rats (Animal Experimental
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 4326
M.-Y. SONG, F.-F. TIAN, J. DANG, et al.
Centre, Central South University, China) weighing
180 to 220 g were equally divided into control and
PTZ groups, each containing five subgroups of 12
rats. The PTZ group received 30 mg/kg PTZ (Sigma,
USA) i.p. once per day until the rats were kindled or
sacrificed, while the control rats were injected with
an equal volume of the solvent (saline). Rats were
considered kindled when seizure attacks (score ≥ 3)
occurred after each PTZ injection for five consecutive
days. At time points of 3, 7, 14, 28, and 42 days, after
the first PTZ injection, rats were sacrificed under deep
anesthesia.
Behavior Monitoring. Rats were observed for
the occurrence of PTZ-induced seizures for at least
2 hours within one day before being kindled. The
convulsive behavior was evaluated as previously
described [12], using the following estimates: 0, no
behavioral changes; 1, facial movements, ear and
whisker twitching; 2, myoclonic convulsions without
rearing; 3, myoclonic convulsions with rearing;
4, clonic convulsions with loss of posture, and 5,
generalized clonicotonic seizures.
Timm Staining. At different time points, the rats
were deeply anesthetized with 10% chloral hydrate and
perfused intracardially with 300 ml of saline, followed
by 200 ml of 0.1 M phosphate buffer (pH 7.2-7.6)
containing 0.4% sodium sulfide and by 200 ml of 4%
paraformaldehyde at 4°C. The brains were removed,
fixed in 4% paraformaldehyde for 24 h, transferred to
0.1 M phosphate buffer with 30% sucrose, and finally
cut into 30-µm-thick coronal sections.
The sections were stained in the dark for 90 min in
a solution containing 60 ml of 50% gum arabic, 10 ml
of 2.0 M citrate buffer, 30 ml of 0.5 M hydroquinone,
and 0.5 ml of 17% silver nitrate. After washing out
in water, the slides were restained with Nissl solution
(Beyotime, China). After that, the slides were routinely
dehydrated, cleaned, and mounted with gum. The
Timm scores in the inner molecular layer (IML) and in
the CA3 region were estimated as previously reported
[13].
Immunohistochemistry. At different time points,
the rats were deeply anesthetized with 10% chloral
hydrate and perfused intracardially with 300 ml of
saline and 200 ml of 4% paraformaldehyde in 0.1 M
phosphate buffer at 4°C. The brains were removed
and placed in 4% paraformaldehyde overnight, then
transferred into 0.1 M phosphate buffer containing
20% and 30% sucrose. Subsequently, 20-µm-thick
serial sections were prepared for the analysis. The
tissue sections were subjected to conventional
rewarming and heat-induced antigen retrieval in
10 mM sodium citrate buffer at the boiling point
for 24 min with supplementation with cool sodium
citrate buffer every 6 min. Peroxidase and lipids
were eliminated by an admixture of 1% hydrogen and
methanol at 4°C for 30 min. After rinsing in 0.01 M
PBS, the sections were blocked using a 5% goat serum
reagent at room temperature for 2 h and incubated
with anti-CPG15 (rabbit anti-rat polyclonal antibody,
1:50, Santa Cruz, USA) overnight at 4°C. Then,
immunohistochemistry was performed according to the
kit protocol (Zhongshan Goldenbridge Tech, China).
All slices were processed with a Leica DM 5000B
color-image analysis system (Switzerland) for imaging
and analysis; the DG and area CA3 were examined.
Statistical Analysis. Numerical data are expressed
as means ± s.d. Intergroup differences in Timm scores
were compared using the Mann-Whitney U test,
while intragroup differences were compared using the
Kruskal-Wallis H test and then the Nemenyi test for
pairwise comparisons. Differences among multiple
groups were assessed by a one-way ANOVA, and
differences between two groups were evaluated using
the independent-samples t-test. Differences with
P < 0.05 were considered significant. All statistical
analyses were performed using the Statistical package
for social sciences (SPSS), version 17.0.
RESULTS
Behavioral Outcomes. With the exception of three
rats that died after the development of persistent
generalized clonic-tonic seizures within days 3 to 14
and one rat with no kindling developed, the remaining
PTZ-treated rats manifested seizure activity of
different degrees after continuous PTZ injections
within days 21–28 (average, 22.7 ± 2.0 days). The PTZ-
induced seizure activity usually occurred 5–10 min
after injection and lasted 5 to 30 min. No epileptiform
activity was observed behaviorally in control rats.
Severity of MFS in the CA3 Area Correlates with
Evolution of Seizure Behavior. In control rats, there
was no significant difference in the Timm scores in
area CA3 (P > 0.05) (Fig. 3). There were significant
differences in these scores in the above area at each
time point between the PTZ and control groups
(P < 0.05) (Figs. 1A and 3). The degrees of MFS in
the CA3 were consistent with the grades of seizures in
the PTZ group and reached the peak at day 28. On the
other hand, the Timm scores in the IML were 0 or 1
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 4 327
POSSIBLE ROLE OF PROTEIN CPG15 IN HIPPOCAMPAL MOSSY FIBER
F i g. 1. Timm staining in the CA3 area of control and PTZ-
treated rats. The intensity of Timm granules increased with
the development of kindling in area CA3 in the PTZ group.
Р и с. 1. Забарвлення, за Тіммом, у зоні CA3 контрольних
щурів та щурів, котрим ін’єкували пентилентетразол.
Contr.
14
A
Control
PTZ 28
Control
PTZ 28
PTZ 14
PTZ 42 days
PTZ 14
PTZ 42 days
B
28 days
21
F i g.2. Expression of CPG15 in the CA3 region of the
hippocampus (A) and dentate gyrus (B) visualized by
immunohistochemistry in the control group and at different
time points in the PTZ group.
Р и с. 2. Експресія протеїну CPG15 у зоні CA3 гіпокампа
(А) та зубчастій звивині (В) у контрольній групі та гру-
пі пентилентетразолового кіндлінгу в різні моменти
часу (візуалізовано за допомогою імуногістохімічної
методики).
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 4328
M.-Y. SONG, F.-F. TIAN, J. DANG, et al.
throughout the experiment in the PTZ group, with no
difference with respect to the control group (data not
shown).
Expression of Protein CPG15 Is Significantly
Down-Regulated during PTZ Kindling Progression.
The expression of CPG15 was mainly observed in
the neuronal membranes within different regions of
the hippocampus. Compared with the control group,
the expression of CPG15 in pyramidal cells of the
CA3 region and in hilar neurons of the DG were
significantly down-regulated (P < 0. 05) in the PTZ
group (Fig. 1A, B and Fig. 3A, B; Table 1). This
expression decreased gradually from day 3 to day 14
and returned to the control level at day 28, but down-
regulated again at day 42. No obvious distinction was
observed in both CA3 and DG areas among different
time points in the control group (Table 2).
DISCUSSION
We examined the potential role of protein CPG15 in
MFS using the PTZ kindling rat model. We found
that MFS preceded the appearance of spontaneous
recurrent seizures (SRSs) in such rats. The expression
of protein CPG15 is in agreement with the progression
of MFS.
The occurrence and development of epilepsy are
usually associated with neuronal loss [14], MFS [15],
and synaptic reorganization in the hippocampus. These
alterations, especially MFS, are highly associated with
the appearance of SRSs in humans and in epileptic
animal models.
0
0
3
3
7
7
14
14
28
28
42
42 days
0.02
0.04
0.02
0.06
0.08
0.04
0.10
0.12
0.06
0.14 A
B
*
* * *
0.08
F i g. 3. Quantitative analysis of CPG15 protein expression in the
CA3 area (A) and dental gyrus (B). Vertical scale) Arbitrary units;
horizontal scale) days after the first PTZ injection. Open and
filled columns, control and PTZ groups, respectively. The data are
expressed as means ± s.d.
Р и с. 3. Кількісний аналіз експресії протеїну CPG15 у зоні CA3
(А) та зубчастій звивині (В).
T a b l e 1. Quantitative analysis of CPG15 expression in the PTZ group.
Т а б л и ц я 1. Кількісний аналіз експресії CPG15 у групі ПТЗ
Group Time points, days DG CA3
PTZ 3 0.045±0.008* 0.103±0.022
7 0.026±0.004* 0.087±0.007
14 0.023±0.003* 0.063±0.004*
28 0.042±0.007 0.106±0.008
42 0.027±0.003* 0.072±0.009*
Footnote. The data are expressed as means ± s.d.; differences from the control, *P < 0.05
T a b l e 2. Quantitative analysis of CPG15 expression in the control group.
Т а б л и ц я 2. Кількісний аналіз експресії CPG15 у групі контролю
Group Time points, days DG CA3
Control 3 0.066±0.006 0.118±0.009
7 0.060±0.011 0.118±0.010
14 0.051±0.008 0.101±0.016
28 0.055±0.002 0.109±0.0003
42 0.056±0.009 0.100±0.008
Footnote. Designations are similar to those in Table 1.
* *
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 4 329
POSSIBLE ROLE OF PROTEIN CPG15 IN HIPPOCAMPAL MOSSY FIBER
Our study demonstrated that the degree of aberrant
MFS is consistent with the severity of seizures, and
initiation of MFS precedes the occurrence of SRS.
However, there are also some reservations. As was
found in several other studies, MFS was not associated
with the progression of spontaneous seizures [16,
17]. In our study, however, MFS could be observed
on day 3, i.e., before the appearance of clear SRSs,
indicating that MFS is rather likely to be the cause of
such seizures.
CPG15 is a gene highly expressed in the nervous
system; in the adult age, it is restricted to the region
endowed with a high degree of plasticity, namely in
the hippocampus. The expression of CPG15 protein
was down-regulated gradually in the CA3 area and
DG region in the PTZ group. The spatial and temporal
distribution consistencies of CPG15 and Timm
staining supported the existence of a correlation
between expression of this protein and the process of
MFS. This finding, thus, suggests that CPG15 and its
protein product may be significantly involved in the
synaptic specificity of MFS.
Neurotrophins form a group of factors involved in
nerve cell survival, proliferation, differentiation, and
synaptic functions. These factors are generated by
neural tissues, muscles, and astrocytes. Some studies
have shown that neurotrophins are highly associated
with epileptogenesis and the MFS phenomenon [18–
21]. In other studies, it was proposed that epilepsy-
related neural activity is the trigger of MFS. Protein
CPG15 is a novel neurotrophin; it is a downstream
target of the classic synaptic plasticity signaling
cascade, involving the MAPK, CaMK, and CREB
[22]. Both in vivo and in vitro studies [23] have
demonstrated that CPG15 may represent a common
effector of neurotrophins with respect to the neuronal
activity function. Neural activity and neurotrophins
induce synaptic remodeling, in particular, by altering
the gene expression. Based on previous research,
CPG15 can regulate axonal and dendritic arbor
growth, as well as maturation of synapses and survival
of neurons in the CNS. However, the mechanisms
underlying the relationship between CPG15 and MFS
were not investigated in our study.
In vivo studies [24] demonstrated that CPG15
protein must be attached to the plasma membrane by
its GPI anchor to manifest its neurotrophic effects.
GPI-anchored molecules encompass a large group
of proteins of great functional diversity, including
many axon-guidance molecules, such as ephrins and
NCAM. These molecules are able, through contact
attraction or repulsion, to regulate axonal pathfinding
and growth. So, CPG15, being a GPI-anchored
molecule, can, through contacts with axons, trigger a
series of molecular events providing regulation of the
axonal growth, pathfinding, and synaptic plasticity.
Considering that CPG15 affects and regulates the
above events, it should be qualified as an activity-
induced signaling molecule capable of communicating
between neighboring cells [25]. The receptor of
CPG15 and the downstream of the above conduction
pathway remain, however, unknown.
In conclusion, our study demonstrated that MFS
is not the outcome of the SRS initiation. Our results
indicate, for the first time, that expression of CPG15
may be involved in the development of MFS and
synaptic reorganization. A throughout understanding
of the molecular mechanisms underlying MFS may
lead to therapeutic interventions that protect the brain
from spontaneous seizures.
Acknowledgement. This work was supported by the
Fundamental Research Funds for the Central Universities
(Central South University, 2013zzts093).
All animals were treated humanely, and this study
conformed to the guidelines for the Care and Use of Laboratory
Animals published by the National Institutes of Health (NIH,
Bethesda, USA). All animal-use protocols were approved by
the Animal Ethics Committee of the Central South University
(China).
All authors have contributed significantly and are in
agreement with the content of the manuscript. The authors
of this communication, M.-Y. Song, F.-F. Tian, J. Dang,
W.-J. Huang, and J.-L. Guo, confirm the absense of any conflict
related to comercial or financial interests, to interrelations with
organizations or persons in any way involved in the research,
and to interrelations of the co-authors.
М.-Ю. Сон1, Ф.-Ф. Тьян1, Дж. Дан1, В.-Дж. Хуан1,
Дж.-Л. Гуо1
МОЖЛИВА РОЛЬ ПРОТЕЇНУ CPG15 У СПРУТИНГУ
МОХОВИТИХ ВОЛОКОН У ГІПОКАМПІ В УМОВАХ
ПЕНТИЛЕНТЕТРАЗОЛОВОГО КІНДЛІНГУ
1 Лікарня Ксянг’я при Центральному Південному
університеті, Чанша (Китай).
Р е з ю м е
Ми досліджували зміни експресії продукту гена CPG15
у зубчастій звивині (ЗЗ) та зоні CA3 гіпокампа в моделі
пентилентетразолового (ПТЗ-) кіндлінгу та можливу роль
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 4330
M.-Y. SONG, F.-F. TIAN, J. DANG, et al.
цього гена у феномені спрутингу моховитих волокон
(СМВ). Піддослідні щури були поділені на групи контро-
лю та ПТЗ-кіндлінгу. Модель епілепсії створювали за допо-
могою внутрішньоочеревинних ін’єкцій пентилентетразолу
(ПТЗ); контрольним щурам ін’єкували фізіологічний
розчин. На третю, сьому, 14-ту, 28-му та 42-гу добу після
першої ін’єкції ПТЗ оцінювали забарвлення, за Тіммом, у
зоні CA3. Локалізацію протеїну CPG15 у stratum granulo-
sum ЗЗ та зоні CA3 гіпокампа визначали з використанням
імуногістохімічної методики. Інтенсивність забарвлення, за
Тіммом, у зоні CA3 поступово збільшувалася починаючи з
третьої доби та була вірогідно вищою, ніж така в контролі,
протягом усього наступного періоду. Рівень протеїну CPG15
у ЗЗ та полі CA3 поступово зменшувався до 14-ї доби та
повертався до нормальних значень на 28-му добу. Отримані
результати вперше вказують на те, що CPG15 може бути
залученим у процес СМВ. Зрозуміння молекулярних ме-
ханізмів, на яких базується цей феномен, може призвес-
ти до розробки успішних терапевтичних заходів, кот-
рі обмежували б епілептогенез.
REFERENCES
1. L. P. Andrade-Valenḉa, M. M. Valenḉa, T. R. Velasco, et al.,
“Mesial temporal lobe epilepsy: clinical and neuropathologic
findings of familial and sporadic forms,” Epilepsia, 6, 1046-
1054 (2008).
2. S. R. Lamont, B. J. Stanwell, R. Hill, et al., “Ketamine pre-
treatment dissociates the effects of electroconvulsive
stimulation on mossy fiber sprouting and cellular proliferation
in the dentate gyrus,” Brain Res., 1053, 27-32 (2008).
3. L. W. Kuo, C. Y. Lee, J. H. Chen, et al., “Mossy fiber sprouting
in pilocarpine-induced status epilepticus rat hippocampus: a
correlative study of diffusion spectrum imaging and histology,”
NeuroImage, 41, 789-800 (2008).
4. R. Koyama and Y. Ikegaya, “Mossy fiber sprouting as a potential
therapeutic target for epilepsy,” Current Neurovascul. Res., 1,
No. 1, 3-10 (2004).
5. H. Lin, Y. Huang, Y. Wang, and J. Jia, “Spatiotemporal profile
of N-cadherin expression in the mossy fiber sprouting and
synaptic plasticity following seizures,” Mol. Cell. Biochem.,
358, Nos. 1/2, 201-205 (2011).
6. A. J. Holtmaat, J. A. Gorter, J. De Wit, et al., “Transient
downregulation of Sema3A mRNA in a rat model for temporal
lobe epilepsy. A novel molecular event potentially contributing
to mossy fiber sprouting,” Exp. Neurol., 182, 142-150 (2003).
7. R. Koyama, M. K. Yamada, N. Nishiyama, et al., “Brain-derived
neurotrophic factor induces hyperexcitable reentrant circuits in
the dentate gyrus,” J. Neurosci., 24, No. 33, 7215-7224 (2004).
8. E. Nedivi, D. Hevroni, D. Naot, et al., “Numerous candidate
plasticity-related genes revealed by different cDNA cloning,”
Nature, 363, No. 6431, 718-722 (1993).
9. A. Javaherian and H. T. Cline, “Coordinated motor neuron axon
growth and neuromuscular synaptogenesis are promoted by
cpg15 in vivo,” Neuron, 45, 505-512 (2005).
10. T. Fujino, J. H. Leslie, R. Eavri, et al., “CPG15 regulates
synapse stability in the developing and adult brain,” Genes
Dev., 25, 2674-2685 (2005).
11. U. Putz, C. Harwell, and E. Nedivi, “Soluble CPG15, expressed
during early development, rescues cortical progenitors from
apoptosis,” Nat. Neurosci., 8, 322-331(2005).
12. F. F. Tian, C. Zeng, Y. E. Ma, et al., “Potential roles of Cdk5/
p35 and tau protein in hippocampal mossy fiber sprouting in
the PTZ kindling model,” Clin. Lab., 56, 127-136 (2010).
13. G. L. Holmes, M. Sarkisian, Y. Ben-Ari, and N. Chevassus-Au-
Louis, “Mossy fiber sprouting after recurrent seizures during
early development in rats,” J. Comp. Neurol., 404, 537-553
(1999).
14. J. E. Cavazos and D. J. Cross, “The role of synaptic
reorganization in mesial temporal lobe epilepsy,” Epilepsy
Behav., 8, 483-493 (2006).
15. L. H. Zeng, N. R. Rensing, and M. Wong, “The mammalian
target of rapamycin signaling pathway mediates epileptogenesis
in a model of temporal lobe epilepsy,” J. Neurosci., 29, 6964-
6972 (2009).
16. F. H. Lew and P. S. Buckmaster, “Is there a critical period
for mossy fiber sprouting in a mouse model of temporal lobe
epilepsy?” Epilepsia, 52, No. 12, 2326-2332 (2011).
17. J. Nissinen, K. Lukasiuk, and A. Pitkanen, “Is mossy fiber
sprouting present at the time of the first spontaneous seizures
in rat experimental temporal lobe epilepsy?” Hippocampus, 11,
299-310 (2001).
18. C. Heinrich, S. Lahteinen, F. Suzuki, et al., “Increase in BDNF-
mediated TrkB signaling promotes epileptogenesis in a mouse
model of mesial temporal lobe epilepsy,” Neurobiol. Dis., 42,
No. 1, 35-47 (2011).
19. B. Paradiso, S. Zucchini, T. Su, et al. , “Localized
overexpression of FGF-2 and BDNF in hippocampus reduces
mossy fiber sprouting and spontaneous seizures up to 4 weeks
after pilocarpine-induced status epilepticus,” Epilepsia, 52,
No. 3, 572-578 (2011).
20. C. A. Altar, P. Laeng, L. W. Jurata, et al., “Electroconvulsive
seizures regulate gene expression of distinct neurotrophic
signaling pathways,” J. Neurosci., 24, No. 11, 2667-2677
(2004).
21. R. M. Risbud, C. Lee, and B. E. Porter, “Neurotrophin-3 mRNA
a putative target of miR21 following status epilepticus,” Brain
Res., 14, No. 24, 53-59 (2011).
22.T. Fujino, W. A. Lee, and E. Nedivi, “Regulation of cpg15 by
signaling pathways that mediate synaptic plasticity,” Mol. Cell
Neurosci., 24, 538-554 (2003).
23. G. S. Naeve, M. Ramakrishnan, R. Kramer, et al., “Neuritin:
a gene induced by neural activity and neurotrophins that
promotes neuritogenesis,” Proc. Natl. Acad. Sci., 94, No. 6,
2648-2653 (1997).
24. I. Cantallops and H. T. Cline, “Rapid activity-dependent
delivery of the neurotrophic protein CPG15 to the axon surface
of neurons in intact Xenopus tadpoles,” Dev. Neurobiol., 68,
No. 6, 744-759 (2008).
25. E. Nedivi, G. Y. Wu, and H. T. Cline, “Promotion of dendritic
growth by CPG15, an activity-induced signaling molecule,”
Science, 281, No. 5384, 1863-1866 (1998).
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| id | nasplib_isofts_kiev_ua-123456789-148203 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 0028-2561 |
| language | English |
| last_indexed | 2025-12-07T16:15:51Z |
| publishDate | 2015 |
| publisher | Інститут фізіології ім. О.О. Богомольця НАН України |
| record_format | dspace |
| spelling | Song, M.Y. Tian, F.F. Dang, J. Huang, W.J. Guo, J.L. 2019-02-17T17:37:40Z 2019-02-17T17:37:40Z 2015 Possible Role of Protein CPG15 in Hippocampal Mossy Fiber Sprouting under Conditions of Pentylenetetrazole Kindling / M.Y. Song, F.F. Tian, J. Dang, W.J. Huang, J.L. Guo // Нейрофизиология. — 2015. — Т. 47, № 4. — С. 325-330. — Бібліогр.: 25 назв. — англ. 0028-2561 https://nasplib.isofts.kiev.ua/handle/123456789/148203 577.218:612.825.3 We examined changes in expression of the candidate plasticity-related gene 15 (CPG15) in the dentate gyrus (DG) and hippocampal CA3 region in the pentylenetetrazole (PTZ) kindling model and investigated the role of this gene in the phenomenon of mossy fiber sprouting (MFS). Experimental rats were divided into the control and PTZ groups. The epileptic model was created by intraperitoneal PTZ injection, while control rats were injected with saline. At days 3, 7, 14, 28, and 42 after the first PTZ injection, Timm staining was scored in the CA3 hippocampal area, and a product of CPG15 (protein CPG15) was labeled in the DG stratum granulosum and in the CA3 area using immunohistochemistry. The Timm scores in the CA3 region increased gradually from day 3 and were significantly higher than those in the control within the subsequent period. The level of CPG15 protein in the DG and CA3 area decreased gradually until day 14 and returned to the normal level at day 28. The results obtained indicate, for the first time, that CPG15 may be involved in the process of MFS. Understanding the molecular mechanisms underlying this phenomenon may lead to successful therapeutic interventions that limit epileptogenesis. Ми досліджували зміни експресії продукту гена CPG15 у зубчастій звивині (ЗЗ) та зоні CA3 гіпокампа в моделі пентилентетразолового (ПТЗ-) кіндлінгу та можливу роль цього гена у феномені спрутингу моховитих волокон (СМВ). Піддослідні щури були поділені на групи контролю та ПТЗ-кіндлінгу. Модель епілепсії створювали за допомогою внутрішньоочеревинних ін’єкцій пентилентетразолу (ПТЗ); контрольним щурам ін’єкували фізіологічний розчин. На третю, сьому, 14-ту, 28-му та 42-гу добу після першої ін’єкції ПТЗ оцінювали забарвлення, за Тіммом, у зоні CA3. Локалізацію протеїну CPG15 у stratum granulosum ЗЗ та зоні CA3 гіпокампа визначали з використанням імуногістохімічної методики. Інтенсивність забарвлення, за Тіммом, у зоні CA3 поступово збільшувалася починаючи з третьої доби та була вірогідно вищою, ніж така в контролі, протягом усього наступного періоду. Рівень протеїну CPG15 у ЗЗ та полі CA3 поступово зменшувався до 14-ї доби та повертався до нормальних значень на 28-му добу. Отримані результати вперше вказують на те, що CPG15 може бути залученим у процес СМВ. Зрозуміння молекулярних механізмів, на яких базується цей феномен, може призвести до розробки успішних терапевтичних заходів, котрі обмежували б епілептогенез. This work was supported by the Fundamental Research Funds for the Central Universities (Central South University, 2013zzts093). en Інститут фізіології ім. О.О. Богомольця НАН України Нейрофизиология Possible Role of Protein CPG15 in Hippocampal Mossy Fiber Sprouting Under Conditions of Pentylenetetrazole Kindling Можлива роль протеїну CPG15 у спрутингу моховитих волокон у гіпокампі в умовах пентилентетразолового кіндлінгу Article published earlier |
| spellingShingle | Possible Role of Protein CPG15 in Hippocampal Mossy Fiber Sprouting Under Conditions of Pentylenetetrazole Kindling Song, M.Y. Tian, F.F. Dang, J. Huang, W.J. Guo, J.L. |
| title | Possible Role of Protein CPG15 in Hippocampal Mossy Fiber Sprouting Under Conditions of Pentylenetetrazole Kindling |
| title_alt | Можлива роль протеїну CPG15 у спрутингу моховитих волокон у гіпокампі в умовах пентилентетразолового кіндлінгу |
| title_full | Possible Role of Protein CPG15 in Hippocampal Mossy Fiber Sprouting Under Conditions of Pentylenetetrazole Kindling |
| title_fullStr | Possible Role of Protein CPG15 in Hippocampal Mossy Fiber Sprouting Under Conditions of Pentylenetetrazole Kindling |
| title_full_unstemmed | Possible Role of Protein CPG15 in Hippocampal Mossy Fiber Sprouting Under Conditions of Pentylenetetrazole Kindling |
| title_short | Possible Role of Protein CPG15 in Hippocampal Mossy Fiber Sprouting Under Conditions of Pentylenetetrazole Kindling |
| title_sort | possible role of protein cpg15 in hippocampal mossy fiber sprouting under conditions of pentylenetetrazole kindling |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/148203 |
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