H.E. Scharfman (Ed.

)
Progress in Brain Research, Vol. 163
ISSN 0079-6123
Copyright r 2007 Elsevier B.V. All rights reserved

CHAPTER 28

Adult neurogenesis in the intact and epileptic

dentate gyrus

Jack M. Parent

Department of Neurology, University of Michigan Medical Center, 109 Zina Pitcher Place, 5021 BSRB,
Ann Arbor, MI 48109-2200, USA

Abstract: Neurogenesis persists throughout life in the adult mammalian dentate gyrus. Adult-born dentate
granule cells integrate into existing hippocampal circuitry and may provide network plasticity necessary for
certain forms of hippocampus-dependent learning and memory. Neural stem cells and neurogenesis in the
adult dentate gyrus are regulated by a variety of environmental, physiological, and molecular factors. These
include aging, stress, exercise, neurovascular components of the stem cell niche, growth factors, neuro-
transmitters, and hormones. Seizure activity also influences dentate granule cell neurogenesis. Production
of adult-born neurons increases in rodent models of temporal lobe epilepsy, and both newborn and
pre-existing granule neurons contribute to aberrant axonal reorganization in the epileptic hippocampus.
Prolonged seizures also disrupt the migration of dentate granule cell progenitors and lead to hilar-ectopic
granule cells. The ectopic granule neurons appear to integrate abnormally and contribute to network
hyperexcitability. Similar findings of granule cell layer dispersion and ectopic granule neurons in
human TLE suggest that aberrant neurogenesis contributes to epileptogenesis or learning and memory
disturbances in this epilepsy syndrome.

Keywords: neurogenesis; stem cell; epileptogenesis; temporal lobe epilepsy; migration; dentate granule cell

Dentate granule cell neurogenesis persists
throughout life
New neurons are generated throughout life in the
mammalian dentate gyrus (Altman and Das, 1965;
Kaplan and Hinds, 1977; Cameron et al., 1993;
Kuhn et al., 1996). This process, termed neuro-
genesis, begins with neural stem or progenitor cells
that give rise to transit amplifying precursors to
expand the numbers of progeny. In the dentate
gyrus, these progeny form dentate granule cells
Corresponding author. Tel.: +1 734 763 3776;
Fax: +1 734 763 7686; E-mail: parent@umich.edu
(DGCs). Persistent DGC neurogenesis occurs in
all mammalian species examined to date, including
human and nonhuman primates (Eriksson et al.,
1998; Gould et al., 1998; Kornack and Rakic,
1999). Although the majority of DGCs in the rat
are produced near the end of the first postnatal
week, new DGCs continue to be generated at a
lower rate throughout adulthood and into senes-
cence (Schlessinger et al., 1975; Kuhn et al., 1996)
(Fig. 1). The human dentate gyrus, for example,
generates neurons well into the seventh decade of
life (Eriksson et al., 1998; Kempermann et al.,
2004). Estimates suggest that approximately 9000
DGCs are added daily to the dentate gyrus of
young adult rats, and 6% of the granule cell

DOI: 10.1016/S0079-6123(07)63028-3 529

530

Fig. 1. Neonatal and adult dentate granule cell neurogenesis. (A, B) Bromodeoxyuridine (BrdU) immunostaining of coronal sections
through the dentate gyrus of 10 day (A) and 10 week (B) old rats shows proliferating granule cell progenitors concentrated at the inner
part of the granule cell layer at the hilar (h) border. Dentate granule cell neurogenesis peaks at the end of the 1st postnatal week (A) but
persists into adulthood (B). BrdU was injected 6 days earlier for both. (C) Retroviral nuclear localization signal-b-galactosidase
reporter labeling of proliferating cell clusters in the dentate subgranular zone (arrows) of an adult rat. Inset shows the right cluster at
higher magnification. Retrovirus was injected 3 days earlier. (D) Doublecortin immunolabeling of immature neurons (arrows) in the
adult rat, with cell bodies close to the SGZ but processes throughout the granule cell and molecular layer gcl, granule cell layers.

layer is thought to consist of recently born neurons
(Cameron and McKay, 2001).
Dentate gyrus neural stem cells reside in the
subgranular zone (SGZ) at the border of the hilus
and DGC layer. The stem cells are a subtype of
radial glia-like astrocyte that expresses glial fibril-
lary acidic protein (GFAP) and nestin (Seri et al.,
2001; Filippov et al., 2003). They proliferate and
give rise to clusters of transit amplifying precur-
sors that divide further to generate neuroblasts
(Fig. 1). The SGZ precursors and neuroblasts are
characterized by a sequence of marker expression
as they mature (reviewed in Kempermann et al.,
2004). The progenitors express doublecortin
(DCX) and polysialylated neural cell adhesion
molecule (PSA-NCAM) during cell division and as
early postmitotic neurons (Fig. 1D). With further
differentiation, postmitotic neurons continue to
expresss DCX and PSA-NCAM, but also begin to
express calretinin and Prox1; subsequently, they
differentiate further into mature granule neurons
that are immunoreactive for Prox1 and calbindin.
Integration and function of adult-born DGCs
Increasing attention has focused on the potential
for adult-generated DGCs to integrate into exist-
ing neural circuitry. Combined retrograde tracer
and mitotic labeling studies using tritiated thymi-
dine or its analogue, bromodeoxyuridine (BrdU),
in adult rodent indicate that mossy fibers of
newborn DGCs project to appropriate targets in
hippocampal area CA3 (Stanfield and Trice, 1988;
Hastings and Gould, 1999; Markakis and Gage,
1999). Acute hippocampal slice recordings from
rodents in which adult-generated DGCs were labe-
led with retroviral reporters or by transgenic
manipulations show that the cells integrate into
hippocampal circuitry and acquire some electro-
physiological characteristics of mature DGCs
(Song et al., 2002b; van Praag et al., 2002; Wadi-
che et al., 2005; Ge et al., 2006). The newborn
neurons appear to receive gamma-aminobutyric
acid (GABA)ergic synaptic inputs at 1 week after
birth and glutamatergic inputs within 2 weeks.

Adult-generated DGCs initially show depolarizing
responses to GABA (Tozuka et al., 2005; Wadiche
et al., 2005; Ge et al., 2006), similar to immature
neurons during early development. Unlike those in
the neonate, however, adult-generated DGCs take
much longer (perhaps 3–6 months) to obtain a full
dendritic arborization pattern (van Praag et al.,
2002). Compared to neighboring mature DGCs,
immature DGCs in the adult have a higher input
resistance and a subthreshold calcium conductance
that may enhance their excitability. In vitro elect-
rophysiological studies also show a decreased
threshold for long-term potentiation (LTP) or
long-term depression, as well as higher-amplitude
LTP, in newborn DGCs compared to their mature
counterparts (Wang et al., 2000; Schmidt-Hieber
et al., 2004).
The precise function of DGCs generated in
adulthood is unknown. Most of the experimental
evidence to date, however, supports a role for
DGC neurogenesis in learning and memory func-
tion (see Doetsch and Hen, 2005 for review). Stim-
ulation of adult DGC neurogenesis with
behavioral interventions such as exercise or envi-
ronmental enrichment is associated with better
performance on certain hippocampal learning
tasks (Bruel-Jungerman et al., 2005; van Praag
et al., 2005; Meshi et al., 2006), although the link
between increased neurogeneis and enrichment-
enhanced performance has recently been called
into question (Meshi et al., 2006). The degree of
adult neurogenesis in some inbred mouse strains
also correlates positively with learning ability
(Kempermann and Gage, 2002). More direct
evidence that neurogenesis supports hippocam-
pal-dependent learning and memory derives
from experiments in which the depletion of
adult-generated neurons disrupts certain forms of
learning (Shors et al., 2001, 2002; Winocur et al.,
2006). These data are supported by the findings
described above that suggest LTP is more easily
elicited and of higher amplitude in immature,
adult-born DGCs (Wang et al., 2000; Schmidt-
Hieber et al., 2004). Recent animal studies also
provide evidence that DGC neurogenesis in the
adult is necessary for the positive effects of anti-
depressant medication (Santarelli et al., 2003).
Despite these accumulating data, knowledge of the
531
entire spectrum of biological functions involving
adult DGC neurogenesis awaits more specific
means of manipulating DGC progenitors in the
adult.
Regulation of adult DGC neurogenesis
A host of physiological states and molecular
factors appear to regulate adult hippocampal
neurogenesis (see Table 1). Neuronal production
declines markedly with age (Seki and Arai, 1993;
Kuhn et al., 1996), probably due to reduced DGC
precursor proliferation and altered differentiation
or delayed maturation of their progeny (Kemper-
mann et al., 1998; Rao et al., 2005). The mecha-
nisms likely reflect active suppression of
neurogenesis with age because removal of cortico-
steroids by adrenalectomy or the infusion of spe-
cific growth factors significantly restores DGC
production in aged rats (Cameron and McKay,
1999; Lichtenwalner et al., 2001; Jin et al., 2003).
In addition to age, acute or chronic stress de-
creases DGC neurogenesis in young adult rodents
and primates (Mirescu and Gould, 2006).
Adult neurogenesis is stimulated by environ-
mental enrichment, which increases the survival
and neuronal differentiation of DGCs generated in
early adulthood through senescence (Kemper-
mann et al., 1997, 1998, 2002; Nilsson et al.,
1999). Exercise also enhances adult neurogenesis,
but this effect relates to increased precursor pro-
liferation rather than survival (van Praag et al.,
1999). Growth factors may play a significant role
in mediating these effects, as blocking brain up-
take of insulin-like growth factor-1 (IGF-1) or
vascular endothelial growth factor (VEGF) pre-
vents the increase in DGC production induced by
enrichment or exercise (Trejo et al., 2001; Fabel
et al., 2003; Cao et al., 2004). Administration of
these growth factors also increases adult neuro-
genesis in the rodent dentate gyrus (Aberg et al.,
2000; Jin et al., 2002; Cao et al., 2004; Schanzer
et al., 2004), but it is unclear whether this effect
results from increased progenitor cell proliferation
(Jin et al., 2002) or survival (Schanzer et al., 2004).
Other mediators of adult hippocampal neuro-
genesis include hormones and neurotransmitters.
532

Table 1. Modulation of adult hippocampal neurogenesis

Variable Change in Mechanism Change in Proliferation Neuronal Survival

neurogenesis neurogenesis differentiation

Physiologic state
Aging Decreased Proliferation/ Decreased m m
neuronal
differentiation
Stress Decreased Proliferation Decreased m
Exercise Increased Proliferation/ Increased m m? m?
?survival/
?differentiation
Environmental Increased Survival Increased m
enrichment
Growth factors
bFGF Increased (early Proliferation Increased m
postnatal) (postnatal)
BDNF Increased Differentiation/ Increased m m
survival
VEGF Increased Proliferation/ Increased m m
survival
IGF-1 Increased Proliferation/ Increased k m
survival/
?differentiation
Neurotransmitters/neuromodulators
Glutamate Decreased Proliferation Decreased m
GABA Increased Differentiation/ Increased m? m
?proliferation
Serotonin Increased Proliferation Increased m
Nitrous oxide Decreased Decreased Decreased k m
proliferation
(promotes
differentiation)
Transcription factors
Wnt Increased Proliferation/ Increased m m?
?differentiation
Sonic Increased Proliferation Increased m
hedgehog
Sox2 Increased ?Proliferation/ m? m?
?differentiation

Adrenalectomy and corticosteroid replacement receptor antagonists or lesion of DGC afferents

studies have shown that circulating stress hor-
mones suppress the rate of DGC production in
adulthood (reviewed in Mirescu and Gould, 2006).
In contrast, cell proliferation in the rat dentate
gyrus increases during proestrus, and the effect is
abolished by ovariectomy (Tanapat et al., 1999).
Glutamatergic inputs also appear to influence
dentate gyrus neurogenesis in the adult rodent.
Activation of N-methyl-D-aspartate (NMDA) re-
ceptors attenuates cell proliferation, and suppress-
ing glutamatergic neurotransmission with NMDA
exerts the opposite effect (Cameron et al., 1995).
Serotonin (5-hydroxytryptamine) also influences
adult neurogenesis. Chronic treatment with anti-
depressant drugs that act as serotonin reuptake
inhibitors increases cell proliferation in the rodent
dentate gyrus (Malberg et al., 2000), and blockade
of serotonin synthesis or administration of a
serotonin neurotoxin decreases new cell produc-
tion (Brezun and Daszuta, 1999). In terms of other
neuromodulators, the number of newly generated
DGCs is negatively regulated by nitric oxide,

which reduces DGC precursor proliferation but
promotes neuronal differentiation (Packer et al.,
2003). Neuronal addition thus continues in adult-
hood under the influence of a balance between
multiple positive and negative regulators of ne-
urogenic activity.
The local microenvironment in regions of on-
going neurogenesis in the adult mammalian brain
provides what is referred to as a ‘‘stem cell niche.’’
This niche governs neuronal production and in-
cludes progenitors, astrocytes, microvasculature,
and microglia (Wurmser et al., 2004). Astrocytes
appear to influence all phases of adult neurogen-
esis, including neural precursor cell proliferation,
migration, and differentiation (Lim and Alvarez-
Buylla, 1999; Song et al., 2002a). Studies of ne-
urogenesis in the adult rodent dentate gyrus and
subventricular zone (SVZ) implicate radial glia-
like astrocytes as the neural stem cells from which
neuroblasts derive (Doetsch et al., 1999; Seri et al.,
2001; Garcia et al., 2004; Merkle et al., 2004).
A vascular presence in the stem cell niche likely
modulates neurogenesis as precursors in the dent-
ate gyrus and SVZ reside in close proximity to the
microvasculature (Palmer et al., 2000; Shen et al.,
2004), and their proliferative activity appears to be
tightly linked with angiogenesis. In the adult, sup-
pression of hippocampal neurogenesis by irradia-
tion may reflect disruption of local angiogenesis
(Monje et al., 2002), and infusion of VEGF into
the adult brain increases the production both of
endothelial cells and DGCs (Jin et al., 2002). In
contrast to astrocytes and endothelial cells, recent
studies suggest that reactive microglia disrupt
neurogenesis in the adult dentate gyrus. Micro-
glial reaction and inflammation induced by brain
irradiation, seizures, or lipopolysaccharide treat-
ment decreases the survival of adult-generated
DGCs, and suppressing microglial activation with
minocycline or indomethacin treatment partially
restores neurogenesis (Ekdahl et al., 2003; Monje
et al., 2003).
Seizure-induced hippocampal neurogenesis
The persistence of neural stem cells in the adult
mammalian forebrain raises the possibility for
533
endogenous repair after brain injury or neurode-
generation. Various brain insults in the adult,
including mechanical lesions, hypoglycemia,
fluid percussion injury, and stroke, stimulate pro-
genitor cell proliferation in the hippocampal
dentate gyrus (Gould and Tanapat, 1997; Liu
et al., 1998; Jin et al., 2001; Suh et al., 2005).
As in the intact brain, many newly generated cells
die, but the vast majority of those that survive
differentiate into neurons, and typically less
than 20% of adult-born cells become glia or
remain undifferentiated. Similar findings are seen
after seizure-induced injury in temporal lobe
epilepsy (TLE) models, which were the first brain
injury models used to demonstrate altered hippo-
campal neurogenesis (Parent et al., 1997). Studies
of adult rodent models of limbic epileptogenesis
or acute seizures indicate that prolonged
seizures potently stimulate DGC neurogenesis
(Bengzon et al., 1997; Gray and Sundstrom,
1998; Parent et al., 1997, 1998; Scott et al.,
1998). In the adult rodent kainate and pilocar-
pine models of temporal lobe epilepsy,
chemoconvulsant-induced status epilepticus (SE)
increases dentate gyrus cell proliferation approx-
imately 5–10-fold after a latent period of at least
several days (Parent et al., 1997; Gray and
Sundstrom, 1998) (Fig. 2A and B). Approxi-
mately 80–90% of the newly generated cells
differentiate into DGCs.
DGC neurogenesis is also enhanced by kindling-
induced epileptogenesis. Electrical kindling of the
amygdala (Parent et al., 1998; Scott et al., 1998),
hippocampus (Bengzon et al., 1997) or perforant
path (Nakagawa et al., 2000) acutely increases
dentate gyrus cell proliferation and neurogenesis.
Similar neurogenic effects occur after acute
seizures induced by intermittent perforant path
or hippocampal stimulation in adult rats (Bengzon
et al., 1997; Parent et al., 1997). Even single,
discrete seizure-like afterdischarges induced by
hippocampal stimulation lead to increased num-
bers of newly differentiated DGCs (Bengzon et al.,
1997). Although more severe seizures enhance
neurogenesis to a greater extent, the survival of
the newborn DGCs may decrease with increased
seizure severity (Mohapel et al., 2004). This effect
may relate to the degree of microglial activation as
534

Fig. 2. Increased cell proliferation and altered dentate gyrus neuroblast migration after SE. (A, B) BrdU incorporation (arrows) in
adult rat dentate gyrus 7 days after saline (A) or pilocarpine (B) treatment followed by a 2 day post-BrdU survival. Subgranular zone
BrdU labeling increases markedly after SE (B) compared to the control (A). (C, D) Doublecortin (DCX) immunoreactivity in the
dentate gyrus of a control (Con; C) and an adult rat 14 days after pilocarpine-induced SE (14d; D). Note the increased hilar DCX
expression and chains of DCX-positive cells extending into the hilus (arrows in D) after SE. E, PSA-NCAM+ neuroblast chains (red,
arrows) alongside GFAP+ hilar astrocytes (green). Dashed lines in C–E denote the granule cell layer (gcl) — hilar (h) border.
(See Color Plate 28.2 in color plate section.)

it is reversed in part by minocycline treatment to project axons aberrantly in the epileptogenic

(Ekdahl et al., 2003).
Seizure-induced hippocampal neurogenesis:
functional significance
In the pilocarpine model of TLE, aberrant mossy
fiber sprouting occurs in parallel with the gener-
ation of increased numbers of DGCs (Parent et al.,
1997). Evidence suggests that developing axons
from newborn DGCs contribute to status epilep-
ticus (SE)-induced aberrant mossy fiber reorgan-
ization in both hippocampal area CA3 and the
dentate inner molecular layer (Parent et al., 1997).
Eliminating DGC progenitors by brain irradiation
before and after pilocarpine treatment, however,
does not suppress mossy fiber sprouting (Parent
et al., 1999). Thus, seizure-induced injury appears
to induce both pre-existing and adult-born DGCs
hippocampal formation.
An increasingly recognized abnormality of
DGC neurogenesis in experimental TLE is the
ectopic location of adult-born granule neurons.
The DGC layer in human TLE is often abnormal
due to dispersion and the presence of ectopic
granule-like neurons in the hilus and inner molec-
ular layer (Houser, 1990; Parent et al., 2006a).
An early report of seizure-induced neurogenesis
described newly differentiating neurons with gran-
ule cell morphology in the dentate hilus and inner
molecular layer after pilocarpine-induced SE in
adult rats (Parent et al., 1997). Hilar-ectopic
DGCs are found in several different experimental
TLE models and may persist for many months
(Parent et al., 1997, 2006a; Scharfman et al., 2000;
Dashtipour et al., 2001). The cells resemble the
granule-like neurons identified in surgical speci-
mens from humans with temporal lobe epilepsy,
both in terms of their morphology and marker
 535

Fig. 3. Schematic showing the effects of prolonged seizures on caudal subventricular zone (SVZ) and dentate gyrus progenitors. In the
intact adult rat (top), progenitors located in the infracallosal SVZ (purple) give rise to white matter oligodendrocytes (orange), while
those in the dentate gyrus (green) give rise to DGCs in the granule cell layer (gcl). After seizure-induced hilar and pyramidal cell layer
(pcl) injury (bottom; jagged arrows), progenitors migrate aberrantly from the caudal SVZ to form glia (a; purple) in the hippocampus
proper or from the dentate subgranular zone to form hilar-ectopic DGCs (b). (See Color Plate 28.3 in color plate section.)

expression (Scharfman et al., 2000; Dashtipour
et al., 2001; Parent et al., 2006a). Studies of ne-
urogenesis in the pilocarpine TLE model indicate
that the hilar-ectopic DGCs migrate aberrantly
from the dentate subgranular proliferative zone to
the hilus (Parent et al., 2006a) (Fig. 3).
Using intracellular recordings in hippocampal
slices from epileptic adult rats, Scharfman and
colleagues (Scharfman et al., 2000) have shown
that the hilar-ectopic granule-like cells are hyper-
excitable and fire in abnormal bursts synchro-
nously with CA3 pyramidal cells. Expression of
the activation-induced immediate early gene c-fos
by hilar-ectopic DGCs during spontaneous limbic
seizures also suggests that they participate in ep-
ileptic circuitry (Scharfman et al., 2002). In addi-
tion, many putatively newborn DGCs located in
the hilus or hilar aspect of the DGC layer after
seizures exhibit a much higher percentage of per-
sistent basal dendrites than is normally found
(Scharfman et al., 2000; Dashtipour et al., 2001).
Work by Dashtipour and colleagues suggests that
the basal dendrites of hilar-ectopic DGCs receive
increased excitatory input (Dashtipour et al.,
2001), suggesting that this structural plasticity
may be a mechanism for seizure generation or
propagation. Further evidence supporting the
epileptogenic nature of hilar-ectopic DGCs comes
from the work of Jung and colleagues (Jung et al.,
2004). Their group used the antimitotic agent
AraC to inhibit DGC neurogenesis after pilocar-
pine treatment, and found that these rats devel-
oped fewer and shorter spontaneous recurrent
seizures than controls. Taken together, these data
suggest that hilar-ectopic DGCs integrate abnor-
mally, are hyperexcitable, and thus may contribute
536
Brain insult in childhood (e.g.,
prolonged febrile seizure)
Altered developmental cues
Aberrant migration
of DGC progenitors
Fig. 4. Aberrant neurogenesis hypothesis of epileptogenesis and memory disturbance in mesial temporal lobe epilepsy. Note the
potential maladaptive positive feedback loop of recurrent seizures on aberrant neurogenesis.
to seizure generation or propagation. The presence
of hilar-ectopic DGCs in hippocampi surgically
resected to treat intractable epilepsy (Houser,
1990; Parent et al., 2006a) raises the possibility
that abnormalities in dentate gyrus persistent ne-
urogenesis contribute to epileptogenesis or cogni-
tive dysfunction in human TLE (Fig. 4).
Seizure-induced neurogenesis: mechanisms
The mechanisms by which seizure activity stimu-
lates neurogenesis or gliogenesis are unknown.
Experiments in which proliferating cells were labe-
led with BrdU prior to seizure induction have
shown that epileptic activity stimulates dentate
gyrus and caudal SVZ precursors that are actively
proliferating prior to injury (Parent et al., 1999,
2006b). Huttman and colleagues used a reporter
mouse in which green fluorescent protein selec-
tively labeled nestin-expressing stem-like cells to
show that kainate-induced seizures specifically
increased the proliferation of the radial glia-like
progenitors in dentate gyrus (Huttmann et al.,
2003). Seizures may act to increase neurogenesis
indirectly through activation of astrocytes, as as-
trocytes stimulate hippocampal neurogenesis via
wnt signaling and perhaps other mechanisms
(Song et al., 2002a; Lie et al., 2005). Alternatively,
the SE-induced death of some mature DGCs may
increase cell turnover in the dentate gyrus via other
mechanisms. Cell death is associated with subse-
quent cell birth in a number of postnatal
neurogenic systems, including the dentate gyrus
RECURRENT IMPAIRED
SEIZURES LEARNING/
MEMORY
Ectopically integrated DGCs
and olfactory bulb of adult rodents (Gould and
McEwen, 1993; Biebl et al., 2000). Seizures also
increase the expression of molecules with the
potential to increase neurogenesis or gliogenesis
such as growth factors (Humpel et al., 1993) and
neurotrophins (Isackson et al., 1991). Specific ne-
urotransmitters or neuromodulatory systems
that normally influence DGC neurogenesis (see
Table 1) also may be altered by seizure activity.
In terms of potential mechanisms underlying
hilar- or molecular-layer ectopic DGC formation,
molecular factors that influence neuronal migra-
tion during development are prime candidates.
The expression of one of these developmental fac-
tors, reelin, persists in the hippocampal dentate
gyrus of adult humans and rodents, and has been
implicated in DGC layer dispersion in human
TLE (Haas et al., 2002). The expression of reelin
decreases markedly in the dentate gyrus after
pilocarpine-induced SE (JMP, personal communi-
cation), suggesting that loss of this migration
guidance factor may be responsible for the aber-
rant migration of DGC progenitors during epile-
ptogenesis. Another potential mechanism is loss of
GABA caused by SE-induced depletion of dentate
interneurons, as this neurotransmitter influences
DGC differentiation (see Table 1) and GABA
decreases neuroblast migration in the other adult
neurogenic region, the SVZ-olfactory bulb path-
way (Liu et al., 2005). In an interesting study,
Scharfman and colleagues showed that hippocam-
pal brain-derived neurotrophic factor (BDNF)
infusion in adult rat increased DGC neurogenesis
and led to the appearance of ectopic DGCs
 537

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Plate 28.2. Increased cell proliferation and altered dentate gyrus neuroblast migration after SE. (A, B) BrdU incorporation (arrows) in
adult rat dentate gyrus 7 days after saline (A) or pilocarpine (B) treatment followed by a 2 day post-BrdU survival. Subgranular zone
BrdU labeling increases markedly after SE (B) compared to the control (A). (C, D) Doublecortin (DCX) immunoreactivity in the
dentate gyrus of a control (Con; C) and an adult rat 14 days after pilocarpine-induced SE (14d; D). Note the increased hilar DCX
expression and chains of DCX-positive cells extending into the hilus (arrows in D) after SE. E, PSA-NCAM+ neuroblast chains (red,
arrows) alongside GFAP+ hilar astrocytes (green). Dashed lines in C–E denote the granule cell layer (gcl) — hilar (h) border. (For
B/W version, see page 534 in the volume.)

Plate 28.3. Schematic showing the effects of prolonged seizures on caudal subventricular zone (SVZ) and dentate gyrus progenitors. In
the intact adult rat (top), progenitors located in the infracallosal SVZ (purple) give rise to white matter oligodendrocytes (orange), while
those in the dentate gyrus (green) give rise to DGCs in the granule cell layer (gcl). After seizure-induced hilar and pyramidal cell layer
(pcl) injury (bottom; jagged arrows), progenitors migrate aberrantly from the caudal SVZ to form glia (a; purple) in the hippocampus
proper or from the dentate subgranular zone to form hilar-ectopic DGCs (b). (For B/W version, see page 535 in the volume.)