Heterogeneous Properties of Dentate
Granule Cells
In most areas of the adult brain, neurons are born at
specific periods of embryonic development. In contrast,
dentate granule cells (DGCs) are generated throughout
developmental and adult life. Morphogenesis of the
granule cell layer (GCL) begins during late embryonic
development as neuroblasts migrating from the second-
ary dentate matrix align to form the outer shell of the
suprapyramidal (upper) blade (Fig. 1; Altman and Bayer
1990). The GCL continues to be formed during early
postnatal life, when the infrapyramidal (lower) blade is
originated and the tertiary dentate matrix is established
in the prospective hilar region. Neural progenitor cells
(NPCs) migrate radially from the tertiary dentate matrix
to the inner part of the GCL. Subsequently, proliferative
NPCs establish at the innermost layer, the subgranular
zone, and will continue to generate DGCs with limited
radial migration (Kempermann and others 2003; Espósito
and others 2005; Zhao and others 2006). Thus, the combi-
nation of tangential and radial migratory waves generates
a 2-dimensional gradient of neuronal ages: 1) Neurons
located in the upper blade of the GCL are older than neu-
rons from the lower blade and 2) neurons of the outer
GCL are older than neurons of the inner GCL.
Early studies on the functional properties of DGCs
were aimed at revealing whether neuronal populations
with different properties were found in the inner GCL,
the putative site of adult-born young neurons. To that
end, Wojtowicz and colleagues (Wang and others 2000)
used whole-cell recordings to compare the plasticity of
glutamatergic postsynaptic responses from DGCs
located in the inner and outer GCL. Synaptic responses
from outer DGCs displayed long-term potentiation
(LTP) in response to high-frequency stimulation of the
medial perforant path only when GABAergic inhibition
was blocked. In contrast, DGCs of the inner GCL dis-
played LTP of glutamatergic currents even when
GABAergic inhibition was left intact. These observa-
tions suggested that individual neurons of the inner GCL
might have either a lower threshold for LTP induction
and/or reduced GABAergic inhibition compared to outer
DGCs. In a follow-up study, the overall contribution of
inner DGCs to the global LTP was analyzed by meas-
urements of field potentials (Snyder and others 2001).
Two types of LTP could be pharmacologically identified:
1) a form of LTP independent of GABAergic transmis-
sion and sensitive to ifenprodil, a specific antagonist of
the NMDA receptor subunit NR2B, and 2) a form of LTP
that was evidenced only after blockade of GABAergic
inhibition, sensitive to the N-methyl-D-aspartate recep-
tor antagonist APV-5 but not to ifenprodil. These obser-
vations suggested the existence of DGCs with distinct
functional properties within the dentate gyrus (DG).
Indeed, Snyder and others (2001) went a step further,
showing that GABA-independent LTP was specifically
eliminated when cell proliferation in the brain was halted
by γ-irradiation 3 weeks prior to electrophysiological
recordings. These observations strongly suggest that
The Timing of Neuronal Development in
Adult Hippocampal Neurogenesis
VERÓNICA C. PIATTI, M. SOLEDAD ESPÓSITO, and ALEJANDRO F. SCHINDER
Fundación Instituto Leloir
Buenos Aires, Argentina
The granule cell layer (GCL) of the adult dentate gyrus (DG) is a heterogeneous structure formed by neurons
of different ages because a significant proportion of neurons continues to be generated throughout life. The
subgranular zone of the DG contains neural progenitor cells (NPCs) that divide, differentiate, and migrate to
produce functional dentate granule cells (DGCs) that become incorporated into the existing hippocampal
circuitry. New available tools to identify adult-born neurons in live and fixed brain sections have allowed the
transition from NPC to functional neuron to be characterized in great detail. Maturation of the neuronal phe-
notype includes changes in membrane excitability and morphology as well as the establishment of appro-
priate connectivity within the existing circuits, a process that lasts several weeks. The events leading to
neuronal maturation share many of the features of the developing brain, and electrical activity is emerging
as a key modulator of neuronal development in the adult DG. The underlying mechanisms are now begin-
ning to be understood. NEUROSCIENTIST 12(6):463–468, 2006. DOI: 10.1177/1073858406293538
KEY WORDS Adult hippocampus, Differentiation, Functional integration, Neural progenitor cells, Stem cells, Synaptogenesis
THE NEUROSCIENTIST 463
VCP and SE contributed equally to this work. Work from our labora-
tory is supported by the Agencia Nacional para la Promoción de
Ciencia y Tecnología, Consejo Nacional de Investigaciones Científicas
y Técnicas, Fundación Antorchas and National Institutes of Health
(Fogarty International Research Collaboration Award).
Address correspondence to: Alejandro F. Schinder, Fundación Instituto
Leloir, Av. Patricias Argentinas 435, (1405) Buenos Aires, Argentina
(e-mail: aschinder@leloir.org.ar).
NEUROSCIENCE UPDATE „
Volume 12, Number 6, 2006
Copyright © 2006 Sage Publications
ISSN 1073-8584

young adult-born neurons (less than 3 weeks old) were
the substrate of such forms of synaptic modification.
More recently, immature DGCs of the inner GCL iden-
tified by their high input resistance (>1.5 GΩ), expres-
sion of the polysialylated form of the neural cell
adhesion molecule, and dendritic tree morphology were
compared to mature DGCs (Schmidt-Hieber and others
2004). Immature neurons showed a lower threshold for the
induction of LTP in the presence of GABAAR antagonists,
probably because of the presence of Ca2+ spikes that can
boost Na+-dependent action potentials increasing mem-
brane excitability. Taken together, these studies have
demonstrated that young neurons of the adult DG are a
distinctive functional population with enhanced synaptic
plasticity and can be readily distinguished from mature
DGCs. Therefore, the adult DG should not be viewed as
static and homogeneous but rather as a highly dynamic
structure with a significant proportion of young DGCs
bearing immature neuronal properties.
Neuronal Development in the
Adult Hippocampus
At the cellular level, adult neurogenesis can be viewed
as a process by which an NPC undergoes discrete devel-
opmental stages that include proliferation, differentia-
tion, survival, migration, and maturation before they
finally become fully functional neurons in the hip-
pocampal circuitry (van Praag and others 2002; Abrous
and others 2005; Ming and Song 2005; Lledo and others
2006; Overstreet-Wadiche and Westbrook 2006). Work
by several laboratories using various techniques to iden-
tify adult-born neurons has recently demonstrated that
NPCs of the adult DG follow a precise pathway through
neuronal maturation and functional integration. Genetic
marking with retroviruses was used to express enhanced
green fluorescent protein (GFP) in the neuronal progeny
of dividing NPCs, allowing accurate dating, electro-
physiological recordings, and morphological analysis of
adult-born neurons (van Praag and others 2002; Espósito
and others 2005; Ge and others 2006; Zhao and others
2006). An alternative method exploits the capacity of the
pro-opiomelanocortin (POMC) promoter to drive the
transient expression of GFP in young neurons of the DG,
allowing the morphological and functional characteriza-
tion of approximately 2-week-old neurons (Overstreet
Wadiche and others 2005).
NPCs of the adult DG follow a precise sequence for
the maturation of neuronal function and connectivity
that requires about 4 weeks and exhibits a striking simi-
larity to the events observed during hippocampal devel-
opment (Fig. 2). The neuronal phenotype is acquired
within the first few days. Those early immature neurons
show small action potentials, express immature neuronal
markers, and are spatially restricted to the subgranular
zone. They lack afferent synaptic contacts and display a
high membrane resistance that reflects a low density of
ion channels but show tonic activation of GABAA recep-
tors. One week later, neurons are localized in the inner
GCL, exhibit spineless dendrite trees that reach the inner
molecular layer, and receive depolarizing GABAergic
inputs of dendritic origin (Ambrogini and others 2004;
Espósito and others 2005; Overstreet-Wadiche and oth-
ers 2005; Wang and others 2005; Ge and others 2006;
Karten and others 2006). By the third week, newborn
neurons begin to receive functional glutamatergic affer-
ents and display repetitive action potentials with high-
frequency adaptation. Detailed morphological analysis
of retrovirally labeled neurons resulted in a starting
point for dendritic spine formation of 16 days, indicative
464 THE NEUROSCIENTIST Neuronal Development in the Adult Hippocampus
Fig. 1. Migration and distribution of dentate granule cells during embryonic and postnatal development. A, In mice
and rats, development of the dentate gyrus begins with NPCs migrating from the primary dentate neuroepithelium to
generate the secondary dentate matrix (sdm). By approximately E19, NPCs arising from the first dentate migration form
the outer shell of the granule cell layer (OGCL). B, After birth, the second dentate migration gives rise to the tertiary den-
tate matrix (tdm). NPCs from this matrix migrate radially to generate the inner granule cell layer (IGCL). C, After P20,
proliferative cells accumulate in the subgranular zone (SGZ), becoming the source of granule cells during adulthood.
Adapted from Altman and Bayer (1990).