Neurogenesis

ISSN: (Print) 2326-2133 (Online) Journal homepage: http://www.tandfonline.com/loi/kngs20

A diametric mode of neuronal circuitry-

neurogenesis coupling in the adult hippocampus
via parvalbumin interneurons

Juan Song, Andrew J Crowther, Reid HJ Olsen, Hongjun Song & Guo-li Ming

To cite this article: Juan Song, Andrew J Crowther, Reid HJ Olsen, Hongjun Song & Guo-li Ming
(2014) A diametric mode of neuronal circuitry-neurogenesis coupling in the adult hippocampus
via parvalbumin interneurons, Neurogenesis, 1:1, e29949, DOI: 10.4161/neur.29949

To link to this article: http://dx.doi.org/10.4161/neur.29949

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 Commentary Commentary
Neurogenesis 1, e29949; July 2014; © 2014 Landes Bioscience

A diametric mode of neuronal circuitry-neurogenesis coupling

in the adult hippocampus via parvalbumin interneurons
Juan Song1,2,3,*, Andrew J Crowther4, Reid HJ Olsen1, Hongjun Song5,6,7, and Guo-li Ming5,6,7
1
Department of Pharmacology; University of North Carolina; Chapel Hill, NC USA; 2Neuroscience Center/Neurobiology Curriculum;
University of North Carolina; Chapel Hill, NC USA; 3School of Medicine; University of North Carolina; Chapel Hill, NC USA;
4
Neurobiology Curriculum; University of North Carolina; Chapel Hill, NC USA; 5Institute for Cell Engineering; Johns Hopkins University
School of Medicine; Baltimore, MD USA; 6Department of Neurology; Johns Hopkins University School of Medicine; Baltimore, MD USA;
7
The Solomon H. Snyder Department of Neuroscience; Johns Hopkins University School of Medicine; Baltimore, MD USA
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A dult neurogenesis occurs within

a specialized microenvironment
(or niche), and is dynamically regu-
Introduction

Neurogenesis occurs throughout life

Keywords: parvalbumin interneurons,
optogenetics, GABAergic inputs, adult
hippocampal neurogenesis, proliferating
neural progenitors
*Correspondence to: Juan Song;
Email: juansong@email.unc.edu
Submitted: 05/06/2014
Revised: 07/13/2014
Accepted: 07/15/2014
Published Online: 07/28/2014
http://dx.doi.org/10.4161/neur.29949
Citation: Song J, Crowther AJ, Olsen RH, Song H,
Ming Gl. A diametric mode of neuronal circuitry-
neurogenesis coupling in the adult hippocampus
via parvalbumin interneurons. Neurogenesis 2014;
1:e29949; http://dx.doi.org/10.4161/neur.29949
Commentary to: Song J, Zhong C, Bonaguidi
MA, Sun GJ, Hsu D, Gu Y, Meletis K, Huang ZJ,
Ge S, Enikolopov G, et al. Neuronal circuitry
mechanism regulating adult quiescent neural
stem-cell fate decision. Nature 2012; 489:150-
4; PMID:22842902; http://dx.doi.org/10.1038/
nature11306
And
Song J, Sun J, Moss J, Wen Z, Sun GJ, Hsu D,
Zhong C, Davoudi H, Christian KM, Toni N, et al.
Parvalbumin interneurons mediate neuronal
circuitry-neurogenesis coupling in the adult
hippocampus. Nat Neurosci 2013; 16:1728-30;
PMID:24212671; http://dx.doi.org/10.1038/nn.3572
lated by experience. However, the niche
mechanism that couples neuronal cir-
cuitry activity to the production of new
neurons is not well-understood. In our
recent two studies published in Nature 1
and Nature Neuroscience, 2 we identi-
fied a novel niche mechanism involving
parvalbumin (PV+) interneurons that
couples local circuit activity to dia-
metric regulation of the activation of
quiescent neural stem cells (NSC) and
the survival of their proliferating neu-
ral progeny, two critical early phases of
adult hippocampal neurogenesis. Using
a combination of optogenetics, lineage-
tracing of adult NSCs, and retroviral
mediated approach for birthdating of
neural progenitors, we demonstrated
that activation of PV+ interneurons, but
not somatostatin (SST+) or vasoactive
intestinal peptide (VIP+) interneurons,
suppresses the activation of quiescent
NSCs, while simultaneously promotes
the survival of proliferative newborn
progeny in the adult mouse dentate
gyrus. In this commentary, we review
our findings and discuss a potential
role for PV+ neuron-mediated GABA
signaling as a key neuronal activity sen-
sor that translates animal’s experience
into regulation of adult hippocampal
neurogenesis.
in discrete regions of the adult mamma-
lian brain and substantial evidence sup-
ports critical roles of adult-born neurons
in specific brain functions, such as learn-
ing, memory and olfactory processing
(reviewed in refs. 3–6). Under normal
physiological conditions, active adult neu-
rogenesis is limited to two brain regions,
the olfactory bulb where newborn neu-
rons arise from the subventricular zone
(SVZ) of the lateral ventricles, and the
dentate granule cell layer of the hippo-
campus where newborn neurons are gen-
erated locally within the subgranular zone
(SGZ). Our current understanding of
what makes these two neurogenic regions
receptive to the integration of de novo
neuronal populations in the adult brain is
very limited. Therefore, identifying criti-
cal features of the neurogenic niche that
foster synaptic integration and survival
of newborn progeny may lead to novel
strategies to enhance functional repair
from endogenous or transplanted neurons
after injury and degenerative neurological
disorders.
Significant progress has been made
in identifying major milestones and pro-
cesses underlying adult neurogenesis
(reviewed in ref. 7). In the adult mouse
dentate gyrus, using cell-stage dependent
markers (nestin, Tbr2, DCX, and NeuN)

www.landesbioscience.com Neurogenesis e29949-1


Figure 1. Adult neurogenesis in the dentate gyrus of the hippocampus. Shown is a schematic sum-
mary of the development of newborn cells as characterized by expression of specific molecular
Downloaded by [181.114.182.35] at 14:55 14 February 2016
markers at each stage.
and cell proliferation marker MCM2 via
lineage-tracing, we showed that quiescent
nestin+MCM2- NSCs give rise to highly
proliferative Tbr2 +MCM2 + intermedi-
ate progenitors, which in turn generate
mitotic DCX+MCM2 + neuroblasts to
become DCX+MCM2- immature post-
mitotic neurons and finally DCX−NeuN+
mature dentate granule neurons (Fig. 1).
Electrophysiological studies have further
revealed a stereotypic process of synaptic
integration of new neurons into the exist-
ing circuitry. In the adult mice, newborn
neurons are tonically activated by ambient
GABA soon after birth, followed by depo-
larizing GABAergic synaptic inputs when
cells are around 1 wk old, and finally glu-
tamatergic synaptic inputs that emerge 1
wk later.8
It is generally believed that there exists
a specialized local environment, or niche,
that both houses somatic stem cells and
regulates their development in vivo. Niche
constituents that support adult SVZ or
SGZ neurogenesis include endothelial
cells, ependymal cells, astrocytes, microg-
lia, and mature neurons (reviewed in refs.
9 and 10). Niche mechanisms underly-
ing activity-dependent regulation of adult
neurogenesis are not well understood. We
recently showed that PV+ interneurons in
the adult hippocampus, via a non-synap-
tic mechanism through GABA, suppress
quiescent radial neural stem cell activa-
tion.1 In sharp contrast to this inhibitory
role of PV+ neuron activity on quiescent
e29949-2 Neurogenesis Volume 1
NSC activation, optogenetic analyses
further showed that PV+ neuron activa-
tion promotes the survival of proliferat-
ing neuronal progeny.2 Together, these
studies identified a novel activity-depen-
dent niche signaling mechanism through
which adult neurogenesis is dynamically
controlled, and revealed a diametric mode
of regulation of two critical early phases
of adult hippocampal neurogenesis via
PV+ neuron activity. Here, we comment
on how GABA signaling mediated by PV+
neurons regulates adult neurogenesis at
distinct developmental stages, and discuss
a potential role for PV+ neuron-mediated
GABA signaling as a sensor of local neuro-
nal circuitry activity and as a key regulator
of the speed and extent of adult mamma-
lian neurogenesis.
PV+ Interneurons as a Major
Source of GABAergic Influence
for Adult NSCs and Progenitors
Hippocampal microcircuits recruit dif-
ferent types of GABAergic interneurons,
which exert inhibitory control at the soma,
proximal dendrites, distal dendrites, and
the axonal initial segment of the principal
cells.11,12 The hippocampal interneurons
are remarkably diverse in their location,
morphology, targets, and expression of
proteins, such as calcium binding pro-
teins.11,13 A number of interneurons with
their axons in close proximity to the SGZ
neurogenic niche can potentially exert
functional impact on adult neurogen-
esis. These interneurons include molecu-
lar layer perforant path interneurons
(MOPP), hilar commissural-associational
pathway related interneurons (HICAP),
hilar perforant path-associated interneu-
rons (HIPP), stratum lacunosum–molec-
ulare (L–M) interneurons, and basket
cells.11,12,14
In contrast to embryonic neurogen-
esis, one hallmark of adult neurogenesis
is its dynamic regulation by experience at
specific stages. For example, exposure to
enriched environment promotes adult hip-
pocampal neurogenesis by increasing new
neuron survival.15 Using an optogenetic
approach, we identified PV+ interneurons
as a critical niche component that couples
neuronal circuitry activity to direct regu-
lation of early stages of adult neurogenesis
in vivo under both normal physiological
conditions and after experience, such as
social isolation and enriched environ-
ment.16 While SST+ and VIP+ interneu-
rons also extend elaborate processes in the
subgranular zone and surrounding areas,
their activities did not modulate quiescent
NSC behavior under identical experimen-
tal conditions, suggesting a specific role of
PV+ interneurons as a niche component.
PV+ interneurons are abundant in the
hippocampus, representing ~20% of all
GABAergic neurons, and have been impli-
cated in higher brain function and cogni-
tive dysfunction.11,17 In the adult dentate
gyrus, PV+ interneurons receive excitatory
inputs from dentate granule cells and, to a
lesser extent, from the entorhinal cortical
input.18 They project axons to the dentate
granule cell layer with extensive coverage
across both transverse and septotemporal
axes.19 A common feature of PV+ inter-
neurons is the formation of ensembles
coupled by both electrical, through GAP
junctions, and chemical connections
through reciprocal innervations.20 Among
multiple subtypes of interneurons in the
adult dentate gyrus, PV+ interneurons
may be uniquely poised to convey relevant
information about environmental stimuli
and hippocampal activity to adult neuro-
genesis. PV+ neurons are involved in feed-
forward and feedback inhibition of local
principal neurons in the hippocampus,
they are also coupled with each other, and
 can fire synchronously. PV+ neurons can
also indirectly regulate adult hippocampal
neurogenesis via modulating its down-
stream targets. For example, decreased PV+
neuron activity may increase activation of
mature dentate granule neurons, which in
turn promotes adult hippocampal neuro-
genesis via release of niche factors.21,22
PV+ Neuron-Mediated GABA
Signaling in Early Stages of Adult
Neurogenesis Regulation
Tonic GABA signaling regulates qui-
escent NSCs
Using a combination of optogenet-
ics to selectively target local interneuron
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populations and a clonal lineage-tracing
system to selectively target individual qui-
escent NSCs (also referred as “radial glia-
like cell”), we identified PV+ interneurons
as a critical and unique niche component
among several different interneuron sub-
types that couples neuronal circuitry
activity to regulate NSC quiescence
and activation through γ2-containing
GABA A Rs in the adult mouse dentate
gyrus. In contrast to the direct synaptic
inputs identified onto immature neurons
in the adult mouse dentate gyrus,23 no
apparent functional GABAergic synaptic
responses were detected when quiescent
NSCs were recorded in acute slices in this
and previous studies,24 suggesting that
GABA spillover from activated PV+ inter-
neuron-mature granule cell synapses indi-
rectly regulates nearby NSCs. The tonic
signal has two very intriguing attributes
that make its involvement in neurogen-
esis regulation especially attractive. First,
because tonic signaling transcends indi-
vidual pre-synaptic/post-synaptic cellular
pairs, it provides a means for acting on
cells that might be located some distance
from the proximity of the signaling syn-
apse. Second, recurrent connections are
extensive between granule cells and inter-
neurons in the SGZ microenvironment
and since the ambient transmitter level
is an integrated signal, it is an especially
attractive candidate signal that reflects the
overall local network activity for poten-
tial translation by the neural progeni-
tors. The neurogenic SGZ region is in a
www.landesbioscience.com Neurogenesis e29949-3
mesh of interneuron terminals; therefore,
adult NSCs are subject to dynamic regu-
lation of various interneuron types pos-
sibly through neurotransmitter GABA.
Interestingly, a recent study showed that
tonic and phasic GABA activation of neu-
ral progenitor cells and immature neurons
is modulated by chemokine stromal cell-
derived factor 1 co-released with GABA
from local interneurons.25 While the
mechanisms underlying such a regulation
remain to be determined, these findings
suggest that additional specificity of regu-
lation could be achieved by co-factors in
the local niche.
Synaptic GABA signaling regulates
proliferating progenitor survival
Significant progress has been made
in characterizing synaptic integration of
newborn neurons into the existing neu-
ronal circuitry (reviewed in ref. 26), yet
little is known about the properties of the
first functional synaptic inputs formed
onto newborn progeny during adult hip-
pocampal neurogenesis. Previous electron
microscopy and electrophysiological anal-
yses have suggested the presence of mor-
phological synapses onto early precursors
in the postnatal SGZ.24,27,28 In agreement
with these early observations, we further
identified one source of presynaptic inputs
from PV+ neurons, and these inputs are
acting on the proliferating progenitors.
This result is surprising because previous
studies have suggested that PV+ neurons
make functional synaptic contacts with
neurons largely upon maturation of tar-
get neurons.29 In contrast to highly effi-
cient synapses from PV+ interneurons onto
mature dentate granule neurons where
GABA release can be induced with acti-
vation of three or fewer Ca 2+ channels,30
these initial PV+ synapses onto newborn
progeny exhibit variable structural forms
and appear to be functionally immature
and are only activated upon a train of
stimuli.
What is the functional role of these
immature synapses in regulation of neu-
ral progenitors at the proliferating phase?
Computational models have suggested
advantages of circuit activity-neurogenesis
coupling for temporal storage and mem-
ory clearing in the adult hippocampus31,32
and for tuning olfactory bulb activity to
improve odorant discrimination.33 Recent
experimental evidence also suggests that a
proper rate of both addition and elimina-
tion of new neurons optimizes behavioral
outcomes in animal models.34-36 At the
cellular level, previous studies of adult
hippocampal neurogenesis have identified
an activity-dependent phase of competi-
tive survival of 2- to 3-wk-old post-mitotic
new neurons via glutamate-NMDAR sig-
naling.37 This critical phase of neuronal
elimination occurs during glutamatergic
synapse formation and is input-specific.
In addition to this activity-dependent
fine-tuning of post-mitotic new neuron
number, we show a large-scale regulation
of neuronal production at the proliferative
phase that is also circuitry activity-depen-
dent, but via GABA signaling. Notably,
this activity-dependent mechanism
appears to be distinct from that during
embryonic neurogenesis when cell death
of proliferating neural progenitors occurs
before any synapse formation. During
adult SVZ neurogenesis, significant cell
death has also been observed in the rostral
migratory stream,38,39 although the role of
neuronal circuitry activity in this process
is unknown. In addition, a second phase
of new neuron number regulation occurs
during experience-regulated synaptic
integration into olfactory bulb circuitry.40
Thus, multi-phasic activity-dependent
control of new neuron numbers may be a
general rule for adult neurogenesis, start-
ing with robust regulation during the
proliferative phase and followed by refine-
ment of individual neuron survival during
the maturation phase.
Local Circuitry Control of Adult
Hippocampal Neurogenesis—
Diametric Regulation of Adult
Neurogenesis by Local PV+
Interneurons
PV+ neuron activity that promotes
proliferating neural progeny survival is
in sharp contrast to its inhibitory role
on quiescent neural stem cell activation
in adult dentate gyrus.1 Together, these
results reveal a diametric mode of adult
hippocampal neurogenesis regulation
via PV+ neuron activity (Fig. 2): during
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Figure 2. Diametric regulation of two sequential proliferative processes of adult hippocampal neurogenesis by PV+ neuron activity. Shown is a model
of diametric regulation of quiescent neural stem cell activation, and survival and maturation of their proliferative neuronal progeny: during low activ-
ity within dentate gyrus (A), decreased PV+ neuron activity suppresses the survival of proliferating neuronal progenitors and simultaneously promotes
expansion of the neural stem cell pool via symmetric cell division; conversely, when the activity in the dentate gyrus is high (B), activation of PV+ neurons
promotes the survival and maturation of proliferating neuronal progenitors and inhibits quiescent neural stem cell activation.

heightened activity within dentate gyrus,
activation of PV+ neurons promotes the
survival of proliferating neuronal pro-
genitors and inhibits quiescent neural
stem cell activation; conversely, when
the activity in the dentate gyrus is low,
decreased PV+ neuron activity suppresses
the survival of proliferating neuronal
progenitors and simultaneously promotes
the activation of quiescent NSCs via
symmetric cell division. Consequently,
sustained low PV+ neuron activity is
expected to expand the quiescent NSC
pool at the expenses of decreased neuro-
genesis presumably by decreasing prolif-
erating progenitor survival. In contrast,
sustained high PV+ neuron activity is
expected to increase neurogenesis by pro-
moting proliferating progenitor survival
and preventing quiescent NSCs from
activation thereby preserving the quies-
cent stem cell pool for long-term sustain-
able neurogenesis.
The potential advantage of such a
diametric mode of neuronal circuitry–
neurogenesis coupling may be associated
with adaptive adult neurogenesis regu-
lation in response to dynamic network
activity. Low levels of neuronal activity
in the dentate gyrus may make it unnec-
essary for additional newborn neurons
to integrate into the existing circuitry.
Meanwhile, expanding the NSC pool via
symmetric cell division during periods
of low PV+ neuron activity may prepare
the dentate gyrus for future adaptive
neurogenesis where the activity returns
and NSCs may undergo asymmetric cell
division to produce more new neurons.
Conversely, heightened dentate gyrus
activity leads to a decrease of quiescent
NSC activation. Such decreased activa-
tion of NSCs can potentially prevent
stem cell depletion to ensure lifelong
neurogenesis.41,42
In addition, it may facilitate time-
stamping of a specific cohort of newborn
neurons during heightened activity of
dentate gyrus by increasing the cohort
of recently born neuronal progeny while
simultaneously suppressing the generation
of new neurons of a different age from
quiescent NSC activation. This could
be particularly important, given recent
behavioral studies suggesting a critical
contribution of newborn neurons at a par-
ticular developmental stage to hippocam-
pal function.43-45
Experience-Dependent
Regulation of Adult
Neurogenesis through Local
Interneurons
Different from other somatic stem cell
compartments where morphogens and
growth factors generally serve as niche
signals, adult neurogenesis is well known
to be dynamically regulated by neuronal
activity and experience. Accumulating
evidence suggests that different steps
of adult neurogenesis are differentially
regulated by physiological and patho-
logical stimuli, including an enriched
environment, stress, learning, and sei-
zures (reviewed in ref. 9). Although these
studies indicate that neuronal activity is
essential for this adult form of structural
plasticity, how electrical activity directly
regulates neural stem cells and their prog-
eny is largely unknown. As adult hip-
pocampal neurogenesis occurs within a
dynamic neuronal network, it is conceiv-
able that the local circuit activity could
serve as an effective readout of current
tissue demands and provide a signal to
tune new neuron production. Indeed, our
results suggest a model that PV+ neurons

e29949-4 Neurogenesis Volume 1

 serve as a unique niche component to
couple environmental stimuli to the regu-
lation of adult NSCs and neural progeni-
tors. Specifically, decreased PV+ neuron
activity by chronic social isolation pro-
motes excessive activation and symmetric
cell division of NSCs at the expenses of
decreased neuronal production,1 whereas
increased PV+ neuron activity by exposure
to an enriched environment promotes the
survival of both proliferating neural pro-
genitors and subsequent mature neurons.2
Though the causal link between altered
neurogenesis and animal behavior has
not been established, these findings point
to the possibility that neuronal activity
modulation by local circuits may provide
the fine control of synaptic integration of
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Acknowledgments
The research in the authors’ labora-
tories was supported by UNC start-up
fund (J.S.), NARSAD (J.S. and G.M.),
Whitehall Foundation (J.S.), American
Heart Association (J.S.), UNC BBSP
and Neurobiology Curriculum train-
ing grant (A.J.C.), UNC Department of
Pharmacology training grant (R.H.J.O.),
NIH (G.M. and H.S.), and MSCRF
(G.M.).
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adult quiescent neural stem-cell fate decision. Nature
2012; 489:150-4; PMID:22842902; http://dx.doi.
org/10.1038/nature11306
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adult-born neurons required for specific
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Summary
Our studies identified a critical role of
PV+ neurons as a key sensor of local neu-
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phases of adult hippocampal neurogen-
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features of this niche mechanism may
constitute a novel strategy to overcome
deficits in early integration and neuronal
survival of either endogenous or trans-
planted cells to promote adult plasticity
and regeneration in brain disorders and
after injury.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were
disclosed.
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