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The Journal of Neuroscience, February 1, 2003, 23(3):732
BRIEF COMMUNICATION
Generation of Functional Inhibitory Neurons in the Adult Rat
Hippocampus
ShuHong
Liu,
Jian
Wang,
DongYa
Zhu,
YangPing
Fu,
Ken
Lukowiak, and
YouMing
Lu
Neuroscience Research Group, Department of Physiology and
Biophysics, Faculty of Medicine, University of Calgary, Calgary,
Alberta, Canada, T2N 4N1
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ABSTRACT |
Several thousand new neurons are produced each day in the adult
mammalian hippocampus, among which only excitatory granule cells (GCs)
have thus far been identified. In the present study, we used mutant
Semliki Forest Virus vectors to express enhanced green fluorescent
protein in the hippocampus, and observed that ~14% of newly
generated neurons in the dentate gyrus of adult rats are GABAergic
basket cells (BCs). With the use of double whole-cell patch-clamp
recordings from BC-GC pairs in hippocampal slices, we demonstrate that
newly generated BCs in the dentate gyrus form inhibitory synapses with
principal GCs. These data show for the first time that functional
inhibitory neurons are recruited in the dentate gyrus of adult rats.
Key words:
neurogenesis; functional inhibitory neurons; GABAergic interneurons; virus vectors; green fluorescent protein; adult
rat dentate gyrus
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Introduction |
There is extensive evidence showing
that new neurons are added to the dentate gyrus of adults in many
species of vertebrates (Kaplan and Hinds, 1977 ; Eriksson et al., 1998;
Gould et al., 1999; Kornack and Rakic, 1999). However, only new
excitatory granule cells (GCs) have been identified to date (Paton and
Nottebohm, 1984; Markakis and Gage, 1999; Cameron and
McKay, 2001; van Praag et al., 2002). It is unknown whether inhibitory
neurons are also newly recruited in the adult dentate gyrus. The
inability to identify newly generated inhibitory neurons in
situ is primarily attributable to the limitations of the
conventional methods used in studying neurogenesis. For example,
double-staining sections with 5-bromodeoxyuridine (BrdU) and a mature
neuronal marker [neuronal-specific nuclear protein (NeuN)] labels
nerve cell nuclei, and thus does not allow morphological analysis of
cell type.
There has been much anticipation of breaking through this barrier by
using a retroviral vector expressing green fluorescent protein (GFP)
(Song et al., 2002; van Praag et al., 2002). For example, a retroviral
vector expressing GFP in dividing cells can be visualized using
fluorescence microscopy, allowing physiological recordings from newly
generated GCs (Song et al., 2002; van Praag et al., 2002).
Unfortunately, only a relatively low infection rate can be achieved
with the previously used retroviral vectors (Miller et al., 1990),
making it difficult to functionally characterize newly added neuronal
subsets (e.g., inhibitory GABAergic neurons). To overcome this problem,
we used mutant Semliki Forest Virus [pSFV(pd)]
vectors, which efficiently introduced enhanced GFP into neurons in the
hippocampus, allowing morphological and functional analysis of newly
generated cell types.
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Materials and Methods |
Animals. Sprague Dawley rats (50% female and 50%
male) from the breeding colony at the University of Calgary were used
in this study. These animals were divided into three groups. In group 1, 10-week-old rats were injected with BrdU (100 mg/kg body weight, i.p.) on 3 consecutive days at 24 hr intervals and killed 6 d (group 1a) or 8 weeks (group 1b) after the last BrdU injection. These
rats were not infused with pSFV(pd)-GFP virus vector,
and their hippocampi were processed for immunostaining. In group 2, 10-week-old rats were injected with BrdU on 3 consecutive days at 24 hr
intervals and then had the pSFV(pd)-GFP virus vectors infused 6 d after the last BrdU injection. In group 3, 8-week-old rats were injected with BrdU on 3 consecutive days at 24 hr intervals and had the pSFV(pd)-GFP virus vectors infused 6 weeks
after the last BrdU injection. This group of animals was used for
electrophysiological recording.
For pSFV(pd)-GFP virus vector infection, animals were
anesthetized (100 µg of ketamine, 10 µg of xylazine in 10 µl of
saline per gram). Activated pSFV(pd)-GFP virus particles
were bilaterally infused (2 µl at 0.2 µl/min) into the hippocampus,
2 mm posterior to bregma, 1.5 mm lateral to the midline, and 2 mm below
dura. At 48 hr after the infusion, animals were anesthetized (Nembutal) and then either fixed with 4% paraformaldehyde in 0.1 M phosphate buffer for immunostaining or prepared
for electrophysiological recordings.
Construction of pSFV(pd)-GFP vectors and packaging of the
recombinant virions. To obtain nontoxic virus vectors with high infection rate, we generated a mutant form of pSFV1 vectors, as reported previously (Lundstrom et al., 1999, 2001). The
SacI-XbaI fragment from pSFV1 (Invitrogen,
Carlsbad, CA) was subcloned into the
pGEM7Zf+ vector (Promega, Madison, WI). A
PCR-based site-directed mutagenesis was used to change
Ser259 to Pro and Arg650 to
Asp in the nsP2 fragment. Subsequently, the original fragments in pSFV1
were replaced by the mutated fragments to obtain pSFV(pd)
vectors. Mutations were confirmed by sequencing. A cDNA encoding
enhanced GFP (Clontech, Palo Alto, CA) was then inserted directly into
pSFV(pd) vector to produce pSFV(pd)-GFP
constructs. In vitro transcribed RNA molecules from
pSFV(pd)-GFP were cotransfected with
pSFV-helper2 RNA (a gift from Markus U. Ehrengruber,
University of Zurich, Zurich, Switzerland) into baby hamster
kidney (BHK)-21 cells. All virus production was performed at
31°C. At 24 hr after electroporation, virus stocks were harvested,
filter sterilized, and activated with chymotrypsin A4 (Invitrogen). The
reaction was terminated with the trypsin inhibitor aprotinin
(Invitrogen) before use. Final virus titers
( 109 infectious units/ml) were
determined by infection of BHK-21 cells with serial dilutions of virus
stocks, followed by fluorescence microscopy examination 3 d after infection.
Immunocytochemistry. Immunostaining was performed on 40 µm
free-floating coronal sections. We applied antibodies in 0.1 M TBS with 3% goat serum and 0.3% Triton X-100.
For BrdU staining, sections were heated (85°C for 5 min) in antigen
unmasking solution (Vector Laboratories, Burlingame, CA), incubated in
2 M HCl (room temperature for 30 min), and
blocked in 3% normal goat serum (room temperature for 1 hr), followed
by incubation with rat monoclonal anti-BrdU (1:200; Accurate Chemical,
Westbury, NY). Subsequently, the sections were incubated in
affinity-purified conjugate-adsorbed second antibody, goat anti-rat Cy3
(1:200; Chemicon, Temecula, CA). These sections were then incubated in
one of the following primary antibodies: mouse anti-NeuN (1:100;
Chemicon), rabbit anti-Unc-33-like phosphoprotein/collapsing response
mediator protein-4 (TUC-4) (1:1000; Chemicon), mouse
anti-GAD65 (1:1000; Chemicon); mouse
anti-parvalbumin (PAV) (1:1000; Sigma, St. Louis, MO), rabbit anti-calretinin (CAL) (1:1000; Chemicon), or rabbit
anti-cholecystokinin octapeptide (CCK) (1:500; Chemicon), and reacted
with either conjugate-adsorbed goat anti-mouse Cy5 (1:100; Chemicon),
or conjugate-adsorbed goat anti-rabbit fluorescein (1:50; Chemicon).
Sections were rinsed, dried, and coverslipped with Dako (Glostrup,
Denmark) fluorescence mounting medium. Control sections were processed
with omission of the primary antisera.
GFP expression and colabeling were viewed and counted with an Olympus
(Tokyo, Japan) IX70 fluorescence microscope. Double or triple labeling
was imaged with a confocal laser-scanning microscope (Olympus
LSM-GB200) and analyzed with a three-dimensional (3D) constructor (Image-Pro Plus software). We produced 3D digital reconstructions from a series of confocal images taken at 0.5 µm
intervals through the region of interest, and optical stacks of 6-12
images were produced for the figures. We quantified the absolute
numbers of
GFP+-BrdU+,
GFP+-BrdU+-TUC-4+,
GFP+-BrdU+-GAD65+,
GAD65+-BrdU+-TUC-4+,
and
BrdU+-PAV+
neurons in the dentate gyrus by sampling every section from the experimental animals.
Electrophysiology. Double whole-cell patch-clamp recordings
were made from hippocampal slices, as described previously (Lu et al.,
2000). Briefly, rats from group 2 and group 3 were anesthetized and
decapitated. Slices in the recording chamber were continuously superfused with artificial CSF (ACSF) (2 ml/min), saturated with 95%
O2/5% CO2 at 30°C ± 1°C. The composition of ACSF (in mM) was 124 NaCl, 3 KCl, 1.25 NaH2PO4,
4 MgCl2, 4 CaCl2, 26 NaHCO3, and 10 dextrose. For double whole-cell
patch-clamp recordings from dentate gyrus
GFP+ basket cell (BC)-GC pairs,
hippocampal slices were visualized with infrared (IR) illumination and
differential interference contrast (DIC), using an Axioskop 2FS plus,
equipped with fluorescence-IR Hamamatsu (Bridgewater, NJ) C2400-07E
optics. A whole-cell recording (tight-seal, >1 G ) with patch
electrode (3-5 M) was initially obtained from a
GFP+ BC at the GC layer. Subsequently, the
second whole-cell recording (tight seal, >10 G) was made from a
GFP+ GC. An extracellular stimulating
electrode (bipolar tungsten; FHC, Bowdoinham, ME) was placed in the
medial perforant fibers, the excitatory input to the dentate gyrus BCs
and GCs. After recording, slices were placed in 4% paraformaldehyde in
0.1 M phosphate buffer overnight and processed
for BrdU staining. Postsynaptic GCs were recorded in voltage-clamp mode
at  70 mV with high concentration intracellular
Cl solution, using an Axopatch 200B
(Axon Instruments, Foster City, CA). Presynaptic BCs were recorded in
current-clamp mode using an Axopatch 1D (Axon Instruments). Action
potentials were evoked by current pulse (2 msec, 1.5-2.5 nA) at a
frequency of 0.1 Hz. The input resistance and series resistance in
postsynaptic pyramidal cells were monitored using prevoltage steps (2
mV, 100 msec). Series resistance ranged from 9 to 12 M. The unitary
GABAA receptor IPSCs were filtered at 5 kHz with
a low-pass filter, digitized at a frequency of 10 kHz, and stored
online using the pClamp8 system. For current-clamp mode, the
intracellular solution contained (in mM) 115 K+-gluconate, 7.5 K+Cl, 27.5 K+-methylsulfate, 10 HEPES, 0.2 EGTA, 2 Mg-ATP, and 0.3 guanosine triphosphate, pH 7.4, 296 mOsm. For
voltage-clamp recordings, the high concentration
Cl solution contained (in
mM) 150 CsCl, 10 HEPES, 0.2 EGTA, 2 Mg-ATP, and
0.3 guanosine triphosphate, pH 7.4, 296 mOsm. A total of 0.1% rhodamine was also included to verify recorded BCs.
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Results |
To determine early new GABAergic neurons in the dentate gyrus of
adult rats, the hippocampal sections of 10-week-old rats treated 6 d previously with BrdU (group 1a) were colabeled with BrdU and
GAD65, an isoform of glutamic acid decarboxylase
that labels immature GABAergic cells (Dupuy and Houser, 1996; Huang et
al., 1999). A considerable number of BrdU-labeled
(BrdU+) cells were observed to be
immunoreactive to GAD65
(GAD65+-BrdU+)
(Fig. 1A). The majority
of
GAD65+-BrdU+
cells had the morphological characteristics (irregular/triangular cells
bodies) of GABAergic interneurons located in the subgranule zone.
Subsequently, we stained these sections with TUC-4, which labels
immature neurons (Minturn et al., 1995). We found that the
GAD65+-BrdU+
cells were colabeled by TUC-4
(GAD65+-BrdU+-TUC-4+)
(Fig. 1A). These findings indicate that new GABAergic
neurons are produced in the dentate gyrus of adult rats.
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Figure 1.
Generation of GABAergic BCs in the adult rat
dentate gyrus. A, A cell labeled with GAD65
(green), BrdU (blue), and TUC-4
(red). B, A PAV+ cell
(green) labeled with BrdU (red).
C, No colabeling of BrdU (red) or NeuN
(blue) with CAL (green).
D, No colabeling of BrdU (red) or NeuN
(blue) with CCK (green).
E, Overview of a confocal laser-scanning image of GFP
expression in a section of the dentate gyrus (DG).
F, A GFP+ BC
(arrowhead) was colabeled with BrdU
(red). G, No colabeling of GFP
(green) with BrdU (red) was observed in
the CA1 area. H, A GFP+ cell labeled
with BrdU (blue) and TUC-4 (red).
I, A GFP+ cell labeled with BrdU
(blue) and GAD65 (red). The
insets from the selected areas (dotted
boxes) in A, B, and
F show the details of the double-labeled
neurons.
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To determine the fate of these early new GABAergic cells, group 1b
animals were killed 6 weeks after the last BrdU injection. Hippocampal
sections were double-labeled with BrdU and standard GABAergic neuronal
markers, including PAV (Kosaka et al., 1985), CAL (Miettinen et al.,
1992), and CCK (Kosaka et al., 1985). We found that some
BrdU+ cells were colabeled with PAV
(BrdU+-PAV+)
(Fig. 1B). Previous studies have shown that
PAV+ cells in the hippocampus are a
particular subpopulation of GABAergic neurons, including BCs and
axoaxonic cells (Kosaka et al., 1985; Freund and Buzsaki, 1996).
Approximately 83% of the
BrdU+-PAV+
cells in our study had the morphological characteristics of GABAergic BCs (Fig. 1B). Moreover,
BrdU+ cells were rarely seen to be
positive for CAL (Fig. 1C) or CCK (Fig.
1D). The data suggest that new GABAergic neurons in
the dentate gyrus differentiate into BCs.
To further investigate newly generated GABAergic BCs, we expressed
enhanced GFP in the hippocampus by infusion of
pSFV(pd)-GFP infectious particles (2 µl of
>109 U/ml). GFP-expressing neurons
(GFP+) were observed over a 4 mm diffusion
zone surrounding the injection sites 48 hr after infection.
GFP+ cell analysis showed that expression
was highly neuron-specific (99%), with glia cells showing little GFP
expression (Fig. 1E). Most of the
GFP+ cells in the dentate gyrus (~82%)
were located in the GC layer and expressed the morphological
characteristics of GCs (i.e., a relatively small round cell body with
dendrites extending toward the molecular layer). The remaining
GFP+ cells (~18%) clearly had the
morphological characteristics of GABAergic BCs (i.e., large-diameter
fusiform cell somata with multipolar dendritic trees and profuse
branching with long thin spines) (Fig. 1E).
We subsequently performed BrdU labeling in these sections. Using
confocal laser-scanning microscopic analysis, we observed that ~13%
of the GFP+ cells were clearly colabeled
with BrdU
(GFP+-BrdU+)
and were located in the GC and subgranule cell layers of the dentate
gyrus. We determined that these
GFP+-BrdU+
cells were double-labeled neurons by performing 3D digital
reconstruction (Fig. 1F). Based on morphological
characteristics (large fusiform cell somata with multipolar dendrites)
(Fig. 1F), ~16% of the GFP+-BrdU+
cells were identified as GABAergic BCs in the dentate gyrus (Table 1). In contrast to these findings in the
dentate gyrus, GFP+ cells were rarely
colabeled with BrdU in the CA1 area (Fig. 1G), indicating
the absence of newborn neurons in the adult CA1 region of the
hippocampus.
To determine further the early new GABAergic BCs in the adult dentate
gyrus, we infected rats with pSFV(pd)-GFP vectors 6 d
after the last BrdU injection (group 2). We found that 91 ± 13%
of the total
GFP+-BrdU+
cells (n = 11 rats) were immunoreactive to TUC-4, an
early neural marker (Table 1). Approximately 16% of these
TUC-4+ neurons were morphologically
characterized as GABAergic BCs (Fig. 1H). Moreover,
staining of these sections with GAD65 revealed that ~89% GAD65+ cells
were also immunoreactive to BrdU
(GFP+-GAD65+-BrdU+)
(Fig. 1I). In comparison with the mature interneurons
labeled 6 weeks after the last BrdU injection (Fig.
1F), these immature GABAergic BCs had smaller
fusiform cell soma (~20-30 µm) with smaller dendritic trees. These
immature interneurons were rarely covered with spine structures,
consistent with a previous study showing that mature spine and
dendritic structures of central neurons are first evident 4 weeks after
birth (Suzuki et al., 1997).
To establish whether the new GABAergic BCs in the adult dentate gyrus
function as inhibitory neurons, we made use of double whole-cell
patch-clamp recordings from monosynaptically connected dentate gyrus
GFP+ BC-GC pairs. This approach was made
possible by several factors: synaptically connected BC-GC pairs in the
dentate gyrus were easily identified by morphological criteria (i.e.,
GFP expression) (Fig. 2A), BCs could be
easily distinguished from GCs by their ability to generate
high-frequency trains of action potentials during current injection
(Fig. 2B) (Kraushaar and Jonas, 2000), and the amplitude of recorded unitary IPSCs evoked by intracellular stimulation of presynaptic BCs was large enough for analysis (Fig. 2C).
The paired recording technique has the important advantage of being able to determine whether newly generated BCs form functional synapses
onto GCs. In addition, staining the hippocampal sections with BrdU
after the recordings permits comparisons of the physiological properties between BrdU+ and
BrdU BC-GC pairs (Table
2). We examined 169 BC-GC pairs from 22 animals and found that 16 of them had BCs labeled with BrdU (Fig.
2A). All measured parameters [mean latency, rise
time (10-90%), decay time constants ( ), peak amplitude, percentage
of failures, and ratio of paired pulse depression (Fig.
2D)] in the BrdU+
BC-GC pairs were statistically similar to those in the
BrdU BC-GC pairs. Thus, the endogenous
precursors can differentiate into functional BCs that establish
reliable inhibitory synapses with the principle GCs in the dentate
gyrus. Consistent with our hypothesis that these BCs are GABAergic
inhibitory neurons, we showed that the unitary IPSCs were completely
blocked by bath application of the GABAA receptor
antagonist bicuculline (10 µM) (Fig.
2C).
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Figure 2.
Newly generated BCs form appropriate synaptic
transmission. A, A confocal laser-scanning microscopic
image of a GFP+ (green) BC
(arrowhead), labeled with BrdU (blue) and
filled with rhodamine (Rho, red), that is
synaptically connected with a GFP+ GC
(arrow). The schematic diagram illustrates a paired
recording configuration from this GFP+
BC-GFP+GC pair in a hippocampal slice.
B, Membrane potentials of this GFP+
BC (top; resting membrane potential, 76 mV) and the
GFP+ GC (bottom; resting membrane
potential, 74 mV), in response to depolarizing currents (200 msec,
1.5 nA) recorded under current-clamp mode. C, Single
action potentials from a BrdU+ and a
BrdU presynaptic BC (top), and 10 consecutive single (middle) and averaged
(bottom) unitary IPSCs at 70 mV, from the paired
GFP+ GC. Note that bath application of 10 µM bicuculline (a GABAA receptor antagonist)
blocked the unitary IPSCs. D, Single action potentials
(top) from a BrdU+ and a
BrdU presynaptic BC, and the averages (3 sweeps)
of the paired-pulse unitary IPSCs (bottom).
E, Ten consecutive single (middle) and
averaged (bottom) EPSCs at 70 mV, from a
BrdU+ BC and a BrdU BC, evoked
by stimulation of the medial perforant fibers. F, Single
paired-pulse EPSCs from a BrdU+ BC and a
BrdU BC in the dentate gyrus.
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To determine whether these new BCs receive an excitatory synaptic
input, we stimulated the medial perforant fibers in the dentate gyrus,
and the EPSCs were recorded from BCs. Figure 2E shows
an example of recordings from a
GFP+-BrdU+
BC and an adjacent BrdU BC. The evoked
EPSCs (single- vs paired-pulse stimulation) (Fig. 2F)
in BrdU+ BCs were analyzed and revealed
properties similar to those recorded in
BrdU BCs. These properties included
large peak conductance, high reliability, fast rise of the evoked
EPSCs, and significant facilitation of the paired-pulse responses
(Table 2). These findings demonstrate that newly generated GABAergic
BCs are functionally integrated into the dentate networks.
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Discussion |
Our findings demonstrate for the first time that functional
inhibitory GABAergic BCs are newly recruited in the dentate gyrus of
adult rats. With the use of mutant SFV vectors that preferentially introduce GFP into neurons, we directly analyzed the physiological properties of newly generated BCs. We thus show functional inhibitory synaptic connections between newly generated BCs and GCs in the dentate
gyrus. New GABAergic BCs in the adult dentate gyrus were also
confirmed by: (1) double staining of triangular, BC-like, BrdU+ cells with PAV and (2) colabeling of
GAD65+-BrdU+
cells with TUC-4.
Two recent reports have shown that functional excitatory GCs are
generated in the adult animal dentate gyrus. A first report by van
Praag et al. (2002) established that retrovirus-GFP vectors label
dividing cells in the dentate gyrus of the adult mouse, and
demonstrated that newly generated cells receive functional synaptic
inputs similar to those found in mature dentate excitatory GCs. A
second report by Song et al. (2002) demonstrated that adult stem cells
infected by retrovirus-GFP vectors retain the functional potentials
shown in fetal tissues. Neurons derived from these stem cells possess
axons and dendrites, are capable of firing action potentials, and are
competent to form appropriate synapses with existing neurons. Both of
these studies, however, focused exclusively on the production of
excitatory GCs. By using mutant SFV vectors combined with double
whole-cell patch-clamp recordings, we have now revealed that functional
inhibitory GABAergic BCs are also generated in the adult dentate gyrus.
GABAergic precursor cells are known to exist in the adult dentate
gyrus, as demonstrated by the fact that isolated endogenous progenitors
from the adult mammalian hippocampus produce functional GABAergic
inhibitory neurons in culture (Vicario-Abejon et al., 2000). Our
discovery of the generation of inhibitory BCs in the adult dentate
gyrus in situ provides compelling evidence that the cultured
GABAergic precursor cells have the same potential in vivo as
in vitro. Because GABAergic inhibitory neurons are critical
for the control of networks within the brain (Freund and Buzsaki,
1996), and because newborn neurons in adulthood replace neurons of the
same class that have died (Magavi et al., 2000; Nottebohm, 2002), our
results suggest a neuronal replacement strategy for the treatment of
some neurological disorders and injuries including epilepsy,
Alzheimer's disease, and stroke.
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FOOTNOTES |
Received Sept. 12, 2002; revised Nov. 18, 2002; accepted Nov. 20, 2002.
This work was supported by grants from the Canadian Institutes of
Health Research (Y.L.), Heart and Stroke Foundation, Canada (Y.L.),
Alberta Heritage Foundation for Medical Research (Y.L.), Canada
Foundation for Innovation (Y.L.), and Alberta Foundation of Innovation
and Science (Y.L.). We thank Drs. Keith Sharkey and Brian MacVicar for
critical comments on this manuscript. We also thank Drs. Quentin
Pittman and Jaideep Bains for their help with stereotaxic work.
Correspondence should be addressed to Dr. YouMing Lu at the above
address. E-mail: luy{at}ucalgary.ca.
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ABSTRACT
Introduction
Compound via MeSH
