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The Journal of Neuroscience, June 1, 2000, 20(11):3993-4001
Inhibition of Activity-Dependent Arc Protein Expression in the
Rat Hippocampus Impairs the Maintenance of Long-Term Potentiation and
the Consolidation of Long-Term Memory
John F.
Guzowski1,
Gregory L.
Lyford2,
Gail D.
Stevenson3,
Frank P.
Houston3,
James L.
McGaugh1,
Paul F.
Worley2, and
Carol A.
Barnes3
1 Center for the Neurobiology of Learning and Memory
and Department of Neurobiology and Behavior, University of California,
Irvine, California 92697-3800, 2 Departments of
Neuroscience and Neurology, Johns Hopkins University School of
Medicine, Baltimore, Maryland 21205, and
3 Departments of Psychology and Neurology and Division of
Neural Systems, Memory, and Aging, University of Arizona, Tucson,
Arizona 85724-5115
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ABSTRACT |
It is widely believed that the brain processes information and
stores memories by modifying and stabilizing synaptic connections between neurons. In experimental models of synaptic plasticity, such as
long-term potentiation (LTP), the stabilization of changes in synaptic
strength requires rapid de novo RNA and protein
synthesis. Candidate genes, which could underlie activity-dependent
plasticity, have been identified on the basis of their rapid induction
in brain neurons. Immediate-early genes (IEGs) are induced in
hippocampal neurons by high-frequency electrical stimulation that
induces LTP and by behavioral training that results in long-term memory (LTM) formation. Here, we investigated the role of the IEG
Arc (also termed Arg3.1) in hippocampal plasticity. Arc
protein is known to be enriched in dendrites of hippocampal neurons
where it associates with cytoskeletal proteins (Lyford et al., 1995 ). Arc is also notable in that its mRNA and protein
accumulate in dendrites at sites of recent synaptic activity (Steward
et al., 1998). We used intrahippocampal infusions of antisense
oligodeoxynucleotides to inhibit Arc protein expression and examined
the effect of this treatment on both LTP and spatial learning. Our
studies show that disruption of Arc protein expression impairs the
maintenance phase of LTP without affecting its induction and impairs
consolidation of LTM for spatial water task training without affecting
task acquisition or short-term memory. Thus, Arc appears
to play a fundamental role in the stabilization of activity-dependent
hippocampal plasticity.
Key words:
neuron; synaptic plasticity, long-term
potentiation; long-term memory; hippocampus; oligodeoxynucleotide; immediate-early; gene; spatial memory
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INTRODUCTION |
Immediate-early genes (IEGs) are
rapidly induced in brain neurons in response to patterned synaptic
activity (Cole et al., 1989; Dragunow et al., 1989). Initial
investigations focused on IEGs that encode transcription factors
(Dragunow and Robertson, 1988; Saffen et al., 1988), primarily because
these genes had been identified previously in molecular studies of cell
growth (Curran et al., 1982; Linzer and Nathans, 1983; Greenberg and Ziff, 1984; Lau and Nathans, 1987). In support of a role for IEGs in
synaptic plasticity, IEG induction and long-term potentiation (LTP) in
the hippocampus were shown to have similar stimulation intensity
thresholds and pharmacology (Cole et al., 1989; Worley et al., 1993).
Recent studies have demonstrated that the IEG response is complex and
includes, in addition to transcription factors, growth factors,
metabolic and signaling enzymes, phosphatases, small GTP-binding
proteins, and structural proteins (Lanahan and Worley, 1998). A current
goal is to understand the specific contribution of these IEG proteins
to activity-dependent synaptic plasticity.
Arc (also termed Arg3.1) is an IEG that was cloned
from brain on the basis of its rapid induction after seizure
stimulation (Link et al., 1995; Lyford et al., 1995). Arc
gene expression is broadly responsive to neuronal activation by
physiological stimuli including hippocampal LTP induction in the
absence of seizures (Link et al., 1995; Lyford et al., 1995) and by
dopamine-dependent mechanisms in the striatum (Fosnaugh et al., 1995;
Berke et al., 1998). The Arc protein is enriched in dendrites where it
localizes in a distribution that parallels that of F-actin (Lyford et
al., 1995). Biochemical studies demonstrated that Arc protein interacts with polymerized crude actin, consistent with a role in
activity-dependent changes in dendritic structure. Arc is
unique among known IEGs in that its mRNA rapidly distributes throughout
the dendritic arbor after induction (Link et al., 1995; Lyford et al.,
1995) and localizes to discrete regions that have received direct
synaptic stimulation (Steward et al., 1998). We have demonstrated
recently that Arc RNA induction in CA1 neurons is
specifically linked to the neural encoding process during spatial
exploration (Guzowski et al., 1999). Although these data are consistent
with the idea that Arc may play an active role in modifying
long-term synaptic responses, direct evidence linking Arc
gene expression to synaptic plasticity is lacking.
Antisense oligodeoxynucleotides (ODNs), which can block the synthesis
of specific proteins (for review, see Ghosh and Cohen, 1992),
have been used to elucidate molecular pathways and to examine the
contribution of specific genes to neuroplastic mechanisms and
behavioral responses (Wahlestedt et al., 1993; Konradi et al., 1994;
Wahlestedt, 1994; Ogawa and Pfaff, 1996; Guzowski and McGaugh, 1997).
In the present study, we have used antisense ODNs to assess the
contribution of Arc to synaptic plasticity in the rat hippocampus and
to behavioral memory. The two lines of experiments described here,
electrophysiology and behavioral studies, were started independently
and proceeded in parallel by the Tucson and Baltimore groups and the
Irvine group, respectively. However, because of the congruence of the
studies and the strong correspondence of the results, we have included
them in one communication. The data presented here indicate that
hippocampal Arc protein expression plays a critical role in the
stabilization, but not the induction, of LTP and in the consolidation
of long-term memory after spatial water task training.
Parts of this paper have been published previously (Lyford et
al., 1996; Guzowski et al., 1997).
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MATERIALS AND METHODS |
Oligodeoxynucleotide design and preparation
ODN pairs were prepared that encoded antisense and scrambled
sequence for the Arc mRNA sequence near the translation
start site (Lyford et al., 1995). The nucleotide composition of each ODN pair was identical. The scrambled ODNs, which served as controls, did not show significant homology to sequences in the GenBank database.
In our initial studies, we examined the usefulness of full
phosphorothioate ODNs but determined that they affected baseline synaptic transmission in our in vivo electrophysiological
studies. Subsequently, we used chimeric phosphorothioate/phosphodiester ODNs, which contained phosphorothioate linkages on the three terminal bases of both the 5' and 3' ends and phosphodiester internal bonds. This nucleotide chemistry was selected because of reports showing that
such ODNs retain biochemical specificity, are more stable than
unmodified phosphodiester ODNs in vivo, and are less toxic than full phosphorothioate ODNs (Hooper et al., 1994; Widnell et al.,
1996). Consistent with these previous reports, the chimeric ODNs did
not adversely affect baseline synaptic responses and were used
subsequently in all of the studies described here.
For the LTP studies, which were conducted in Tucson, two different sets
of 18 mer antisense and scrambled ODNs were used. Reports of successful
use of antisense ODNs typically target the region of the translation
start site (Ghosh and Cohen, 1992). Accordingly, the sequence of
"Arc antisense 1" ODN was from bases 214 to 231, and
that of "Arc antisense 2" ODN was from bases 232 to 249 of the published sequence (GenBank accession number U19866; the
translation start site is at base 217). Corresponding
scrambled-sequence ODNs were prepared in which the third base from each
triplet was moved to the first position (designated "scrambled 1"
and "scrambled 2," respectively). The ODNs were synthesized at the
DNA Synthesis Core Facility at Johns Hopkins University (Baltimore,
MD). The gel filtration-purified ODNs were diluted in artificial CSF.
For the water task experiments, which were conducted in Irvine, the
antisense and scrambled ODNs were 20 mers. The sequence of
"Arc antisense 3" ODN was the reverse complement of
bases 209 to 228 of the published Arc sequence and primarily
overlapped Arc antisense 1. The scrambled control ODN
("scrambled 3") contained the same base composition, but in a
randomized order. The gel filtration-purified ODNs (Midland Certified
Reagent Company) were resuspended in PBS, pH 7.4, and were further
purified on Sephadex G-25 spin columns (Pharmacia, Piscataway, NJ). ODN
concentrations were determined spectrophotometrically, and ODN
integrity was confirmed by denaturing gel electrophoresis.
Procedures for electrophysiological recording experiments
Subjects. A total of 23 male retired breeder
Fischer-344 rats, obtained from Charles River Laboratories (Wilmington,
MA) between the ages of 9 and 11 months (middle-aged), were used for
the in vivo LTP experiments. All rats were handled and given
health checks, housed individually in 45 × 24 × 21 cm
Plexiglas cages, and maintained on food and water available ad
libitum and on a reversed 12:12 hr light/dark schedule with lights
off at 10 A.M. Recording sessions were conducted in the dark phase of
this schedule, and each rat was individually tested at the same time of
day over the weeks of recording.
Surgery. Chronic implantations of bilateral recording
cannulae and stimulating electrodes in the hilus of the fascia
dentata and angular bundle were conducted according to National
Institutes of Health guidelines, essentially as described by Barnes et
al. (1994). Recording cannulae consisted of a Teflon-insulated (25 µm) 26 ga stainless steel tube, sealed with a 200 µm stylet that was flush with the cannula tip. The cannula or electrode enabled electrical recordings to be made during all phases of the infusion procedure. Stimulating electrodes were constructed of 114 µm
Teflon-coated stainless steel wire (Medwire Corporation), with ~300
µm of insulation removed from the tip. Rats were anesthetized with 40 mg/kg Nembutal (sodium pentobarbital), given Bicilin (30,000 units,
i.m.) before the start of surgery to prevent infection, and mounted in
a stereotaxic frame. Bone flaps were removed over the recording (3.8 mm
posterior and 2.0 mm lateral to bregma) and stimulating (8.1 mm
posterior and 4.4 mm lateral) sites, and holes for reference and anchor screws were drilled (see Fig. 1A).
Approximately 30 min before the recording cannulae were lowered into
place, rats were given 2.5 mg/kg Diazepam to reduce the incidence of
afterdischarges caused by this mechanical disturbance. Evoked responses
were optimized electrophysiologically to obtain positive-going
perforant path-granule cell responses. Postoperative care consisted of
a subcutaneous injection of 10 ml of saline, Children's Tylenol for
analgesic purposes, and fresh fruit. Rats recovered in a warmed
humidified incubator until full righting reflexes returned. All rats
were given at least a 1 week recovery period before recording began.
Electrophysiological recording. Adaptation to the
electrophysiological testing environment commenced by connecting the
animal to the recording system and obtaining baseline evoked responses at a rate of 0.1 Hz in each hemisphere (alternating hemispheres). The
time elapsed between removal from the colony room and initiation of
recording was ~30 sec; thus 10 responses could be obtained within
several minutes, making potential alterations in the evoked response by
brain temperature changes (Moser et al., 1993) a negligible factor. A
2.56 sec EEG sample was collected before each stimulus delivery along
with responses to the low-frequency test stimulation (200 msec, 300 µA diphasic constant-current stimuli) during the baseline and LTP
induction periods. The LTP induction protocol used was 10 repetitions
of a 25 msec train (i.e., 10 pulses) delivered at 400 Hz, for a total
of 100 stimulus pulses (see Fig. 1C). All responses were
digitized at 20 kHz by an 80386 computer and stored on disk for
subsequent off-line analysis. The field EPSP was measured as the
voltage difference between two cursors set after the EPSP onset and 0.5 msec beyond this, well before the onset of the population spike. To
calculate the amount of change observed after LTP induction, the
formula (V1  V0)/V0 was used, with the
average amplitude of the EPSP on low-frequency baseline recording days
(see Fig. 1B) set as V0 and the
EPSP amplitude after LTP-inducing stimulation was delivered set as
V1 (see Fig. 1D).
The total consecutive number of days that any given rat was tested
ranged up to 128, depending on how quickly the baseline responses
stabilized and whether afterdischarges were induced by cannula
placement or infusion and "restabilization" of the response was
necessary. Eighteen of the 23 rats implanted had good bilateral evoked
responses. Because it was critical to compare infusion of the antisense
ODN with the scrambled ODN, the final n for the LTP
experiment was 18. The other animals were used to test the effects on
baseline synaptic transmission of phosphorothioate and hybrid ODNs.
Delivery of Arc antisense and scrambled control
oligodeoxynucleotides. To inject the ODN, the stylet was removed
from the guide cannula and a 33 ga infusion needle was inserted through the cannula 200 µm beyond the tip in each hemisphere. The
infusion needles were attached by polyethylene (PE50) tubing to 10 µl
Hamilton syringes, which were controlled by a CMA Microdialysis
(CMA100) microinfusion pump. The infusion needles extended 200 µm
beyond the cannula. A volume of 0.5 µl of the antisense ODN was
delivered at a rate of 0.1 µl/min to one hemisphere, and 0.5 µl of
the scrambled antisense was delivered simultaneously at the same rate
to the other hemisphere. Nine rats were given the Arc
antisense 1 and nine rats the Arc antisense 2 ODN to
one hippocampus and the corresponding scrambled ODN to the
contralateral hippocampus. The hemisphere that received the
antisense ODN was determined randomly. The recording procedure during
infusion was as follows: (1) 10 evoked responses (bilateral) were recorded before infusion; (2) the stylet
was removed, and 10 responses were recorded; (3) the
infusion needle was inserted, and 10 responses were recorded; (4) the
infusion pump was started, and 30 responses were recorded
from each hemisphere during drug delivery; (5) immediately after the
infusion 10 responses were recorded; (6) the infusion needle was
withdrawn, and 10 responses were recorded; and (7) the stylet was
inserted, and a final 10 responses were evoked and recorded in each
hemisphere. After this infusion procedure, the rats were returned to
their home cages for 1.5 hr before being given the LTP-inducing stimulation.
The mechanical manipulations involved in performing the infusions of
ODNs (i.e., withdrawal of stylet, insertion of infusion needle,
infusion of drug, withdrawal of needle, and reinsertion of stylet)
caused no observable alteration in baseline synaptic transmission in
52% of treatments (of 124 total infusions). In the cases in which the
effects from one of these mechanical manipulations were significant
(i.e., afterdischarges resulting in reductions or increases in the
amplitude of the evoked response), the procedure was terminated, and
the data were not used in the analysis. When baseline responses
normalized during the subsequent week, rats that showed change in
response size because of mechanical effects were tested again.
Procedures for behavioral testing experiments
Animals and surgery. Forty-two male Sprague Dawley
rats (225-250 gm at arrival; Charles River Laboratories) were used.
The rats were individually housed in a temperature (22°C)- and
light-controlled vivarium (12:12 hr light/dark cycle with the lights on
at 7:00 A.M.), provided access to food and water ad libitum,
and acclimatized to laboratory conditions for 1 week before surgery.
Under Nembutal general anesthesia (50 mg/kg, i.p.), stainless steel
guide cannulae (10.3 mm; 23 ga) targeting the dorsal hippocampus were
implanted bilaterally using a stereotaxic frame (Kopf Instruments). The following coordinates were used: anteroposterior = 3.6 mm,
mediolateral = ±2.2 mm from bregma, and dorsoventral = 2.5
mm from the skull surface. Postoperative care consisted of a
subcutaneous injection of 3 ml of saline and an intramuscular injection
of Bicilin (30,000 units). Rats recovered in an incubator until full
righting reflexes returned. All rats were given at least a 1 week
recovery period before behavioral training began.
Delivery of Arc antisense and scrambled control
oligodeoxynucleotides. ODNs were delivered to the dorsal
hippocampus of awake, behaving rats via guide cannulae through a 30 ga
infusion needle connected to a 10 µl Hamilton syringe by polyethylene
tubing. The infusion needles extended 1.7 mm beyond the cannulae.
Infusions (1.0 µl) were delivered over 154 sec using a syringe pump
(Sage Instruments) to rats either 3 hr before behavioral training (see Fig. 4) or after training (see Fig. 5). The rats were awake and gently
restrained during the infusion procedure.
Water task training and testing. The apparatus used for the
spatial water task was a black tank (diameter, 1.83 m; height, 0.58 m) filled to a depth of ~20 cm with water (24 ± 2°C). In this task, rats learn to locate a submerged, and hence
hidden, Plexiglas platform (20 × 25 cm) 2 cm below the water's
surface. One day (see Fig. 5) or 2 d (see Fig. 4) before
the experiment, the rats were given a pretraining water task session of
four trials to acclimate them to the demands and stresses of the
training procedure. For the pretraining sessions, the platform was in a location different from that used for the actual training. On the day
of training, the platform remained in a fixed position throughout
training trials and between the two training sessions. The training
sessions were separated by 30 min (see Fig. 4) or 2 min (see Fig. 5). A
training session consisted of a series of six (see Fig. 4) or five (see
Fig. 5) trials with a 20 sec intertrial interval (ITI). For the
post-training infusion experiment (see Fig. 5), the intersession
interval was reduced to 2 min to shorten the entire training procedure,
and the number of trials per session was reduced to five to reduce
fatigue that might have been encountered because of the shortened
intersession interval. On each trial, the rat started from one of five
random positions along the side of the tank. The rat was given 60 sec
to find the submerged platform. If a rat did not mount the platform
within the 60 sec, it was guided to the platform. The time to mount the
platform was recorded as the training latency for each trial. The rat
was allowed to remain on the platform for 10 sec before being removed
to a holding cage for the ITI. At the end of a training session, the
rat was returned to its home cage until the second training session.
After completion of the training, the rats were returned to the
vivarium until retention testing.
The rats were given 90 sec probe tests 48 hr after training to measure
retention. The platform was removed from the tank during the probe
test, and the sessions were videotaped for analysis later. Two viewers
independently analyzed the videotapes for two measures of spatial bias.
The first analysis, platform "crossings," measured the number of
times the rat swam directly over the location where the platform had
been during training and an equivalent area located in the opposite
area of the tank (see Figs. 4,5, training vs opposite). The
second analysis, annulus search time, measured the time the rat spent
in a scoring annulus centered over either the initial training location
or the opposite location in the tank during the probe trial (see Figs.
4,5, training vs opposite). The scoring annulus comprised ~10% of
the total water tank area, and the platform comprised ~2%.
Confirmation of cannulae placements. After behavioral
testing, the majority of the rats were anesthetized and perfused
intracardially with saline and then 4% formalin. The brains were
sectioned at 80 µm, stained with cresyl violet, and analyzed to
confirm that cannulae and infusion needle tracts were within the
appropriate region of the dorsal hippocampus. The remaining rats were
used for biochemical studies on the efficacy of the Arc
antisense ODNs (see Fig. 2 and Immunoblot analysis). One week after
testing, these rats were infused with antisense or scrambled control
ODNs in different hemispheres and then killed after a delay of 6 hr. For these rats, cannulae placements and infusion sites were confirmed visually from the 1 mm coronal sections used for tissue punches (see
Immunoblot analysis). One rat (out of 42) was excluded from further
analysis on the basis of these histological findings.
Statistical analysis. Before statistical analyses were
performed, the data were subjected to the following outlier analysis: Rats that were >2 SDs from their respective group mean for specific training or testing parameters were excluded from further analysis. These parameters included training session mean, platform-crossings difference (See Figs. 4,5, training vs opposite), and annulus search
time difference (see Figs. 4,5, training vs opposite). Two rats (one
antisense ODN-treated rat and one scrambled ODN-treated rat) were
excluded from the post-training ODN infusion experiment (see Fig. 5) by
this analysis, whereas no rats were excluded from the pretraining ODN
infusion experiment (see Fig. 4). ANOVA and repeated-measures ANOVA
were used to analyze individual trials and trial sessions,
respectively. ANOVA was also performed on the probe test measures.
Fischer's post hoc tests were used for pairwise
comparisons. Spatial bias for the training location was assessed using
two-tailed paired t tests to compare training versus opposite probe test measures for a given treatment group. A probability level of <0.05 was accepted as statistical significance for all tests.
Immunoblot analysis
Deeply anesthetized rats that had been given an overdose of
sodium pentobarbital (200 mg, i.p.) were briefly perfused with phosphate buffer, pH 7.4, and their brains were rapidly removed. Tissue
punches near the infusion sites, comprising cells principally from the
dentate gyrus and CA1, were taken with a glass pipet (with an inner
diameter of 1 mm) from 1-mm-thick coronal brain slices. Tissue was
sonicated in 0.1 M phosphate buffer, pH 7.4 (containing
10% glycerol, 5 mM EDTA, 20 µM leupeptin,
0.1 mM
N -p-tosyl-L-lysine chloromethyl
ketone (TLCK), and 1 mM PMSF). Protein concentration was
determined by a modified Bradford assay (Bio-Rad, Hercules, CA). Twenty
micrograms of protein were heated in sample buffer with reducing agent
(NOVEX), loaded and run on 4-12% NuPAGE gels (NOVEX), and then
electroblotted to nitrocellulose membranes for immunoblot analysis.
Blots were incubated with diluted primary antibody overnight at 4°C.
Immunoreactive species were detected by chemiluminescence (SuperSignal;
Pierce, Rockford, IL). Blots were first processed to detect Arc
immunoreactivity. After this, blots were directly reprobed with
antibody to actin. Separate blots using the same protein extracts were
processed to determine Narp (Tsui et al., 1996) and NP1 (Schlimgen et
al., 1995) levels; as with Arc, blots were then reprobed with actin
antibody after detection of either Narp or NP1. SeeBlue Markers (NOVEX)
were run on all gels to ensure that the immunoreactive bands were of the correct relative mobility. The following rabbit polyclonal antibodies and dilutions were used: anti-Arc [1:1000 (Lyford et al.,
1995)], anti-Narp [1:1000 (O'Brien et al., 1999)], anti-NP1 (1:5000; generated in P.F.W.'s laboratory), and anti-actin (1:200; Sigma, St. Louis, MO; catalog #A2066).
For quantitation of immunoblot results, appropriately exposed films
were scanned and converted into TIF files for quantitative analysis using NIH IMAGE software. Control experiments were performed to ensure the linearity of the assay with increasing protein loads. IEG
immunoreactivity levels were normalized using the actin
immunoreactivity value for that sample.
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RESULTS |
Delivery of phosphorothioate and hybrid ODNs to the hippocampus of
awake rats
Our initial studies examined the effect of ODNs on acute
synaptic transmission in vivo. Figure
1 shows a schematic representation of the
placement of the chronically implanted infusion cannula/recording electrode used and examples of the extracellular evoked responses before and after tetanic stimulation. Because natural phosphodiester bonds are metabolically labile in vivo, we first prepared
Arc antisense and scrambled control ODNs containing
phosphorothioate linkages. The phosphorothioate linkage is resistant to
nuclease cleavage and the resulting ODNs are more stable than are
phosphodiester-linked ODNs in vivo (Szklarczyk and
Kaczmarek, 1995). However, infusions of phosphorothioate ODNs were
followed by an immediate reduction in the amplitude of the evoked
response. In each of three independent trials, synaptic responses were
reduced by 58% within 5 min. Antisense and scrambled control ODNs were
equally effective in reducing synaptic transmission. The magnitude of
the block was dose dependent, and ~80% of the response was blocked
after infusion of 0.5 µl of 1 mM ODN solution.
Synaptic responses showed no recovery for at least several hours and
recovered gradually over the subsequent several days. These studies
indicate that phosphorothioate ODNs produce a rapid and
sequence-independent inhibition of synaptic transmission. Similar
findings using phosphorothioate ODNs have been reported by other
investigators (Abraham et al., 1997).
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Figure 1.
A, Schematic illustration of the
placement of the chronically implanted infusion cannula/recording
electrode in the hilus of the fascia dentata. The stimulating electrode
was implanted in the angular bundle to optimize the perforant
path-granule cell evoked field potential. B, Example of
the extracellular hippocampal evoked response elicited from perforant
path stimulation before high-frequency stimulation. C,
Example of the response during the high-frequency burst used to induce
LTP. D, Example of the response on the day after LTP
induction.
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We next examined hybrid ODNs in which three nucleotides at both the 5'
and 3' ends possess phosphorothioate linkages and the remaining
nucleotides are linked by phosphodiester bonds. This ODN chemistry is
resistant to exonuclease degradation and is less toxic (Hooper et al.,
1994; Widnell et al., 1996; Hebb and Robertson, 1997). In contrast to
the phosphorothioate ODNs, hybrid ODNs did not alter synaptic
transmission elicited at low frequency. Infusions of hybrid ODNs from
0.5 to 1 µl (at a concentration of 1.0 mM) did not
produce acute changes in synaptic responses. Moreover, synaptic
responses recorded 24 hr after infusion remained stable. For this
reason, the hybrid ODN chemistry was used in all subsequent electrophysiological and behavioral experiments.
Arc antisense ODNs block Arc protein expression in
the hippocampus
We determined the specificity and efficacy of the Arc
antisense ODNs by immunoblot analysis. Individual rats received
infusions of Arc antisense ODNs in one hippocampus and
scrambled ODNs in the other hippocampus. The infusions of antisense and
scrambled ODNs were alternated between right and left hemispheres for
different rats. Our previous studies demonstrated that infused ODNs
remained localized in the dorsal hippocampus and did not diffuse into
the adjacent hemisphere (Guzowski and McGaugh, 1997). The rats were returned to their cages after the infusion procedure. Six hours later,
the rats were sacrificed, and tissue punches were taken near the
infusion sites. Because Arc is present in a subset of hippocampal neurons in control animals and is regulated by natural synaptic activity (Lyford et al., 1995; Guzowski et al., 1999), this
infusion and sacrificing schedule provides a strong functional test for
the ability of the Arc antisense ODNs to inhibit Arc protein
expression under physiological conditions. Arc antisense ODN
protein extracts from two or three rats were pooled, and likewise, the
scrambled ODN extracts from the same rats were pooled for immunoblot
analysis, which was performed as described in Materials and Methods.
This infusion and pooling protocol was performed with three groups of
rats. Normalized Arc protein levels were decreased by 58% in the
Arc antisense-treated hemispheres as compared with the
scrambled ODN hemispheres within the same rats (Fig. 2; t = 4.84; df = 2; p < 0.05).
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Figure 2.
Intrahippocampal Arc antisense ODNs
block Arc protein expression. A, Rats received infusions
(1 nmol of ODN in 1 µl) of Arc antisense 3 ODN
(AS-3) in one hippocampus and scrambled 3 ODN
(SCR-3) in the other 6 hr before death and tissue
dissection. Protein extracts were prepared as described in Materials
and Methods. Group pools were obtained from two to three rats, with the
AS-3-treated and SCR-3-treated
hemispheres pooled separately. Immunoblot analysis was performed for
the synaptic activity regulated and neuron-specific IEG proteins Arc
and Narp and for the neuron-specific protein NP1. After detection with
either Arc, Narp, or NP1 antibodies, the blots were reprobed with actin
antibody. Immunoreactivity levels of the three proteins were normalized
to those of actin for each sample. B, Normalized protein
levels from Arc antisense ODN samples are expressed as a
percentage of normalized Arc levels for the corresponding scrambled ODN
samples for the same group. Arc antisense ODN treatment
caused a reduction in Arc protein levels
(t = 4.84; *p < 0.05),
without affecting the levels of either Narp or NP1.
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To confirm that the observed decrease in Arc protein levels in the
antisense ODN-treated hemispheres was not caused by a general effect on
synaptic activity, we also measured the protein levels of another IEG
known to be regulated by synaptic activity, Narp (Tsui et al., 1996).
In striking contrast to Arc, Narp levels were not affected by the
Arc antisense ODN treatment (Fig. 2; t = 0.46; df = 2; p > 0.05). As a further control, we
confirmed that the expression of another neuron-specific gene, NP1, was not altered by antisense ODN infusion (Fig. 2; t = 0.44; df = 2; p > 0.05). These data provide
strong evidence that the Arc antisense ODNs specifically
inhibit Arc protein expression, without affecting the levels of other
neuronal proteins.
Arc antisense ODNs selectively block LTP maintenance
but not induction
The experimental design sought to administer a single dose of
specific ODN that would block the transient induction of Arc protein
after a high-frequency stimulus. Induction of Arc mRNA and
protein in the dentate gyrus after a maximal electroconvulsive shock peaks within 1-3 hr and returns to baseline by 8 hr
(Lyford et al., 1995; Wallace et al., 1998). Similar kinetics
was confirmed in preliminary studies after LTP-inducing
high-frequency (HF) stimuli. The timing of the ODN delivery
relative to administration of the conditioning stimulus was selected to
provide sufficient time for uptake into neurons while being short
enough that the ODNs might remain active during the time of induction.
Significant intracellular accumulation of ODNs occurs within 15 min of
intracerebral ODN infusion, and even the relatively labile
phosphodiester ODNs are readily detected in neurons 4 hr later (Ogawa
et al., 1995). On the basis of these general parameters, we established
a protocol in which the antisense and scrambled control ODNs were
administered 1.5 hr before the LTP-inducing stimulus.
HF synaptic stimulation was delivered to awake, behaving rats, and the
evoked response amplitudes were recorded 20 min after, 4 hr after, and
subsequently daily for as long as several weeks until responses
returned to prestimulation levels. Because there was no statistically
significant difference between Arc antisense 1 and
Arc antisense 2 ODNs on the attenuation of LTP maintenance [F(1,14) = 0.03; p > 0.05], the data from these two treatments are pooled below. As shown
in Figure 3, the initial amplitude of LTP
did not differ between antisense and scrambled ODN-treated hemispheres,
and the LTP amplitude and decay in the scrambled ODN-treated
hemispheres were similar to that of other reports in chronically
prepared rats (Barnes et al., 1994). However, LTP decayed more
rapidly in the Arc antisense ODN-treated hemispheres and was
several SEMs below that of the scrambled ODN-treated hemispheres at
5 d. For example, on day 5, the mean LTP remaining in the nine rats that obtained Arc antisense 1 was 4% (± 0.02), and
was 7% (± 0.04) in the nine rats that obtained Arc
antisense 2. Differences between the antisense and scrambled
ODN-treated hemispheres were detected as early as 4 hr after LTP
induction.
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|
Figure 3.
Arc antisense ODN treatment impairs
the maintenance of LTP. The mean ± SEM change in EPSP amplitude
measured immediately after LTP induction, at 4 hr, and then at 24 hr
intervals for 5 d in the 18 rats that had stable data for both
scrambled and antisense infusions. Note that there was no difference in
LTP magnitude between treatments initially but that LTP decayed more
rapidly in the Arc antisense ODN-treated hemispheres over
subsequent days.
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Intrahippocampal Arc antisense ODN infusions
specifically impair long-term memory consolidation
Fluorescent in situ hybridization studies show that
Arc RNA is expressed in a discrete population of cells in
the granule cell layer and hilus of the dentate gyrus and in the
pyramidal cell layer of the hippocampus (CA1-CA3) and that this
expression is increased in a spatial exploration paradigm (Guzowski et
al., 1999). This observation, combined with the above finding that disruption of Arc expression interferes with the maintenance of LTP,
suggests that Arc may play a central role in cellular neuroplastic mechanisms of the hippocampal formation. Consequently, ODN-mediated disruption of Arc expression should interfere with
hippocampal function. We tested this hypothesis by examining the effect
of intrahippocampal infusions of Arc antisense or scrambled
ODNs on the learning of, and memory for, the hippocampal-dependent, spatial version of the Morris water task (Morris et al., 1982).
Two experiments of similar design were conducted. For each experiment,
the rats underwent stereotaxic surgery to implant guide cannulae
targeting the dorsal hippocampus. The rats were given at least 1 week
to recover from surgery and were then briefly handled on 3 different
days. One or two days before experimental training, the rats received a
pretraining session of four trials to familiarize them with the task
demands. In this pretraining session, the submerged platform was in a
location different from that used on the day of the experiment.
For the first experiment, the rats received bilateral infusions of
either Arc antisense 3 ODN or scrambled 3 ODN into the dorsal hippocampus 3 hr before behavioral training (n = 6-7 rats per group; infusions of 1 nmol of ODN in 1 µl). In a
previous study, we showed that 1 µl of ODN infused at the same
stereotaxic coordinates remained localized to the dorsal hippocampus,
without diffusing into the ventral hippocampus or into other structures (Guzowski and McGaugh, 1997). Three hours after ODN infusions, the rats
were trained in the hidden platform, or spatial, version of the Morris
water task. This training consisted of two training sessions with a 30 min interval between the sessions. Each session consisted of six
training trials with an intertrial interval of 20 sec. No differences
were observed between the two groups during the pretraining or training
sessions as revealed by repeated-measures ANOVA.
The rats were given a 90 sec probe test 2 d later. Two measures of
spatial bias were recorded (platform crossings and annulus search
time see Materials and Methods), and both showed the same resultthe
scrambled ODN group exhibited a spatial bias for the training location
during the probe test (Fig. 4; paired
t test; platform crossings, t = 4.4; df = 6; p < 0.005; annulus search time, t = 7.1; df = 6; p < 0.001), whereas the
Arc antisense ODN-treated rats did not (platform crossings,
t = 0.3; df = 5; p > 0.05;
annulus search time, t = 1.4; df = 5;
p > 0.05).
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Figure 4.
Pretraining intrahippocampal infusion of
Arc antisense ODNs impairs 48 hr retention test
performance, without affecting task acquisition or short-term memory.
A, The experimental timeline is shown.
Arc antisense 3 ODN or scrambled 3 ODN were administered
bilaterally 3 hr before training in the spatial water task (1 nmol in 1 µl; n = 6-7 rats per group). The two training
sessions were separated by 30 min. A 90 sec probe test was given 48 hr
later. B, Acquisition data from the pretraining and
training sessions are shown. No differences were seen for either the
pretraining or training sessions between the antisense and scramble ODN
groups (p > 0.05, repeated-measures ANOVA).
C, D, The platform-crossings (C)
and annulus search time (D) retention test
measures are shown. Scrambled ODN-treated rats demonstrated a spatial
bias for the training location, whereas the Arc
antisense ODN-treated rats did not [*p < 0.005, comparing training vs opposite measures within a group (2-tailed paired
t test)].
|
|
In the second experiment, we used a post-training ODN infusion
strategy. We reasoned that because intraneuronal accumulation of ODNs
can be seen 15 min after intracerebral infusion (Ogawa et al., 1995)
and Arc RNA accumulates in the cytoplasm and dendrites within 30-120 min of neuronal stimulation (Wallace et al., 1998; Guzowski et al., 1999), Arc antisense ODNs given after
training could block Arc protein expression induced by recent
experience. The rats were given two spatial water task training
sessions of five trials each separated by 2 min. Immediately
after the second training session, separate groups of rats
were given bilateral infusions of either Arc antisense 3 ODN
or scrambled 3 ODN (1 nmol of ODN in 1 µl; n = 8-9
rats per group). The time between the two training sessions was
shortened to 2 min in this experiment to minimize the total time of
training, such that infusions of Arc antisense ODNs after
training might be most effective. A third group received Arc
antisense ODN infusions 8 hr after training (n = 8 rats). Based on the rapid induction of Arc RNA expression after spatial learning (Guzowski et al., 1999) (J. F. Guzowski and
J. L. McGaugh, unpublished observations), it was predicted that
the 8 hr-delayed infusion of Arc antisense ODN should not affect LTM consolidation. Because infusions were given after training, concerns of ODN effects on task acquisition were eliminated, and, as
expected, all groups performed similarly during the training trials.
The rats were then given a retention probe test 2 d later. Probe
tests were again analyzed for spatial bias. Probe trial performance of
the scrambled ODN (immediate) and Arc antisense ODN (8 hr-delayed) groups was similarboth groups exhibited a selective bias
for the training location over the opposite location (Fig.
5; scrambled-immediate, platform
crossings, t = 4.4; df = 7; p < 0.01; annulus search time, t = 4.6; p < 0.01; antisense-delayed, platform crossings, t = 3.6; df = 8; p < 0.01; annulus search time,
t = 5.3; p < 0.001). In contrast, the
Arc antisense (immediate) group did not exhibit a spatial
bias for the training location on the more stringent measurement of
platform crossings (Fig. 5; t = 0.7; df = 7;
p > 0.05). The Arc antisense ODN
(immediate) group did, however, exhibit a spatial bias on the less
stringent annulus search time measure (Fig. 5;
t = 3.1; p < 0.01). Although the
magnitude of this bias (training vs opposite) was less than that for
the scrambled ODN (immediate) and Arc antisense ODN (8 hr-delayed) groups, it was not statistically significant. Overall,
these results are consistent with those seen with the pretraining ODN
infusions.
View larger version (33K):
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[in a new window]
|
Figure 5.
Intrahippocampal Arc antisense ODN
infusions given immediately but not 8 hr after training impair 48 hr
retention test performance. A, The experimental timeline
is shown. Three groups of rats were given two water task training
sessions separated by 2 min. Separate groups of rats were given
bilateral intrahippocampal infusions of either scrambled 3 ODN
(n = 8) or Arc antisense 3 ODN
(n = 9) immediately after training. The third group
received intrahippocampal infusions of Arc antisense 3 ODN 8 hr after training (n = 8). Two days later,
all rats were given a 90 sec probe test. B, Acquisition
data from the pretraining and two training sessions are shown. All
groups performed similarly during the pretraining or training sessions
(p > 0.05, repeated-measures ANOVA).
C, D, The platform-crossings (C)
and annulus search time (D) retention test
measures are shown. The groups given scrambled ODN infusions
immediately after training and Arc antisense ODNs 8 hr
after training demonstrated a spatial bias for the training location on
both measures. In contrast, the group given the Arc
antisense ODNs immediately after training exhibited impairment on the
more stringent retention measure platform crossings but not on the
annulus search time measure [*p < 0.02, comparing training vs opposite measures within a group (2-tailed paired
t test)].
|
|
| |
DISCUSSION |
The principal findings of this study are that ODN-mediated
disruption of Arc protein expression impairs the stabilization of
activity-dependent changes in synaptic efficacy and memory consolidation. Delivery of the Arc antisense ODNs into the
hippocampus of the awake, behaving rat did not inhibit the initial
induction of LTP; however, the magnitude of synaptic enhancement was
reduced within 4 hr compared with responses in the contralateral
hippocampus of the same rat that received a scrambled control ODN.
Similarly, intrahippocampal infusion of Arc antisense ODNs
did not affect the ability of rats to learn the spatial water task but
did impair LTM as assessed 48 hr later. The finding that Arc
antisense ODNs delivered immediately after training, but not 8 hr
later, caused a similar impairment in the 48 hr probe test performance
confirms that the antisense ODNs specifically affected time-limited
memory consolidation processes. The lack of effect of the
Arc antisense ODNs at 8 hr after training is consistent with
the rapid and transient time course of Arc induction;
experience-dependent Arc RNA expression in the hippocampus
occurs rapidly and returns to baseline levels by 2 hr after behavioral
training (Guzowski et al., 1999) (Guzowski and McGaugh, unpublished observations).
The specificity of the antisense ODN effects on LTP and LTM is
supported by several lines of evidence. For the LTP studies, two
independent, and nonoverlapping, sets of antisense and control ODNs
provided identical resultsfor each set, treatment with the antisense
ODN did not affect LTP induction but led to a more rapid decay of the
enhanced response as compared with the scrambled control ODN. The
effect of the Arc antisense ODNs was robust and remained
statistically significant throughout the time course of the decay of
LTP over 4 d. In the behavioral studies, the lack of effect of the
antisense ODN on initial task acquisition or short-term performance in
the pretraining infusion experiment (Fig. 4) demonstrates that the
Arc antisense ODN did not impair hippocampal function at the
time of training. The effect of the antisense ODN on the probe test
performance suggests either a specific effect on memory consolidation
or a delayed toxic effect of the antisense ODN on memory retrieval
mechanisms. The absence of an effect of the Arc antisense
ODNs when infused 8 hr after training provides an important control
that mitigates against a delayed toxic effect. The fact that the
Arc antisense ODN was only effective in impairing the 48 hr
retention performance when administered immediately, but not 8 hr,
after training confirms that the antisense ODN had the predicted
time-limited effect on memory consolidation.
In many ways, the in vivo LTP preparation provides an ideal
system in which to apply antisense technology to the study of synaptic
plasticity. In naïve rats, Arc protein is naturally expressed
in a small subset of granule cell neurons of the normal hippocampus
(~1 of 100) but is rapidly induced in the entire population of these
neurons after seizure or synaptic stimulation that induces LTP (Lyford
et al., 1995). In contrast to other uses of the ODN approach, in which
a constitutively expressed protein is targeted and reductions in
expression are limited by the rate of protein turnover, the current
application needs only to block stimulus-induced increases.
Electrophysiological recordings can be used to monitor continuously the
effects of the ODN on the population of neurons that receive the most
direct application of the ODN. Because IEG levels are not increased
until after the initial events essential to the initiation of LTP, it
is anticipated that they do not play a role in this process. Indeed,
LTP induction in the hippocampus is not blocked by inhibitors of either
RNA or protein synthesis, nor was it blocked by the Arc
antisense ODNs. Accordingly, preservation of LTP induction serves as an
anticipated control for physiological viability of the tissue. In
principle, the same approach pertains for use of antisense technology
to examine the contribution of other IEGs to long-term synaptic
plasticity. Like Arc, many of these proteins appear to be
expressed at low levels naturally in granule cell neurons, and their
induction after a synaptic stimulus might be blocked with a single
administration of antisense ODNs. Our current estimates are that
perhaps 30 IEGs are induced rapidly in hippocampal neurons in
association with LTP (Lanahan and Worley, 1998). This antisense
strategy might be useful for identifying those that are most important
for durable plastic changes in the brain.
For the reasons described above, the anatomical and temporal
specificity of antisense ODN approaches is also well suited to investigating the role of different IEGs in learning and memory processes. For example, the distinction between defects in memory consolidation and retrieval cannot be drawn, at present, from experiments using mice with germ-line null mutations (knock-out mice).
Although advances in transgenic approaches now allow some degree of
temporal control (Mayford et al., 1996) and region-specific null
mutations (Tsien et al., 1996), no current approach can provide the
combination of precise temporal and anatomical resolution. Using the
temporal precision afforded by antisense ODN infusions, we have shown
that disruption of Arc expression within the dorsal hippocampus impairs
LTM consolidation processes and does not affect task acquisition,
short-term memory, or memory retrieval in the spatial water task.
Although disruption of many different genes has been linked to
disruption of LTP, most of these genes or proteins are implicated in
the induction phase of LTP. By contrast, Arc plays a
selective role in LTP maintenance. How might Arc contribute
to LTP maintenance and memory consolidation? Our current understanding
of Arc suggests that it possesses two functional domains. The
C-terminal half of Arc shows modest homology to spectrin and interacts
with structural proteins (Lyford et al., 1995). Arc protein also
interacts with calcium and calmodulin-dependent protein kinase type II
(CaMKII) (G. L. Lyford, A. Chowdhurry, and P. F. Worley,
unpublished observations). The mRNAs of both Arc and
CaMKII are present in neuronal dendrites where they are
hypothesized to be locally synthesized, perhaps in response to specific
forms of synaptic input. In hippocampal granule cell dendrites,
CaMKII mRNA is constitutively present whereas Arc
mRNA is only transiently present after plasticity-inducing stimuli.
Thus, Arc may function as an anchoring or targeting protein for CaMKII
or to modulate the activity or substrate specificity of CaMKII (G. L. Lyford and P. F. Worley, unpublished observations).
Arc has many interesting properties that should provide
insight into mRNA and protein targeting and mechanisms that contribute to synapse-specific effects of an IEG. Our studies demonstrate that Arc
is essential for LTP maintenance and memory consolidation processes. In
many model systems, including LTP, Arc is one of the most
dynamically regulated IEGs. Arc transcription is also induced several-fold in CA1 and in cortical neurons in response to such
natural stimuli as exposure to a novel environment and in
spatial-learning paradigms (Guzowski et al., 1999) (Guzowski and
McGaugh, unpublished observations). Furthermore, Arc is
strongly induced in the striatum in response to dopaminergic agonists
including cocaine (Fosnaugh et al., 1995; Berke et al., 1998). Thus,
Arc likely plays a fundamental role in many natural
functions of neurons in the brain.
| |
FOOTNOTES |
Received Feb. 14, 2000; accepted March 20, 2000.
This work was supported by National Institutes of Health Grants AG
09219, MH 01227, MH 53603, MH 01152, and MH 12526. We thank M. Papapavlou, K. Nguyen, and G. Rao for assistance with various aspects
of these experiments.
Correspondence should be addressed to Dr. C. A. Barnes at the
above address. E-mail: carol{at}nsma.arizona.edu.
Dr. Guzowski's present address: Division of Neural Systems, Memory,
and Aging, University of Arizona, Tucson, AZ 85724-5115.
| |
REFERENCES |
-
Abraham WC,
Logan B,
Thompson VL,
Williams JM,
Tate WP
(1997)
Sequence-independent effects of phosphorothiolated oligonucleotides on synaptic transmission and excitability in the hippocampus in vivo.
Neuropharmacology
36:345-352[Web of Science][Medline].
-
Barnes CA,
Jung MW,
McNaughton BL,
Korol DL,
Andreasson K,
Worley PF
(1994)
LTP saturation and spatial learning disruption: effects of task variables and saturation levels.
J Neurosci
14:5793-5806[Abstract].
-
Berke JD,
Paletzki RF,
Aronson GJ,
Hyman SE,
Gerfen CR
(1998)
A complex program of striatal gene expression induced by dopaminergic stimulation.
J Neurosci
18:5301-5310[Abstract/Free Full Text].
-
Cole AJ,
Saffen DW,
Baraban JM,
Worley PF
(1989)
Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation.
Nature
340:474-476[Medline].
-
Curran T,
Peters G,
Van Beveren C,
Teich NM,
Verma IM
(1982)
FBJ murine osteosarcoma virus: identification and molecular cloning of biologically active proviral DNA.
J Virol
44:674-682[Abstract/Free Full Text].
-
Dragunow M,
Robertson HA
(1988)
Seizure-inducible c-fos protein(s) in mammalian neurons.
Trends Pharmacol Sci
9:5-6[Medline].
-
Dragunow M,
Abraham WC,
Goulding M,
Mason SE,
Robertson HA,
Faull RL
(1989)
Long-term potentiation and the induction of c-fos mRNA and proteins in the dentate gyrus of unanesthetized rats.
Neurosci Lett
101:274-280[Web of Science][Medline].
-
Fosnaugh JS,
Bhat RV,
Yamagata K,
Worley PF,
Baraban JM
(1995)
Activation of arc, a putative "effector" immediate early gene, by cocaine in rat brain.
J Neurochem
64:2377-2380[Medline].
-
Ghosh MK,
Cohen JS
(1992)
Oligodeoxynucleotides as antisense inhibitors of gene expression.
Prog Nucleic Acid Res Mol Biol
42:79-126[Web of Science][Medline].
-
Greenberg ME,
Ziff L
(1984)
Stimulation of 3T3 cells induces transcription of the c-fos protooncogene.
Nature
331:433-437.
-
Guzowski JF,
McGaugh JL
(1997)
Antisense oligodeoxynucleotide-mediated disruption of hippocampal cAMP response element binding protein levels impairs consolidation of memory for water maze training.
Proc Natl Acad Sci USA
94:2693-2698[Abstract/Free Full Text].
-
Guzowski JF,
Hittner JM,
Barnes CA,
Worley PF,
McGaugh JL
(1997)
Behavioral regulation of the immediate-early gene Arc and its role in memory consolidation.
Soc Neurosci Abstr
23:822.11.
-
Guzowski JF,
McNaughton BL,
Barnes CA,
Worley PF
(1999)
Environment-specific induction of the immediate-early gene Arc in hippocampal neuronal ensembles.
Nat Neurosci
2:1120-1124[Web of Science][Medline].
-
Hebb MO,
Robertson HA
(1997)
End-capped antisense oligodeoxynucleotides effectively inhibit gene expression in vivo and offer a low-toxicity alternative to fully modified phosphorothioate oligodeoxynucleotides.
Brain Res Mol Brain Res
47:223-228[Medline].
-
Hooper ML,
Chiasson BJ,
Robertson HA
(1994)
Infusion into the brain of an antisense oligonucleotide to the immediate-early gene c-fos suppresses production of fos and produces a behavioral effect.
Neuroscience
63:917-924[Web of Science][Medline].
-
Konradi C,
Cole RL,
Heckers S,
Hyman SE
(1994)
Amphetamine regulates gene expression in rat striatum via transcription factor CREB.
J Neurosci
14:5623-5634[Abstract].
-
Lanahan A,
Worley P
(1998)
Immediate-early genes and synaptic function.
Neurobiol Learn Mem
70:37-43[Web of Science][Medline].
-
Lau LF,
Nathans D
(1987)
Expression of a set of growth-related immediate early genes in BALB/c3T3 cells: coordinate regulation with c-fos or c-myc.
Proc Natl Acad Sci USA
84:1182-1186[Abstract/Free Full Text].
-
Link W,
Konietzko U,
Kauselmann G,
Krug M,
Schwanke B,
Frey U,
Kuhl D
(1995)
Somatodendritic expression of an immediate early gene is regulated by synaptic activity.
Proc Natl Acad Sci USA
92:5734-5738[Abstract/Free Full Text].
-
Linzer DIH,
Nathans D
(1983)
Growth-related changes in specific mRNAs of cultured mouse cells.
Proc Natl Acad Sci USA
80:4271-4275[Abstract/Free Full Text].
-
Lyford GL,
Yamagata K,
Kaufmann WE,
Barnes CA,
Sanders LK,
Copeland NG,
Gilbert DJ,
Jenkins NA,
Lanahan AA,
Worley PF
(1995)
Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites.
Neuron
14:433-445[Web of Science][Medline].
-
Lyford GL,
Stevenson GD,
Barnes CA,
Worley PF
(1996)
Injection of Arc antisense oligonucleotides selectively blocks hippocampal LTP maintenance in vivo.
Soc Neurosci Abstr
22:734.3.
-
Mayford M,
Bach ME,
Huang Y-Y,
Wang L,
Hawkins RD,
Kandel ER
(1996)
Control of memory formation through regulated expression of a CaMKII transgene.
Science
274:1678-1683[Abstract/Free Full Text].
-
Morris RGM,
Garrud P,
Rawlins JNP,
O'Keefe J
(1982)
Place navigation impaired in rats with hippocampal lesions.
Nature
297:681-683[Medline].
-
Moser E,
Mathiesen I,
Andersen P
(1993)
Association between brain temperature and dentate field potentials in exploring and swimming rats.
Science
259:1324-1326[Abstract/Free Full Text].
-
O'Brien RJ,
Xu D,
Petralia RS,
Steward O,
Huganir RL,
Worley P
(1999)
Synaptic clustering of AMPA receptors by the extracellular immediate-early gene product Narp.
Neuron
23:309-323[Web of Science][Medline].
-
Ogawa S,
Pfaff DW
(1996)
Application of antisense DNA method for the study of molecular bases of brain function and behavior.
Behav Genet
26:279-292[Medline].
-
Ogawa S,
Brown HE,
Okano HJ,
Pfaff DW
(1995)
Cellular uptake of intracerebrally administered oligodeoxynucleotides in mouse brain.
Regul Pept
59:143-149[Web of Science][Medline].
-
Saffen DW,
Cole AJ,
Worley PF,
Christy BA,
Ryder K,
Baraban JM
(1988)
Convulsant-induced increase in transcription factor messenger RNAs in rat brain.
Proc Natl Acad Sci USA
85:7795-7799[Abstract/Free Full Text].
-
Schlimgen AK,
Helms JA,
Vogel H,
Perin MS
(1995)
Neuronal pentraxin, a secreted protein with homology to acute phase proteins of the immune system.
Neuron
14:519-526[Web of Science][Medline].
-
Steward O,
Wallace CS,
Lyford GL,
Worley PF
(1998)
Synaptic activation causes the mRNA for the IEG Arc to localize selectively near activated postsynaptic sites on dendrites.
Neuron
21:741-751[Web of Science][Medline].
-
Szklarczyk A,
Kaczmarek L
(1995)
Antisense oligodeoxyribonucleotides: stability and distribution after intracerebral injection into rat brain.
J Neurosci Methods
60:181-187[Web of Science][Medline].
-
Tsien JZ,
Chen DF,
Gerber D,
Tom C,
Mercer EH,
Anderson DJ,
Mayford M,
Kandel ER,
Tonegawa S
(1996)
Subregion- and cell type-restricted gene knockout in mouse brain.
Cell
87:1317-1326[Web of Science][Medline].
-
Tsui C,
Copeland NG,
Gilbert DJ,
Jenkins NA,
Barnes CA,
Worley PF
(1996)
Narp, a novel member of the pentraxin family, promotes neurite outgrowth and is dynamically regulated by neuronal activity.
J Neurosci
16:2463-2478[Abstract/Free Full Text].
-
Wahlestedt C
(1994)
Antisense oligonucleotide strategies in neuropharmacology.
Trends Pharmacol Sci
15:42-46[Medline].
-
Wahlestedt C,
Pich EM,
Koob GF,
Yee F,
Heilig M
(1993)
Modulation of anxiety and neuropeptide Y-Y1 receptors by antisense oligodeoxynucleotides.
Science
259:528-531[Abstract/Free Full Text].
-
Wallace C,
Lyford G,
Worley P,
Steward O
(1998)
Differential intracellular sorting of immediate early gene mRNAs depends on signals in the mRNA sequence.
J Neurosci
18:26-35[Abstract/Free Full Text].
-
Widnell KL,
Self DW,
Lane SB,
Russell DS,
Vaidya VA,
Miserendino MJD,
Rubin CS,
Duman RS,
Nestler EJ
(1996)
Regulation of CREB expression: in vivo evidence for a functional role in morphine action in the nucleus accumbens.
J Pharmacol Exp Ther
276:306-315[Abstract/Free Full Text].
-
Worley PF,
Bhat RV,
Baraban JM,
Erickson CA,
McNaughton BL,
Barnes CA
(1993)
Thresholds for synaptic activation of transcription factors in hippocampus: correlation with long-term enhancement.
J Neurosci
13:4776-4786[Abstract].
Copyright © 2000 Society for Neuroscience 0270-6474/00/20113993-09$05.00/0
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|
|
|
S. Rosi, M. Andres-Mach, K. M. Fishman, W. Levy, R. A. Ferguson, and J. R. Fike
Cranial Irradiation Alters the Behaviorally Induced Immediate-Early Gene Arc (Activity-Regulated Cytoskeleton-Associated Protein)
Cancer Res.,
December 1, 2008;
68(23):
9763 - 9770.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. E. Ploski, V. J. Pierre, J. Smucny, K. Park, M. S. Monsey, K. A. Overeem, and G. E. Schafe
The Activity-Regulated Cytoskeletal-Associated Protein (Arc/Arg3.1) Is Required for Memory Consolidation of Pavlovian Fear Conditioning in the Lateral Amygdala
J. Neurosci.,
November 19, 2008;
28(47):
12383 - 12395.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. R. Bramham, P. F. Worley, M. J. Moore, and J. F. Guzowski
The Immediate Early Gene Arc/Arg3.1: Regulation, Mechanisms, and Function
J. Neurosci.,
November 12, 2008;
28(46):
11760 - 11767.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. E. Canal, Q. Chang, and P. E. Gold
Intra-amygdala injections of CREB antisense impair inhibitory avoidance memory: Role of norepinephrine and acetylcholine
Learn. Mem.,
August 26, 2008;
15(9):
677 - 686.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Yang, M. Krause, G. Rao, B. L. McNaughton, and C. A. Barnes
Synaptic Commitment: Developmentally Regulated Reciprocal Changes in Hippocampal Granule Cell NMDA and AMPA Receptors Over the Lifespan
J Neurophysiol,
June 1, 2008;
99(6):
2760 - 2768.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. C. Pandey, H. Zhang, R. Ugale, A. Prakash, T. Xu, and K. Misra
Effector Immediate-Early Gene Arc in the Amygdala Plays a Critical Role in Alcoholism
J. Neurosci.,
March 5, 2008;
28(10):
2589 - 2600.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. F. Marrone, M. J. Schaner, B. L. McNaughton, P. F. Worley, and C. A. Barnes
Immediate-Early Gene Expression at Rest Recapitulates Recent Experience
J. Neurosci.,
January 30, 2008;
28(5):
1030 - 1033.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. P. Kelly, Y.-F. Cheung, C. Favilla, S. J. Siegel, S. J. Kanes, M. D. Houslay, and T. Abel
Constitutive activation of the G-protein subunit G{alpha}s within forebrain neurons causes PKA-dependent alterations in fear conditioning and cortical Arc mRNA expression
Learn. Mem.,
January 28, 2008;
15(2):
75 - 83.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. A. C. Bloomer, H. M. A. VanDongen, and A. M. J. VanDongen
Arc/Arg3.1 Translation Is Controlled by Convergent N-Methyl-D-aspartate and Gs-coupled Receptor Signaling Pathways
J. Biol. Chem.,
January 4, 2008;
283(1):
582 - 592.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Granado, O. Ortiz, L. M. Suarez, E. D. Martin, V. Cena, J. M. Solis, and R. Moratalla
D1 but not D5 Dopamine Receptors Are Critical for LTP, Spatial Learning, and LTP-Induced arc and zif268 Expression in the Hippocampus
Cereb Cortex,
January 1, 2008;
18(1):
1 - 12.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kubik, T. Miyashita, and J. F. Guzowski
Using immediate-early genes to map hippocampal subregional functions
Learn. Mem.,
November 15, 2007;
14(11):
758 - 770.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Antunes-Martins, K. Mizuno, E. E. Irvine, E. M. Lepicard, and K. P. Giese
Sex-dependent up-regulation of two splicing factors, Psf and Srp20, during hippocampal memory formation
Learn. Mem.,
October 1, 2007;
14(10):
693 - 702.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Messaoudi, T. Kanhema, J. Soule, A. Tiron, G. Dagyte, B. da Silva, and C. R. Bramham
Sustained Arc/Arg3.1 Synthesis Controls Long-Term Potentiation Consolidation through Regulation of Local Actin Polymerization in the Dentate Gyrus In Vivo
J. Neurosci.,
September 26, 2007;
27(39):
10445 - 10455.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Huang, J. K. Chotiner, and O. Steward
Actin Polymerization and ERK Phosphorylation Are Required for Arc/Arg3.1 mRNA Targeting to Activated Synaptic Sites on Dendrites
J. Neurosci.,
August 22, 2007;
27(34):
9054 - 9067.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Knobloch, M. Farinelli, U. Konietzko, R. M. Nitsch, and I. M. Mansuy
A{beta} Oligomer-Mediated Long-Term Potentiation Impairment Involves Protein Phosphatase 1-Dependent Mechanisms
J. Neurosci.,
July 18, 2007;
27(29):
7648 - 7653.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. H. Milekic, G. Pollonini, and C. M. Alberini
Temporal requirement of C/EBP{beta} in the amygdala following reactivation but not acquisition of inhibitory avoidance
Learn. Mem.,
July 18, 2007;
14(7):
504 - 511.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Steward, F. Huang, and J. F. Guzowski
A form of perforant path LTP can occur without ERK1/2 phosphorylation or immediate early gene induction
Learn. Mem.,
June 1, 2007;
14(6):
433 - 445.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. A. Countryman and P. E. Gold
Rapid forgetting of social transmission of food preferences in aged rats: Relationship to hippocampal CREB activation
Learn. Mem.,
May 3, 2007;
14(5):
350 - 358.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. B. Rowe, E. M. Blalock, K.-C. Chen, I. Kadish, D. Wang, J. E. Barrett, O. Thibault, N. M. Porter, G. M. Rose, and P. W. Landfield
Hippocampal Expression Analyses Reveal Selective Association of Immediate-Early, Neuroenergetic, and Myelinogenic Pathways with Cognitive Impairment in Aged Rats
J. Neurosci.,
March 21, 2007;
27(12):
3098 - 3110.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Chin, C. M. Massaro, J. J. Palop, M. T. Thwin, G.-Q. Yu, N. Bien-Ly, A. Bender, and L. Mucke
Reelin Depletion in the Entorhinal Cortex of Human Amyloid Precursor Protein Transgenic Mice and Humans with Alzheimer's Disease
J. Neurosci.,
March 14, 2007;
27(11):
2727 - 2733.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. G. Parsons, G. M. Gafford, and F. J. Helmstetter
Translational Control via the Mammalian Target of Rapamycin Pathway Is Critical for the Formation and Stability of Long-Term Fear Memory in Amygdala Neurons
J. Neurosci.,
December 13, 2006;
26(50):
12977 - 12983.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Ramirez-Amaya, D. F. Marrone, F. H. Gage, P. F. Worley, and C. A. Barnes
Integration of New Neurons into Functional Neural Networks.
J. Neurosci.,
November 22, 2006;
26(47):
12237 - 12241.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. S. Park, R. Gong, J. Stuart, and S.-J. Tang
Molecular Network and Chromosomal Clustering of Genes Involved in Synaptic Plasticity in the Hippocampus
J. Biol. Chem.,
October 6, 2006;
281(40):
30195 - 30211.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. O'Mahony, J. Raber, M. Montano, E. Foehr, V. Han, S.-m. Lu, H. Kwon, A. LeFevour, S. Chakraborty-Sett, and W. C. Greene
NF-{kappa}B/Rel Regulates Inhibitory and Excitatory Neuronal Function and Synaptic Plasticity.
Mol. Cell. Biol.,
October 1, 2006;
26(19):
7283 - 7298.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. S. Montana and J. T. Littleton
Expression Profiling of a Hypercontraction-induced Myopathy in Drosophila Suggests a Compensatory Cytoskeletal Remodeling Response
J. Biol. Chem.,
March 24, 2006;
281(12):
8100 - 8109.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. R. Fletcher, M. E. Calhoun, P. R. Rapp, and M. L. Shapiro
Fornix Lesions Decouple the Induction of Hippocampal Arc Transcription from Behavior But Not Plasticity
J. Neurosci.,
February 1, 2006;
26(5):
1507 - 1515.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. F. Guzowski, T. Miyashita, M. K. Chawla, J. Sanderson, L. I. Maes, F. P. Houston, P. Lipa, B. L. McNaughton, P. F. Worley, and C. A. Barnes
Recent behavioral history modifies coupling between cell activity and Arc gene transcription in hippocampal CA1 neurons
PNAS,
January 24, 2006;
103(4):
1077 - 1082.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Mokin, J. S. Lindahl, and J. Keifer
Immediate-Early Gene-Encoded Protein Arc Is Associated With Synaptic Delivery of GluR4-containing AMPA Receptors During In Vitro Classical Conditioning
J Neurophysiol,
January 1, 2006;
95(1):
215 - 224.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Li, J. Carter, X. Gao, J. Whitehead, and W. G. Tourtellotte
The Neuroplasticity-Associated Arc Gene Is a Direct Transcriptional Target of Early Growth Response (Egr) Transcription Factors
Mol. Cell. Biol.,
December 1, 2005;
25(23):
10286 - 10300.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J. Palop, J. Chin, N. Bien-Ly, C. Massaro, B. Z. Yeung, G.-Q. Yu, and L. Mucke
Vulnerability of Dentate Granule Cells to Disruption of Arc Expression in Human Amyloid Precursor Protein Transgenic Mice
J. Neurosci.,
October 19, 2005;
25(42):
9686 - 9693.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Chin, J. J. Palop, J. Puolivali, C. Massaro, N. Bien-Ly, H. Gerstein, K. Scearce-Levie, E. Masliah, and L. Mucke
Fyn Kinase Induces Synaptic and Cognitive Impairments in a Transgenic Mouse Model of Alzheimer's Disease
J. Neurosci.,
October 19, 2005;
25(42):
9694 - 9703.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. Gusev, C. Cui, D. L. Alkon, and A. N. Gubin
Topography of Arc/Arg3.1 mRNA Expression in the Dorsal and Ventral Hippocampus Induced by Recent and Remote Spatial Memory Recall: Dissociation of CA3 and CA1 Activation
J. Neurosci.,
October 12, 2005;
25(41):
9384 - 9397.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. K. McIntyre, T. Miyashita, B. Setlow, K. D. Marjon, O. Steward, J. F. Guzowski, and J. L. McGaugh
Memory-influencing intra-basolateral amygdala drug infusions modulate expression of Arc protein in the hippocampus
PNAS,
July 26, 2005;
102(30):
10718 - 10723.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W.-P. Zhang, J. F. Guzowski, and S. A. Thomas
Mapping neuronal activation and the influence of adrenergic signaling during contextual memory retrieval
Learn. Mem.,
May 1, 2005;
12(3):
239 - 247.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Mokin and J. Keifer
Expression of the immediate-early gene-encoded protein Egr-1 (zif268) during in vitro classical conditioning
Learn. Mem.,
March 1, 2005;
12(2):
144 - 149.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Ramirez-Amaya, A. Vazdarjanova, D. Mikhael, S. Rosi, P. F. Worley, and C. A. Barnes
Spatial Exploration-Induced Arc mRNA and Protein Expression: Evidence for Selective, Network-Specific Reactivation
J. Neurosci.,
February 16, 2005;
25(7):
1761 - 1768.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Rosi, V. Ramirez-Amaya, A. Vazdarjanova, P. F. Worley, C. A. Barnes, and G. L. Wenk
Neuroinflammation Alters the Hippocampal Pattern of Behaviorally Induced Arc Expression
J. Neurosci.,
January 19, 2005;
25(3):
723 - 731.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. N. Lacor, M. C. Buniel, L. Chang, S. J. Fernandez, Y. Gong, K. L. Viola, M. P. Lambert, P. T. Velasco, E. H. Bigio, C. E. Finch, et al.
Synaptic Targeting by Alzheimer's-Related Amyloid {beta} Oligomers
J. Neurosci.,
November 10, 2004;
24(45):
10191 - 10200.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. L. Barth, R. C. Gerkin, and K. L. Dean
Alteration of Neuronal Firing Properties after In Vivo Experience in a FosGFP Transgenic Mouse
J. Neurosci.,
July 21, 2004;
24(29):
6466 - 6475.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Vazdarjanova and J. F. Guzowski
Differences in Hippocampal Neuronal Population Responses to Modifications of an Environmental Context: Evidence for Distinct, Yet Complementary, Functions of CA3 and CA1 Ensembles
J. Neurosci.,
July 21, 2004;
24(29):
6489 - 6496.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Cirelli and G. Tononi
Locus Ceruleus Control of State-Dependent Gene Expression
J. Neurosci.,
June 9, 2004;
24(23):
5410 - 5419.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. C. Lee, B. J. Everitt, and K. L. Thomas
Independent Cellular Processes for Hippocampal Memory Consolidation and Reconsolidation
Science,
May 7, 2004;
304(5672):
839 - 843.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Small, M. K. Chawla, M. Buonocore, P. R. Rapp, and C. A. Barnes
From The Cover: Imaging correlates of brain function in monkeys and rats isolates a hippocampal subregion differentially vulnerable to aging
PNAS,
May 4, 2004;
101(18):
7181 - 7186.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. O'Connor, A. Genin, S. Davis, K. K. Karishma, V. Doyere, C. I. De Zeeuw, G. Sanger, S. P. Hunt, G. Richter-Levin, J. Mallet, et al.
Differential Amplification of Intron-containing Transcripts Reveals Long Term Potentiation-associated Up-regulation of Specific Pde10A Phosphodiesterase Splice Variants
J. Biol. Chem.,
April 16, 2004;
279(16):
15841 - 15849.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Alder, S. Thakker-Varia, D. A. Bangasser, M. Kuroiwa, M. R. Plummer, T. J. Shors, and I. B. Black
Brain-Derived Neurotrophic Factor-Induced Gene Expression Reveals Novel Actions of VGF in Hippocampal Synaptic Plasticity
J. Neurosci.,
November 26, 2003;
23(34):
10800 - 10808.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. M. Smart, G. M. Edelman, and P. W. Vanderklish
BDNF induces translocation of initiation factor 4E to mRNA granules: Evidence for a role of synaptic microfilaments and integrins
PNAS,
November 25, 2003;
100(24):
14403 - 14408.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. P. Kelly and S. A. Deadwyler
Experience-Dependent Regulation of the Immediate-Early Gene Arc Differs across Brain Regions
J. Neurosci.,
July 23, 2003;
23(16):
6443 - 6451.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Hoeffer, S. Sanyal, and M. Ramaswami
Acute Induction of Conserved Synaptic Signaling Pathways in Drosophila Melanogaster
J. Neurosci.,
July 16, 2003;
23(15):
6362 - 6372.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Dickey, J. F. Loring, J. Montgomery, M. N. Gordon, P. S. Eastman, and D. Morgan
Selectively Reduced Expression of Synaptic Plasticity-Related Genes in Amyloid Precursor Protein + Presenilin-1 Transgenic Mice
J. Neurosci.,
June 15, 2003;
23(12):
5219 - 5226.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Blalock, K.-C. Chen, K. Sharrow, J. P. Herman, N. M. Porter, T. C. Foster, and P. W. Landfield
Gene Microarrays in Hippocampal Aging: Statistical Profiling Identifies Novel Processes Correlated with Cognitive Impairment
J. Neurosci.,
May 1, 2003;
23(9):
3807 - 3819.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Montag-Sallaz and D. Montag
Learning-Induced arg 3.1/arc mRNA Expression in the Mouse Brain
Learn. Mem.,
March 1, 2003;
10(2):
99 - 107.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Crow and J. J. Xue-Bian
One-Trial In Vitro Conditioning Regulates a Cytoskeletal-Related Protein (CSP24) in the Conditioned Stimulus Pathway of Hermissenda
J. Neurosci.,
December 15, 2002;
22(24):
10514 - 10518.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Vazdarjanova, B. L. McNaughton, C. A. Barnes, P. F. Worley, and J. F. Guzowski
Experience-Dependent Coincident Expression of the Effector Immediate-Early Genes Arc and Homer 1a in Hippocampal and Neocortical Neuronal Networks
J. Neurosci.,
December 1, 2002;
22(23):
10067 - 10071.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. J. Tyler, M. Alonso, C. R. Bramham, and L. D. Pozzo-Miller
From Acquisition to Consolidation: On the Role of Brain-Derived Neurotrophic Factor Signaling in Hippocampal-Dependent Learning
Learn. Mem.,
September 1, 2002;
9(5):
224 - 237.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Messaoudi, S.-W. Ying, T. Kanhema, S. D. Croll, and C. R. Bramham
Brain-Derived Neurotrophic Factor Triggers Transcription-Dependent, Late Phase Long-Term Potentiation In Vivo
J. Neurosci.,
September 1, 2002;
22(17):
7453 - 7461.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Igaz, M. R. M. Vianna, J. H. Medina, and I. Izquierdo
Two Time Periods of Hippocampal mRNA Synthesis Are Required for Memory Consolidation of Fear-Motivated Learning
J. Neurosci.,
August 1, 2002;
22(15):
6781 - 6789.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Rosenblum, M. Futter, K. Voss, M. Erent, P. A. Skehel, P. French, L. Obosi, M. W. Jones, and T. V. P. Bliss
The Role of Extracellular Regulated Kinases I/II in Late-Phase Long-Term Potentiation
J. Neurosci.,
July 1, 2002;
22(13):
5432 - 5441.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-W. Ying, M. Futter, K. Rosenblum, M. J. Webber, S. P. Hunt, T. V. P. Bliss, and C. R. Bramham
Brain-Derived Neurotrophic Factor Induces Long-Term Potentiation in Intact Adult Hippocampus: Requirement for ERK Activation Coupled to CREB and Upregulation of Arc Synthesis
J. Neurosci.,
March 1, 2002;
22(5):
1532 - 1540.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. W. Vanderklish and G. M. Edelman
Dendritic spines elongate after stimulation of group 1 metabotropic glutamate receptors in cultured hippocampal neurons
PNAS,
January 24, 2002;
(2002)
32681099.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. F. Guzowski, B. Setlow, E. K. Wagner, and J. L. McGaugh
Experience-Dependent Gene Expression in the Rat Hippocampus after Spatial Learning: A Comparison of the Immediate-Early Genes Arc, c-fos, and zif268
J. Neurosci.,
July 15, 2001;
21(14):
5089 - 5098.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Cirelli and G. Tononi
Differential Expression of Plasticity-Related Genes in Waking and Sleep and Their Regulation by the Noradrenergic System
J. Neurosci.,
December 15, 2000;
20(24):
9187 - 9194.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. W. Vanderklish and G. M. Edelman
Dendritic spines elongate after stimulation of group 1 metabotropic glutamate receptors in cultured hippocampal neurons
PNAS,
February 5, 2002;
99(3):
1639 - 1644.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Yin, G. M. Edelman, and P. W. Vanderklish
The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes
PNAS,
February 19, 2002;
99(4):
2368 - 2373.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
Memory
