Brain Research, 325 (1985) 71-78

Elsevier

71

BRE 10457

Long-Term Potentiation in the Dentate Gyrus: Effects of Noradrenaline

Depletion in the Awake Rat
G. B. ROBINSON and R J. RACINE
Department of Psychology, McMaster Umversity, Hamdton, Ontarto L8S 4K1 (Canada)
(Accepted April 17th, 1984)
Key words long-term potentiation - - noradrenallne - - memory - - h~ppocampus- - dentate gyrus - - reserpine

The chronic rat preparation was uuhzed to study the effects of noradrenaline (NA) depletion on field potentials recorded from the
hilus of the fascia dentata. Both single pulses and high-frequency trams were applied to the perforant path (PP). The effects of NA depletion on baseline responses as well as on long-term potentiauon (LTP) were examined. Reduced NA levels resulted in an increase in
the population spike amplitude and a depression of the population excitatory postsynaptic potential (EPSP). Depleted animals
showed significantly higher levels of LTP of the population EPSP, but reduced levels of population spike LTP (measured 13-15 min
after tetamzaUon). There were, however, no differences m LTP levels 1 week after the potentiation tests. These results demonstrate
that NA levels do not affect that component of LTP which can persist for several weeks.

INTRODUCTION
It has been suggested that noradrenaline (NA)
serves as a neuromodulator of cortical plasticity3, 7,16.
Crow 7, for example, suggested that the locus coeruleus, a major source of ascending N A fibres 1,32,36,
was involved in learning and memory. In his view, locus coeruleus activation served to strenghten connections between those neural elements involved in the
learning process. Although there is no direct proof of
this hypothesis, manipulations of N A levels are
known to
affect performance
on
learning
tasks21,23,24,26. The performance on many of these
tasks is thought to depend upon the function of the
hippocampus 22.
More recently, the long-term potentiation (LTP)
phenomenon has provided a possible neural model of
learning and m e m o r y 11. LTP is a long-lasting increase in synaptic response amplitude as a result of
prior activation. LTP is readily observed at hippocampal synapses, particularly those on the dendrites
of granule cells (GCs) in the dentate gyrus 4,6,9. Application of stimulation trains to perforant path (PP) fibres, arising from cells in the entorhinal cortex14,33,

induces an increase in the strength of the P P - G C response. This increase, evident in the amplitude increment of both the population excitatory postsynaptic
potential (EPSP) and population spike (a measure of
cell discharge2), can persist for several weeks9, 27.
The dentate gyrus also receives N A fibres from the
locus coeruleus17,19, 31. If LTP underlies learning and
memory processes, the presence of N A terminals
provides a model system for the investigation of
Crow's 7 hypothesis. A reduction of N A levels should,
theoretically, result in reduced levels of LTP. Bliss et
al.5 attempted to test this in the acute rat preparation 5,12. Hippocampal N A levels were reduced by 6hydroxydopamine or reserpine pretreatment. Subsequent LTP of the EPSP was found to be significantly
depressed when compared to non-depleted control
animals. LTP of the population spike, however, was
not significantly &fferent between depleted and nondepleted animals.
There are a number of possible explanations for
this differential effect of N A depletion on LTP of the
population spike and EPSP. First, LTP usually results in a much larger increase in the population spike
than can be accounted for by increases in the

Correspondence" R. J Racine, Department of Psychology, McMaster University, Hamilton, Ontario L8S 4K1, Canada
0006-8993/85/$03.30 1985 Elsevier Science Publishers B V

72
EPSP 9.34,35. This suggests the presence of different
underlying processes, which may be differentially affected by manipulation of NA levels. This is the explanation favored by Bliss et al. 5 and Goddard 12. A
second possibility is that NA depletion results in disinhibition of the granule cells 3,12. Previous investigators have demonstrated a tonic inhibitory role for
hippocampal NA 18.25,28-3. Reduction of NA levels
may result in tonic depolarization of the granule
cells. Depolarization would reduce the driving force
on those ionic movements responsible for the EPSP
while leaving the membrane potential closer to the
threshold for cell discharge. Increased synaptic input, as a result of the LTP treatment, would be more
likely to initiate cell discharge, while producing a
smaller apparent increase in EPSP amplitude. If this
is the case, then the effects reported by Bliss et al. 5
might reflect a masking, rather than a blocking, of
LTP.
Other effects of NA include a reduction of anomalous inward rectification TM, a decrease in calcium-activated potassium conductance 13, and a reduction of
inhibitory postsynaptic potentials by presynaptlc action i5.
We have used a chronic preparation to further investigate the role of NA in LTP. The chronic preparation, for drug-LTP studies, has 3 main advantages
over the acute preparation: (1) input-output (I-O)
curves can be determined, within animals, in both the
depleted and non-depleted state; (2) each animal can
serve as its own control for comparison of LTP levels
under the two conditions; and (3) the decay of LTP
can be followed over the course of several weeks
Thus. one can examine the effects of NA depletion
on that component of LTP which can persist for several days or weeks 9,27.
MATERIALS AND METHODS

Surgery
Ten male L o n g - E v a n s Hooded rats (385-520 g)
were anesthetized with 0.60 ml (i.p.) of sodium pentobarbitol (65 mg/ml). With the skull flat, electrodes
were implanted in the PP and the hilus of the dentate
gyrus. The coordinates, relative to bregma, were 3.8
mm posterior and 2.3 mm lateral for the recording
electrode and 7.9 mm posterior and 4.6 mm lateral
for the stimulating electrode. In addition, there were

4 anchoring screws, two of which also served as

ground electrodes. All electrodes were implanted
under electrophysiological control in order to maximize the PP-GC response amplitude The electrodes
were mounted m a 9-pin connector and held in place
by dental acrylic. Following surgery, rats were injected with Derapen-C (penicilhn-G, 0.15 cc, Lm )
There was a 2-3 week recovery period before testing.

Stimulation
PP-GC field responses were amplified by a Grass
7P5B preamplifer (cut-off frequencies, 1 Hz and 3
kHz). Stimulation consisted of both single test pulses
and high-frequency trains delivered by a Grass $88
stimulator. A photoelectric stimulus isolation unit
(Grass SIU6B) was used to deliver constant current
pulses. Data was collected on line by an L S t - l l computer.
All animals served as their own controls and were
tested both with and without reserpine pretreatment.
Reserpine rejections were separated by 20-21 h. The
first injection (5 mg/kg) immediately followed the
first I-O series. The second injection (2.5 mg/kg) was
given 2-3 h before the start of the second I-O series.
These dosages were previously shown to reduce NA
levels to 92.5% of control values 5. Three weeks
elapsed between tests in the same animal and the order of testing was counterbalanced.
Three I-O series were determined for each ammal
during both drugged and non-drugged conditions: (1)
24 h prior to the start of the potentiation tests; (2) immediately prior to the start of the potentiation tests;
and (3) 30 min after the last PP trains. Pulse width
was adjusted to consistently evoke a small spike at a
pulse intensity of 300 #A. Ten responses were then
collected at each of 8 intensities (100, 200, 300, 400,
500, 700, 1000 and 1200/xA). Stimulation rate was
0.05 Hz.
During the potentiation trials, two trains (20 pulses
at 400 Hz) were given at each intensity of an ascending intensity series. The inter-tram interval for each
train pair was 5 s and the tram pairs were applied
once every 15 min. Train intensity was varied by mcreasing the pulse amplitude. The intensities were
150,200, 250,300, 400, 600, 900 and 1200 pA. Pulse
width was held constant as determined prior to the IO tests Test responses were sampled at 0.05 Hz for

73

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Fig 1. Effect of NA depletion on PP-GC population responses at 8 different PP pulse mtenslues. A and B. over a 24 h period there was
httle change m the amphtude of either the PP-GC populanon EPSP (A) or spike (B) m non-depleted animals. C and D. when tested 24
h after reserpine treatment there was a significant decrease m the PP-GC population EPSP (C) and a significant increase in the populauon spNe amphtude (D). The standard error of the means are also illustrated
15 man before and after each train pair. A 30 min test
period followed the last train pair. The decay of LTP
was followed for a 2 w e e k period, by sampling and
averaging 20 test responses each day for 4 days and
again at 7 days and 14 days

Data analysis
Spike amplitude was measured as the amplitude of
a hne drawn from spike peak to a tangent line connecting the onset and offset of the spike. EPSP amplitude was calculated as the slope between two constant latency points on the rising phase of the EPSP.
For the plotting of I-O curves, the largest mean pretrain values for both the EPSP and,spike measures,

determined from the imtial I-O series, were assigned

a value of 1. All other mean values were then converted to s o m e fraction or multiple of 1.
Potentiation was measured as the percent change
of each response from the mean pre-train baseline.
T w o pre-train baseline responses were determined.
One served as baseline for the long-term decay
curves and was the average of 60 responses (20/day)
collected over the 3 days prior to the potentiation
tests. The other served as baseline during the train
run and was the average of 45 responses (0.05 Hz)
obtained before the first train was applied. All analyses were performed by the computer. Final response
measures were compared using a two-way analysis of

74
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Fig. 2

variance for repeated measures.

RESULTS

Effects of NA depletion on PP-GC field responses

Fig. 1 illustrates the effects of NA depletion on PPGC field responses. In the control condition there
was a tendency for both the population EPSP
(Fig. 1A) and spike (Fig. 1B) to show a small increase over the 24 h period. In comparison, following
NA depletion, there was a significant decrease (P <
0.001) in the population EPSP (Fig. 1C). This was
accompanied by a significant increase (P < 0.001) in
the amplitude of the population spike (Fig. 1D)
Reserpine treatment did not reduce the threshold
stimulation for eliciting a population spike. If, however, the threshold for cell discharge was calculated

m terms of EPSP amplitude, it was found that population spikes in NA-depleted animals were evoked
by EPSPs that were only 38% of the amplitude required in the non-depleted state. At the upper end of
the I-O curve, EPSPs that were only half as large as
the pre-depletion maximum were accompanied by
population spikes that were 2 - 3 times larger than
pre-depletion amplitudes.

Effects of NA depletton on L TP
The effect of N A depletion on LTP depended upon
the component measured (population EPSP vs population spike), and the baseline from which it was
measured (predrugged vs drugged). The effect also
depended upon whether the measures were corrected for drug effects.
Fig. 2A illustrates the mean percent change in the

75
though the LTP of the population EPSP was larger in
the drugged state, the potentiated response was still
below the non-drugged pre-train baseline amplitude.
The reverse was true for the population spike; LTP
was smaller in the drugged state, but the potentiated
responses were still considerably larger than the potentiated non-drugged responses.

population EPSP measured during the drugged state

and against the drugged baseline. LTP of the PP-GC
population EPSP was significantly (P < 0.01) greater
in depleted animals than in non-depleted animals.
Thirteen to 15 min after applying the final PP train,
the mean percent increase was 53% in depleted animals compared to 18% in non-depleted animals.
Fig. 2B shows the effect of the potentiating trains
on the population spike amplitude. In this case, the
depleted animals showed significantly less (P < 0.05)
potentiation than non-depleted animals.
The increased LTP of the EPSP and the decreased
LTP of the population spike was confirmed by a comparison of pre-train and post-train I-O curves
(Figs. 2C, D). It is also clear from Fig. 2C that, al-

Effects of anesthetic
Our EPSP results were in the opposite direction of
those reported by the Bliss et al. s study. Bliss et al.
reported reduced LTP in depleted anesthetized animals while we found increased LTP in depleted unanesthetized animals. To allow a more direct comparison of our EPSP potentiation effects with those re-

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field responses were subtracted from the combined effects of reserpine and PP trains. C: population EPSP D" population sp~ke

76
ported by Bhss et al , 3 ad&tlonal chromc ammals
were tested under the influence of pentobarbltal anesthesm.
Anesthetized reserpine-pretreated ammals showed similar levels of LTP of the EPSP as seen m unanesthetized animals. Anesthetized animals, for example, showed a mean percent increase in EPSP amplitude of 45% following the 1200/~A PP trains, compared to the 53% increase seen in the unanesthetlzed
group.

Decay of L TP
Catecholamine depletion had large effects on the
baseline amplitudes. Consequently, it was difficult to
interpret the effects on LTP. For this reason, we followed the course of LTP over days as the drug effects
were cleared from the system. Fig. 3 illustrates the
decay of the population EPSP (Fig. 3A) and spike
(Fig. 3B) over a 2 week period, The EPSP in non-depleted animals was potentiated by 23% 1 day after
the last trains and gradually returned to pre-train levels over the 2 week period. In contrast, the depleted
animals showed additional increases in response amplitude for several days and then began to decay.
Even though the depleted animals were showing additional amplitude increments, while the non-depleted animals were showing decay, the depleted responses remained below their pre-depletion amplitude (Fig. 3A).
Although the absolute amplitude of the potentiated population spike was initially larger in depleted, compared to non-depleted animals, the two
groups were approximately equal 1-2 weeks after
the trams (Fig. 3B). Spike decay was more rapid in
depleted than in non-depleted animals. This ~s reflected by decay time constants of 8.7 and 16 days for
depleted and for non-depleted animals, respectively.
These curves, however, are confounded by the
prolonged recovery from drug effects in the depleted
animals. Th~s additional component presumably accounts for the poor fit of a single exponential to the
depleted animals decay curve (Fig. 3B). To determine if NA depletion had an effect on the durahon of
LTP, it was necessary to subtract the effects of reserpine from the combined effects of reserpine and PP
train-reduced effects. Thus, in an additional 6 animals, recovery from reserpine-induced changes in
the PP-GC field response were monitored for a 2

week period. The resulting curves were then subtracted from those obtained w~th the combined treatment.
Fig. 3C, D illustrate the results ot this manipulation. The levels of LTP for both the population EPSP
(Fig. 3C) and spike (Fig. 3D) were similar for depleted and non-depleted animals after controlhng for
the effects of depleuon itself. Thus, for both components of the PP-GC field response, NA depletion had
a non-significant effect on that component of LTP
which can persist for several days to several weeks
DISCUSSION

Effect of NA depletion on PP-GC field potenttals

NA depletion resulted in a significant increase m
the amplitude of the PP-GC population spike and a
significant reduction in the EPSP amphtude. These
findings are consistent with the proposed dismhibition hypothesis~.12. Following NA depletion, the GC
population would remain in a somewhat depolarized
state, A given amount of synaptlc current would produce a smaller voltage displacement but would be
more likely to inmate cell &scharge
Evidence in support of this hypothesis has been obtained from experiments on CA1 pyramidal cells.
Locus coeruleus trains reduce the level of spontaneous activity recorded from the pyramidal cell populatlon and this stimulation reduced-inhibition is
eliminated by prior treatment with 6-hydroxydopamineZS-30. Apphcation of NA to hippocampal shces
also reduces spontaneous actwity and reduces the
amplitude of synaptically evoked potentials 18.25 Together, this evidence suggests that NA has a hyperpolarizing effect on pyramidal cells. It is likely that
NA has similar effects on the GCs of the dentate gyrus (see ref 5). It must be kept in mind, however,
that other effects of NA have been reported that are
more consistent with an excitatory action13,1-~20
Effect of NA depletton on L TP
The major finding of the present study was the lack
of effect of reduced NA levels on that component of
LTP which can last for several days or weeks. LTP of
both the population spike and EPSP, in both depleted and non-depleted animals, was remarkably
similar 1 week after the last PP train. When the effects of NA depletion Itself were controlled for. the

77
similarity between the two decay curves was even
more apparent. Thus, reducing central NA levels
does not affect the longer-lasting components of
LTP.
In agreement with the reports by Bliss et al. 5 and
Goddard 12, we found that NA depletion did not reduce or eliminate short-term potentiation. Also,
within the range of intensities tested, thresholds for
LTP m depleted and non-depleted animals were
identical. The major difference between the present
study and the previous reports concerned the effect
of NA depletion on that component of LTP measured during the depleted state. In the Bliss et al. 5
study, LTP of the EPSP was reduced by an average of
50% in depleted animals when compared to non-depleted animals whereas spike LTP levels were approximately equal. We found significantly greater
levels of LTP of the EPSP and significantly reduced
levels of LTP of the population spike in depleted animals. These effects may have been due to depletioninduced changes in PP-GC transmission, rather than
to alterations in LTP. This conclusion is supported by
the fact that no differences in LTP were found when
the measures were corrected for drug effects or when
the drug had cleared from the system. Dunwiddie et
al. 10 also found that NA depletion, by either reserpine or DSP4, had no effect on LTP measured in area
CA1 in a slice preparation.
The differences between our results and those of
Bliss et al.5 were apparently not due to an interaction
between the anesthetic and reserpine, as anesthetized and depleted chronics were no different from

awake, depleted chronics in response to PP trains. It

is possible that the effect reported by Bliss et al. 5 was
due to an unusually large LTP effect in their control
group rather than to a depressed LTP in their depleted group. A second control group, used in a subsequent experiment (reported in the same paper),
exhibited levels of LTP of the EPSP equivalent to
their NA depleted group.
These results indicate that it is important to control, in drug-LTP studies, for the effects of the drug
on synaptic transmission itself. DolphinS, for example, found that the glutamate receptor antagonist, ~,D-glutamylglycine, appeared to block LTP. When
the antagonist was cleared from the dentate gyrus,
however, the levels of LTP were similar to those exhibited by controls.
In conclusion, NA depletion does not appear to affect that component of LTP which can persist for
days or weeks. In agreement with others 10, NA depletion may also have no effect on the early components of LTP. If LTP is the neuronal substrate of
learning and memory, then these findings suggest
that NA levels should not affect long-term information storage for tasks requiring primarily hippocampal processing.

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ACKNOWLEDGEMENTS
This research was supported by an operating grant
to R.J.R. and a postgraduate scholarship to G.B.R.,
from the Natural Sciences and Engineering Research
Council of Canada.

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