Neuroscience Letters, 127 (I 991) 61-66
© 1991 Elsevier Scientific Publishers Ireland Ltd. 0304-3940/91/$ 03.50
A DONIS 0304394091002707
61
NSL 07787
2-Amino-3-phosphonopropionic acid, an inhibitor of glutamatestimulated phosphoinositide turnover, blocks induction of homosynaptic
long-term depression, but not potentiation, in rat hippocampus
Patric K. Stanton I, Sumantra Chattarji 2 and Terrence J. Sejnowski 2,3
1Departments of Neuroscience and Neurology, Albert Einstein College of Medicine, Bronx, N Y 10461 (U.S.A.), 2Computational Neurobiology
Laboratory, The Salk Institute, La Jolla, CA 92037 (U.S.A.) and 3Department of Biology, University of California at San Diego, La Jolla CA 92093
(U.S.A.)
(Received 14 December 1990; Accepted 20 February 1991)
Key words: Hippocampus; CAI; Long-term potentiation (LTP); Long-term depression (LTD); Metabotropic receptor; 2-Amino-3-phosphonopropionate (AP3); Hebbian synapse; Neuronal plasticity
Recently, we have reported an associative long-term depression (LTD) of synaptic strength in hippocampal field CAI that is produced when a
low-frequency test input is negatively correlated in time with a high-frequency conditioning input. We have also found that pairing of synaptic
activity with postsynaptic hyperpolarization is sufficient to induce LTD. We report here that 2-amino-3-phosphonopropionate (AP3), a selective
inhibitor of phosphoinositide (PI) turnover mediated by the metabotropic glutamate receptor, blocks the induction of associative LTD in hippocampal field CA1, but does not impair the induction of LTP. Our data suggest that metabotropic glutamate receptor activation is involved in the induction of LTD.
The hippocampus, a cortical structure involved in
learning and memory [21], is capable of exhibiting both
long-term potentiation (LTP) and depression (LTD) of
synaptic strength in response to certain patterns of afferent firing. LTP in the hippocampus is produced by brief,
high-frequency stimulation of excitatory afferents [4].
Associative LTP is elicited when low-frequency test inputs, which do not produce LTP when stimulated alone,
are activated simultaneously with high-frequency conditioning inputs to the same neurons [2,16]. Induction of
LTP requires the simultaneous depolarization of the
postsynaptic membrane and activation of glutamate
receptors of the N-methyl-D-aspartate (NMDA) subtype
[6,10,12,30]. Earliest reports of long-term depression
(LTD) of synaptic transmission in the hippocampus described a heterosynaptic LTD for inputs that are inactive
[19] or weakly active [17,18] during high-frequency stimulation of a separate converging input. Recently, we
described an associative form of LTD in field CA1 that
is produced when a low-frequency test input is negatively
correlated in time with a second, high-frequency conditioning input [5,27]. In these studies, LTD of synaptic
Correspondence: P.K. Stanton, Neural Systems Laboratory, Albert
Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY
10461, U.S.A.
strength was also produced by activating presynaptic
terminals while hyperpolarizing the postsynaptic neuron
with somatic current injection. Furthermore, we also
found that the NMDA receptor antagonist 2-amino-5phosphonovaleric acid (APS) failed to block LTD [27],
suggesting the involvement of a non-NMDA subtype of
glutamate receptor in the induction of LTD.
Recent studies have uncovered a second messengercoupled, or metabotropic, subtype of glutamate receptor
that stimulates phosphoinositide (PI) hydrolysis in the
hippocampus and neocortex [23,25]. The discovery of a
selective agonist for this receptor, trans-l-aminocyclopentane-1,3-dicarboxylic acid (ACPD), has allowed this
receptor to be distinguished pharmacologically from the
ionotropic excitatory amino acid receptors (AMPA,
NMDA, kainate) [22]. Dudek and Bear [7] have shown
that, in kitten visual cortex, excitatory amino acid-stimulated PI turnover correlates well with the critical period
for ocular dominance plasticity. These authors suggested that this mechanism might contribute to use-dependent depression of synaptic strength [3]. Furthermore, it has also been reported that 2-amino-3-phosphonopropionic acid (AP3) is a potent and selective inhibitor of metabotropic receptor-mediated PI turnover
[23,24], and mobilization of intracellular Ca 2+ [13]. In
view of these results, we investigated the possible invol-
62
vement of metabotropic receptors in LTD, by testing the
ability of AP3 to block associative LTD in hippocampal
field CA 1.
Hippocampal slices (400 pm thick) from adult male
Sprague-Dawley rats were prepared by standard methods [26] and incubated in a modified Haas-style interface
slice perfusion chamber [11]. Slices were maintained at
34-35°C, pH 7.4, in an artificial cerebrospinal fluid
(ACSF) medium bubbled with a 95% 02/5% CO2 mixture. ACSF composition was (raM): NaC1 126, KC1 5,
NaH2PO4 1.25, MgCI2 2, CaC12 2, NaHCO3 26, and glucose 10. Extracellular recording electrodes (1-5 Mr2)
were filled with 2 M NaCI, while intracellular electrodes
(70- 120 Mg2) were filled with 2 M potassium acetate.
Intracellular potentials were amplified through an Axoclamp IIA amplifier with an active bridge circuit in current clamp mode (Axon Instruments). Bipolar stimulating electrodes were made from 50 pm diameter tefloninsulated platinum-iridium wire [26]. D,L-AP3 and
D-AP5 (Cambridge Research Biochemicals) were dissolved directly in artificial cerebrospinal fluid immediately before bath application.
Extracellular evoked field potentials were recorded
a
TEST
COND
F
b
F
ASSOCIATIVE STIMULUS PARADIGMS
IN
TESTINPUT
I
I
I
Illll
Illll
Illll
I
CONO,TIONINOI.
TIIIII
PHASE
OUT OF PHASE
TESTINPUT
I
I
I
Illll
CONDITIONING IIIII
INPUT
IIIII
Illll
.., -d
C
3O
Z
TEST + C0ND
OUT OF PHASE
TEST C0ND
--
E0
rn
<
en
10
TEST + C0ND
OUT OF PHASE
0,
o
-10
~3 - 2 0
Z
<
-30
-40
-50
0
L
I
i
i
15
30
45
60
J
~
t
~
L
75 90 105 120 135 150 165
TIME (min)
d
2O
(i~)
10
(17) (:3)
L TD
,-q
o
<
m -10
(I7)
(13)
,-a
o
~ -20
~ -30
Z
<
m -40
(17)
POP SPIKE AMPL|TUDE
EPSP SLOPE
-50
-60
(~1)
OUT OF PHASE
APS
OUT OF PHASE
WASH IN
IN AP3
AP3
WASHOUT
Fig. I 2-Amino-3-phosphonopropionic acid (AP3) blocks induction
of associative LTD by out of phase stimulation of synapses on hippocampa l CA I pyralmdal neurons, a: schematic diagram of the recording
arrangement in the CAI pyramidal cell somatic and dendritic layers,
and stimulus sites activating two independent groups of Schaffer collateral/commissural afferents (COND and TEST). b: schematic diagram
of the stimulus paradigms used for extracellular experiments. Conditioning input stimuli were four trains of bursts, given at 10 s intervals,
each train containing 10 bursts. Each burst consisted of 5 stimuli at
100 Hz, with an interburst interval of 200 ms. Thus, each train lasted
2 s, with 50 pulses per train. When these inputs were IN PHASE, the
test single shocks were superimposed on the middle of each burst of
the conditioning input. During OUT OF PHASE stimulation, single
shocks were timed symmetrically between the bursts [4,21]. c: time
course of the average percent changes in peak initial slope of the field
EPSP (EPSP SLOPE, closed circles) and population spike amplitude
(POP SPIKE AMPLITUDE, open circles) of the TEST input evoked
potentials. Each point represents the mean + S.E.M. of 7 separate
experiments in which the same time course of stimulations were given.
First, the test and conditioning stimuli were given alone, causing no
long-term changes in TEST input responses, 25 ~M AP3 was then bath
applied, and out of phase stimulation of the TEST plus C O N D inputs
failed to elicit LTD. After washout of AP3, a second identical out of
phase stimulation now elicited associative LTD of the test input responses (*, P < 0.05, paired t-test), d: summary of all extracellular experiments showing that AP3 blocks associative LTD. In control medium,
out of phase stimulation elicited LTD of both population spikes (solid
bars) and EPSP slopes (hatched bars) recorded 30 min after stimulation (*, P < 0.05, paired t-test compared to prestimulated baselines). In
contrast, the same out of phase stimulation in the presence of 20 25
pM AP3 (out of phase in AP3) no longer produced LTD. Note that
there were no persistent effects of the application of AP3 itself (AP3
wash in) or the subsequent washout (AP3 washout). (n) = number of
slices.
63
f r o m the apical d e n d r i t i c ( p o p u l a t i o n EPSP) a n d s o m a t i c
( p o p u l a t i o n spike) layers o f CA1 p y r a m i d a l neurons,
while s t i m u l a t i n g electrodes were p l a c e d o n either side in
s t r a t u m r a d i a t u m , to activate s e p a r a t e c o n v e r g i n g
s y n a p t i c i n p u t s (Fig. 1a). O n e i n p u t was selected at rand o m as the test site, while the o t h e r served as the condit i o n i n g stimulus i n p u t p a t h w a y . F o u r l o w - f r e q u e n c y
trains o f test stimuli (5 H z / 2 s, every 15 s) were first applied a l o n e (Fig. lb; T E S T ) a n d d i d n o t themselves induce long-lasting changes in s y n a p t i c strength. T h e cond i t i o n i n g site was then s t i m u l a t e d a l o n e at high frequency (Fig. lb; C O N D : 5 pulse/100 H z bursts), eliciting
h o m o s y n a p t i c L T P o f the c o n d i t i o n i n g p a t h w a y ( n o t
shown) w i t h o u t persistently altering a m p l i t u d e o f responses to the test input. A f t e r these c o n t r o l c o n d i t i o n s
were met, D , L - A P 3 (25 # M ) was b a t h a p p l i e d (solid bar,
8
TEST
CONTROL
After (30 rnin)
Before
After (30 re,n)
Before
120 mse¢ 12mV
5 [
4
1
AP3 20uld
5 Hz Stina
Stlm +
Stlm -~
Stim +
Hyperpo]
Hyperpol
Depol
• TEST
30
Fig. lc) for 30 min p r i o r to the a p p l i c a t i o n o f o u t o f
phase s t i m u l a t i o n o f b o t h p a t h w a y s t o g e t h e r ( T E S T +
C O N D ) . This stimulus p a r a d i g m , which n o r m a l l y elicited associative L T D o f the test p a t h w a y , d i d n o t d o so
in the presence o f AP3. T h e slices were then w a s h e d in
drug-free m e d i u m for 45 min, a n d a second identical o u t
o f p h a s e s t i m u l a t i o n was a p p l i e d to b o t h p a t h w a y s , n o w
eliciting L T D o f the test p a t h w a y (*, P < 0 . 0 5 p a i r e d ttest c o m p a r e d to p r e s t i m u l a t e d baselines, n = 7 slices).
All e x p e r i m e n t s involving a p p l i c a t i o n o f A P 3 (20-25
# M ) are s u m m a r i z e d in Fig. l d , showing the percent
changes in test p a t h w a y e v o k e d E P S P slopes a n d p o p u l a tion spike a m p l i t u d e s r e c o r d e d 30 m i n after each stimulation. O u t o f p h a s e s t i m u l a t i o n o f test a n d c o n d i t i o n i n g
p a t h w a y s n o r m a l l y elicited significant L T D o f test p a t h w a y E P S P a n d p o p u l a t i o n spike, illustrated 30 m i n post-
60
Time
STIM + HYPERPOL
90
120
(mln)
STIM + DEPOL
150
Fig. 2. AP3 blocks LTD induced by pairing postsynaptic hyperpolarization with stimulation of synapses on CA1 pyramidal neurons, but
does not block LTP induced by pairing of postsynaptic depolarization
with synaptic activation, a: intracellular current-clamp records of
evoked EPSPs (O denotes stimulus artifact) before and 30 min after
pairing hyperpolarizing current injection (constant -0.6 nA current
produced a - 2 0 mV hyperpolarization of the soma in the absence of
synaptic stimulation) with TEST input synaptic activation (four 5 Hz/2
s trains). In the presence of AP3 (20/~M), TEST responses showed no
persistent changes. After a 60 min drug-free wash, the same hyperpolarization paired with TEST input stimulation were applied a second
time, now eliciting homosynaptic LTD of the test pathway. CONTROL synaptic inputs, unstimulated during hyperpolarization,
showed no changes in either condition. (RMP = - 6 5 mV, RN = 50
12). b: time course of the changes in intracellular EPSP slopes in another experiment. Arrows indicate the times of stimulation of the TEST
pathway, while a CA1 pyramidal neuron was at resting potential,
hyperpolarized by - 2 0 mV (Hyperpol) or depolarized by + 20 mV
(Depol). Single responses from the test input (filled circles) show that
5 Hz stimulation at rest produced no persistent changes in synaptic
strength. In AP3 (20/~M), 5 Hz stimulation of the TEST input while
the cell was hyperpolarized by - 2 0 mV (-0.8 nA injected current)
also failed to elicit any long-lasting alterations in EPSPs. Following
washout of AP3 for 30 min, the same 5 Hz stimulation was paired with
hyperpolarization a second time, and now elicited homosynaptic LTD
of the TEST pathway. Finally, this same stimulation in conjunction
with + 20 mV depolarization elicited LTP of the test pathway, indicating that both LTD and LTP mechanisms were functional in this neuron. (RMP = - 6 2 mV, RN = 44 MO). c: summary of intracellular
experiments showing that AP3 blocks LTD, without impairing LTP,
in CAI pyramidal neurons. In drug-free medium (CONTROL, solid
bars), pairing of TEST stimulation (four 5 Hz/2 s trains) with - 2 0 mV
hyperpolarization (Stim + Hyperpol) elicited LTD (*, P<0.05 compared to prestimulation baselines) of maximal EPSP slope measured
30 min after stimulation. In AP3 (20/~M, hatched bars), the same pairing of stimulation with hyperpolarization failed to induce LTD. In
contrast, pairing of this same TEST stimulation with + 20 mV depolarization (Stim + Depol) elicited robust LTP in both CONTROL and
AP3. (Mean + S.E.M., (n) = number of cells.)
64
stimulation (OUT OF PHASE, * P < 0 . 0 5 paired t-test,
(n) = number of slices). In contrast, a 30 min bath application of AP3 prior to the same out of phase stimulation
completely blocked LTD in CA1 pyramidal neurons
(OUT OF PHASE IN AP3), without producing any significant changes in EPSP slope or population spike
amplitude by itself (AP3 WASH IN).
In previous studies, we have shown that LTD can be
induced by pairing hyperpolarizing current injected into
the soma with presynaptic activation [27]; Similar results
have been reported in visual cortical neurons [1]. Therefore, we also examined the ability of AP3 to block LTD
induced by such pairing in intracellular recordings from
CA I pyramidal neurons. Fig. 2a illustrates typical
EPSPs recorded intracellularly in CA1 pyramidal neurons and evoked by stimulating on the Schaffer collateral
(TEST) or subicular (CONTROL) sides in the apical
dendritic layer (stratum radiatum). AP3 (20 #M) was
bath applied for 30 min prior to stimulation, and had no
significant effect on resting membrane potential, input
resistance, evoked synaptic potentials or threshold for
action potential firing (not shown). The soma was then
hyperpolarized - 2 0 mV by intracellular current injection through the recording electrode, and the test pathway stimulated with 4 low-frequency trains (5 Hz/2 s,
every 15 s). Current injection was then turned off, and
the evoked EPSPs in each pathway tested by alternating
single shocks each 30 s. Fig. 2a shows evoked responses
immediately before, and 30 min after, test pathway stimulation paired with hyperpolarization. In the presence
of AP3, stimulation did not produce persistent alterations in evoked potentials in either test or control pathways. Thereafter, the slice was washed in drug-free
medium for 60 min and the same stimulation and hyperpolarizing current was applied a second time, which now
elicited LTD, an approximately 50% reduction in the test
pathway evoked EPSP 30 min after the second stimulation.
Fig. 2b shows the time course of a representative
intracellular experiment, graphing the maximum initial
slope (V/s) of the EPSP evoked by test (closed circles),
and control (open circles), pathway stimulation. First,
test pathway stimulation (5 Hz/2 s × 4) was applied
alone, and had no effect on synaptic strength. Then, AP3
(20 #M, bar) was bath applied for 30 min prior to another series of four 5 Hz trains given while hyperpolarizing by - 20 mV. This pairing failed to elicit LTD of test
pathway synaptic strength, after which AP3 was washed
out for an additional 30 min and the same stimulation
paired with hyperpolarization applied a second time. This
stimulation paradigm now elicited marked homosynaptic
LTD of the test pathway, persisting for 30 min. At this
time, another series of four low-frequency trains was
again applied to the test pathway, this time while depolarizing the neuron by + 2 0 mV, eliciting associative
LTP of this pathway, which returned evoked responses
to their original amplitude. Intracellular experiments are
summarized in Fig. 2c, illustrating the percent change in
EPSP slope elicited by pairing of synaptic stimulation
with hyperpolarization (LTD) or with depolarization
(LTP), in the absence and presence of 20 #M AP3. AP3
completely prevented the induction of LTD, measured
30 min after stimulation (n = 10). Then, AP3 was washed
out and the same stimulation given a second time, which
now led to significant LTD of the test pathway (*,
P<0.05, paired t-test compared to pre-stimulus baselines, n = 9). In contrast, LTP was unaffected by the same
concentration of AP3 (Fig. 2c; LTP, n = 5).
Our observations that AP3 had no effect on induction
of associative LTP, induced either by in phase stimuli or
pairing depolarization with synaptic activation, suggests
that AP3 does not significantly block N M D A receptors.
We further verified that N M D A receptors do not play
a direct role in LTD induction by applying the N M D A
antagonist AP5 during the pairing of intracellular hyperpolarization with presynaptic stimulation. The experimental paradigm was identical to previous studies,
except that D-AP5 (20 #M) was bath applied. LTD was
elicited in the presence of AP5 ( - 5 2 . 6 __ 8.8%, n = 6),
and did not differ from that observed in control drugfree experiments. In our initial studies, we also found
that AP5, which blocked LTP induction at synapses on
apical dendrites of CAi pyramidal neurons, had no effect on LTD of these same synapses [27]. Our present
findings supply the first evidence implicating a specific
n o n - N M D A glutamate receptor, the metabotropic
(ACPD) glutamate receptor, in the induction of LTD in
the hippocampus.
The evidence for homosynaptic depression in neocortex is consistent with the characteristics of LTD that we
have found in the hippocampus. Studies in neocortical
slices [1,8] suggest that there is a narrow window of
membrane potentials for eliciting depression: there is no
long-term change in synaptic strength if the membrane
potential is below the threshold for depression, and LTP
occurs if the membrane potential is above a second
threshold. However, at present, mechanisms linking the
voltage sensitivity of LTD to the involvement of metabotropic receptors are not clear. Furthermore, another
common feature underlying hippocampal and neocortical LTD is that it results when a synapse is active and
when its use is uncorrelated with activity at other
synapses on the same neuron. The signal for lack of correlation might be the changes in calcium levels in dendritic spines. One such mechanism, absence of calcium influx through N M D A receptor channels during presy-
65
n a p t i c activity, is a p p a r e n t l y n o t sufficient to induce
L T D o r reverse L T P [9]. But the extent, s p a t i a l l o c a t i o n
a n d time course o f rise in i n t r a c e l l u l a r calcium c o n c e n t r a t i o n m a y nonetheless be i m p o r t a n t , since a c t i v a t i o n o f
m e t a b o t r o p i c r e c e p t o r s c a n trigger the release o f calcium
f r o m i n t r a c e l l u l a r stores [13,20].
R e c e n t evidence indicates t h a t in kitten striate cortex,
the a g e - d e p e n d e n t c o u p l i n g o f e x c i t a t o r y a m i n o acid-stim u l a t e d PI h y d r o l y s i s correlates with p o s t n a t a l c h a n g e s
in cortical susceptibility to visual d e p r i v a t i o n [7]. F u r t h e r m o r e , A P 3 t r e a t m e n t in 2 - m o n t h - o l d kittens can b l o c k
the e l e c t r o p h y s i o l o g i c a l effects o f m o n o c u l a r d e p r i v a t i o n
o n the striate c o r t e x c o n t r a l a t e r a l to the d e p r i v e d eye [3].
Thus, in the visual cortex, e x p e r i e n c e - d e p e n d e n t reductions in s y n a p t i c strength m a y be d e p e n d e n t on m e t a b o t r o p i c r e c e p t o r a c t i v a t i o n l e a d i n g to L T D o f d e p r i v e d
eye synapses. In the cerebellum, L T D at parallel fiberP u r k i n j e cell synapses occurs when parallel fiber i n p u t s
are p a i r e d with c l i m b i n g fiber i n p u t s [14]. R e c e n t studies
suggest that, in this f o r m o f L T D , A M P A - s p e c i f i c glutam a t e r e c e p t o r s m e d i a t i n g p a r a l l e l fiber-Purkinje cell responses are desensitized t h r o u g h a process which involves
c o - a c t i v a t i o n o f m e t a b o t r o p i c A C P D receptors [15]. I n
a g r e e m e n t with these recent findings, o u r results suggest
t h a t a c t i v a t i o n o f m e t a b o t r o p i c r e c e p t o r s m a y be
r e q u i r e d for i n d u c t i o n o f L T D at h i p p o c a m p a l synapses.
H o w e v e r , this i n t e r p r e t a t i o n is b a s e d on a s s u m p t i o n s o f
the specificity a n d m e c h a n i s m o f a c t i o n o f A P 3 t h a t are
still uncertain. T h e r e is evidence suggesting v a r i a t i o n s
between the p h a r m a c o l o g y o f e l e c t r o p h y s i o l o g i c a l effects a n d o t h e r b i o c h e m i c a l responses elicited b y m e t a b o t r o p i c r e c e p t o r a c t i v a t i o n [28,29]. F u r t h e r studies will
be r e q u i r e d to d e t e r m i n e the b i o c h e m i c a l links between
m e t a b o t r o p i c r e c e p t o r s t i m u l a t i o n a n d the i n d u c t i o n o f
LTD.
This w o r k was s u p p o r t e d b y an Office o f N a v a l Research Y o u n g I n v e s t i g a t o r A w a r d , K l i n g e n s t e i n F o u n d a t i o n F e l l o w s h i p , a n d N I H G r a n t M H 4 5 7 5 2 to P.K.S.,
a n d g r a n t s f r o m the M a t h e r s F o u n d a t i o n , D r o w n F o u n d a t i o n , a n d the Office o f N a v a l R e s e a r c h to T.J.S. W e
are m o s t grateful to Dr. M a r k Bear a n d Serena D u d e k
for helpful discussions.
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