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The Journal of Neuroscience, July 1, 1998, 18(13):4870-4882
Evidence for Metabotropic Glutamate Receptor Activation in the
Induction of Depolarization-Induced Suppression of Inhibition in
Hippocampal CA1
Wade
Morishita,
Sergei A.
Kirov, and
Bradley E.
Alger
Department of Physiology, University of Maryland School of
Medicine, Baltimore, Maryland 21201
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ABSTRACT |
Depolarization-induced suppression of inhibition (DSI) is a
transient reduction of GABAA receptor-mediated IPSCs that
is mediated by a retrograde signal from principal cells to
interneurons. Using whole-cell recordings, we tested the hypothesis
that mGluRs are involved in the DSI process in hippocampal CA1, as has
been proposed for cerebellar DSI. Group II mGluR agonists failed to
affect either evoked monosynaptic IPSCs or DSI, and forskolin, which
blocks cerebellar DSI, did not affect CA1 DSI. Group I and group III mGluR agonists reduced IPSCs, but only group I agonists occluded DSI.
(S)-MCPG blocked
(1S,3R)-ACPD-induced IPSC suppression and markedly reduced DSI, whereas group III antagonists had no effect on
DSI. Many other similarities between DSI and the
(1S,3R)-ACPD-induced suppression of IPSCs
also were found. Our data suggest that a glutamate-like substance
released from pyramidal cells could mediate CA1 DSI by reducing GABA
release from interneurons via the activation of group I mGluRs.
Key words:
IPSP; GABA; retrograde signal; voltage clamp; mGluR; synaptic inhibition
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INTRODUCTION |
Depolarization-induced suppression
of inhibition (DSI) is a phenomenon seen in both hippocampal CA1
pyramidal cells (Pitler and Alger, 1992 , 1994; Alger et al., 1996;
Morishita and Alger, 1997a) and cerebellar Purkinje cells (Llano et
al., 1991; Vincent et al., 1992; Vincent and Marty, 1993). It involves
the transient (~1 min) suppression of GABAA
receptor-mediated (GABAARmediated) IPSCs impinging on
these cells after depolarization of their membranes that is sufficient
to open voltage-gated Ca2+ channels. Despite the
clearly postsynaptic locus of induction of DSI, the actual suppression
of inhibition occurs via a presynaptic mechanism. Many experiments have
led to the conclusion that the quantal content of
GABAAR-mediated IPSCs is reduced, with no evidence of a
decrease in postsynaptic GABAAR responsiveness neither
iontophoretic GABAAR-mediated responses nor quantal size is
reducedduring DSI. Taken together, the postsynaptic site of induction
plus the presynaptic site of expression strongly imply that a
retrograde signal must pass between the principal cells and their
interneurons (Alger and Pitler, 1995).
It has been suggested recently that glutamate, released from Purkinje
cells and acting on a presynaptic group II mGluR on the GABA-releasing
basket cells, is the retrograde messenger for DSI in the cerebellum
(Glitsch et al., 1996). Supporting evidence includes the findings that
the specific mGluR agonist DCG-IV mimics and occludes DSI and that the
mGluR antagonist L-AP3 reduces DSI [for review of mGluR
pharmacology, see Pin and Duvoisin (1995)]. Group II mGluRs (mGluR2
and mGluR3) decrease cAMP production (Conn et al., 1994), which can
reduce GABA release (Capogna et al., 1995). Glitsch et al. (1996) found
that in cerebellum forskolin, an activator of adenylate cyclase, also
reduced DSI, which was consistent with their hypothesis.
Despite many similarities, hippocampal DSI and cerebellar DSI differ in
some ways (Alger and Pitler, 1995). For example, whereas cerebellar DSI
reduces TTX-insensitive mIPSC frequency, in CA1 pyramidal cells mIPSCs
are unaffected by DSI. That and other data have suggested that there
are two mechanisms for DSI expression in cerebellum, but only one is
significantly present in CA1. In view of these differences it was of
particular interest to test the hypothesis that the retrograde process
in hippocampus might be mediated by glutamate acting on presynaptic
group II mGluRs.
We made whole-cell voltage-clamp recordings of monosynaptic, evoked
IPSCs in CA1 pyramidal cells in the rat hippocampal slice and used a
battery of mGluR agonists and antagonists to test the mGluR hypothesis
of DSI. Antagonism of DSI by (S)-MCPG and
similarities between the actions of mGluR agonists and DSI support the
hypothesis that glutamate, or a glutamate-like compound, could be the
retrograde messenger of DSI in CA1 pyramidal cells, although the
mechanism does not involve the group II mGluR subtype. This hypothesis
has interesting implications for understanding both the mechanism by
which the DSI process mediates DSI and the apparent differences between
hippocampal and cerebellar DSI.
Some of the data in this report have appeared in abstract form (Alger
et al., 1997).
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MATERIALS AND METHODS |
Preparation of hippocampal slices. Adult male Sprague
Dawley rats (125-250 gm) were anesthetized deeply with halothane and decapitated; the brain was removed, and the hippocampi were dissected free. The hippocampi were mounted on an agar block in a slicing chamber
containing ice-cold saline. Transverse slices (400 µm) were cut with
a Vibratome (Technical Products International, Chicago, IL) and allowed
to recover in a holding chamber at the interface of a physiological
saline and humidified 95% O2/5% CO2
atmosphere at room temperature. After a minimum 1 hr incubation, a
single slice was transferred to a submersion-type recording chamber
(Nicoll and Alger, 1981), where it was perfused with oxygenated saline (29-31°C) at a flow rate of 0.5-1 ml/min.
Solutions. Patch electrodes with resistances 3-6 M
usually were filled with (in mM):
CsCH3SO3 100, CsCl 50 or 60, BAPTA 2, CaCl2 0.2, MgCl2 1, MgATP 2 or 4, HEPES 10, Tris-GTP 0.3, and 2-(triethylamino)-N-(2,6-dimethylphenyl)
acetamide (QX-314) 5, pH adjusted to 7.3 with KOH, osmolarity 310-320
mOsm. In some experiments 145 mM KCl was used in place of
the Cs salts; other constituents were the same. The results using these
two electrode solutions did not differ. Physiological saline contained
(in mM): NaCl 120, KCl 3.5, NaH2PO4
1.25, NaHCO3 25, CaCl2 2, MgSO4 2, and glucose 10, equilibrated with a 95% O2/5%
CO2 mixture, pH 7.3. 6-Cyano-7-nitroquinoxaline-2,3-dione
(CNQX; 20 µM) and
D,L-2-amino-5-phosphonovaleric acid (APV; 50 µM) were used in all experiments in the extracellular saline to block ionotropic glutamate responses. TTX, 0.5 µM, was present in the bath solution for experiments on
miniature IPSCs (mIPSCs) to block action potential-dependent
transmitter release. Recording of mIPSCs was initiated only after
high-intensity stimulation elicited no IPSC.
The metabotropic glutamate receptor (mGluR) agonists
L-quisqualic acid (Quis),
(S)-3,5-dihydroxyphenylglycine (DHPG),
(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid
[(1S,3R)-ACPD],
(2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV),
(2S,1'S,2'S)-2-(carboxycyclopropyl)glycine
(L-CCG-I), L(+)-2-amino-4-phosphonobutyric acid
(L-AP4), as well as the mGluR antagonists
L(+)-2-amino-3-phosphonopropionic acid (L-AP3),
(S)-4-carboxyphenylglycine (4CPG),
(RS)- -methylserine-O-phosphate (MSOP),
(S)-2-amino-2-methyl-4-phosphonobutanoic acid
(M-AP4), and
(S)--methyl-4-carboxyphenylglycine
[(S)-MCPG] were purchased from Tocris Cookson
(Bristol, UK). CNQX was acquired from Research Biochemicals (Natick,
MA), BAPTA from Molecular Probes (Eugene, OR), and TTX from Calbiochem
(La Jolla, CA). QX-314 was generously donated by Astra (Sodertalje,
Sweden) or was purchased from Alomone Labs (Jerusalem, Israel). All
other drugs and chemicals were from Sigma (St. Louis, MO). Drugs were
either iontophoretically- or bath-applied. All agonists and antagonists
of mGluRs were prepared as concentrated stock solutions:
(1S,3R)-ACPD, L-CCG-I, quisqualate, L-AP4, and DHPG were dissolved at 1000× final
concentration in 1 equivalent (eq) of NaOH (except for DHPG, which was
prepared in distilled water); L-AP3 and
(S)-MCPG were solubilized at 100× final
concentration in 1 eq or 1.1 eq of NaOH. All other bath-applied drugs
were prepared as 1:1000 concentrated stock solutions.
Electrophysiology and data analysis. Tight-seal whole-cell
recordings were obtained from CA1 pyramidal cells via the "blind" technique (Blanton et al., 1989). The cells were voltage-clamped at
 70 mV immediately after break-in, using either an Axopatch 200A or
Axoclamp 2B amplifier (Axon Instruments, Foster City, CA). Acceptable
cells had resting potentials more than or equal to 55 mV and input
resistances >40 M. Series resistance and input resistance were
monitored continuously (every 2, 16, or 120 sec) by observing changes
in the amplitude characteristics of the capacitive current elicited by
a 5 mV, 50 msec hyperpolarizing rectangular voltage step. Experiments
with unstable series resistances or series resistances >30 M were
discarded. Series resistance compensation was between 50 and 70%.
Liquid junction potentials were small and were not corrected for.
Evoked inhibitory postsynaptic currents were recorded by stimulating
either stratum oriens or stratum radiatum at 0.33 or 0.5 Hz with a
bipolar concentric stimulating electrode (Rhodes Electronics).
Extracellular field EPSPs were recorded with electrodes (resistances
2-5 M) filled with buffered salt solution having the same
composition as the physiological saline. Mossy-fiber field EPSPs
recorded in s. lucidum were evoked by a stimulating electrode placed in
s. granulosum of the dentate gyrus. CA1 field EPSPs were recorded in s.
radiatum. To record CA1 field EPSPs, we removed the CA3 region and
placed a stimulating electrode in s. radiatum near the cut edge. Field
EPSPs were evoked at 0.1 Hz. Signals were filtered at 2 kHz with an
eight-pole Bessel filter (Frequency Devices, Haverhill, MA), digitized
at 10 kHz with a DigiData 1200 interface board (Axon Instruments), and
analyzed with pCLAMP 6 software (Axon Instruments). Data also were
stored on VHS videotape after being acquired at 22 kHz with a 14-bit PCM digitizer (Neuro-Corder DR-484, Neuro Data Instruments).
Iontophoresis of (1S,3R)-ACPD was performed in
some experiments. (1S,3R)-ACPD was dissolved at
25 mM in 1 eq of NaOH and was present at full strength in
the iontophoretic pipettes. The drug was ejected from glass pipettes
with resistances of 1-2 M positioned in the vicinity of the
recording patch electrode. Iontophoretic currents of 155 to 600 nA
lasting from 2 to 4 sec were used.
Positive voltage step commands to ~0 mV for a duration of 1-2 sec
were used to elicit DSI every 90-120 sec. With this protocol an
unclamped Ca2+ spike current and
K+ currents were present in the current trace. DSI
was expressed as the percent reduction of the control response by
calculating the mean amplitude of 7 or 10 IPSCs in the control
(pre-DSI) period and the mean amplitude of the same number of IPSCs
after the DSI step. Because DSI often is not maximal immediately after
the step and takes ~1-3 sec to develop (Pitler and Alger, 1994;
Alger et al., 1996), we typically omitted the first two IPSCs during
the DSI period from the calculations.
To quantify drug effects on DSI, we compared the mean of two to four
complete DSI trials in control (predrug period) with the mean of the
equal number of DSI trials at the time of maximum drug effect. The
percent reduction of IPSC amplitude by the given drug was calculated by
comparing the mean amplitudes in the pre-DSI period in control and
during the drug effect. The percent reduction of IPSCs by iontophoretic
(1S,3R)-ACPD application was computed in the same
manner, comparing the mean amplitude of 7-10 IPSCs before and after
drug ejection at the time of maximum effect. Unless otherwise stated, a
Student's paired t test was used to determine statistical
significance of effects (p < 0.05), and all
data are reported as the mean ± SEM.
The significance of (1S,3R)-ACPD effects on
mIPSCs was assessed by Kolmogorov-Smirnov (K-S) statistics with a
significance level of p < 0.005. Cumulative frequency
amplitude distributions of TTX-insensitive mIPSCs were obtained over 1 min in the control period and during the subsequent application of
(1S,3R)-ACPD. Averaged cumulative frequency
amplitude distributions were constructed by normalizing individual
distributions to the median amplitude of the corresponding control
distributions. Data from individual cells were averaged by calculating
the normalized amplitudes at fixed cumulative frequency intervals.
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RESULTS |
(1S,3R)-ACPD reduces IPSCs and DSI
The results presented in this report are based on whole-cell
voltage-clamp experiments done on 134 cells recorded in the CA1 pyramidal layer of the rat hippocampal slice. The ionotropic glutamate receptor antagonists CNQX (20 µM) and APV (50 µM) were present in all experiments except for those on
field potential EPSPs.
Confirming previous reports (Desai et al., 1994; Jouvenceau et al.,
1995), we found that the mGluR agonist
(1S,3R)-ACPD bath-applied at 50 (n = 15) or 100 µM (n = 4) substantially suppressed the evoked monosynaptic GABAA
R-mediated IPSC (55.6 ± 5.3%; Fig.
1A,D, n = 19). In 18 of these cells DSI was present; the mean suppression of
the IPSC during DSI was 51 ± 3.4% of the control amplitude. (1S,3R)-ACPD reduced the IPSC by 53.9 ± 5.3% and reduced DSI in these cells to 17 ± 4% suppression. In
10 cells we tested for recovery and found that DSI recovered after 50 µM (1S,3R)-ACPD was washed out
(control DSI, 54 ± 4.3%; wash DSI, 50 ± 5.6%) (Fig. 1C).
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Figure 1.
Activation of mGluRs by
(1S,3R)-ACPD reduces DSI of evoked
monosynaptic GABAAR-mediated IPSCs recorded from
hippocampal CA1 pyramidal cells. A, Illustrated is a
control DSI trial on a series of evoked IPSCs (these inward currents
are shown as downward deflections). DSI was elicited by
a depolarizing voltage step [depolarizing voltage steps (see Materials
and Methods) are indicated by filled arrows in all
figures] and is represented by the transient reduction of the IPSCs.
The center trace is from a DSI trial on the same cell
during the fifth minute of bath application of
(1S,3R)-ACPD. The IPSCs are reduced in
amplitude, and DSI is occluded. The right trace is from
a DSI trial recorded 22 min after washout of
(1S,3R)-ACPD. B, Recorded
from another cell, the first current trace (left) shows
the control DSI trial. The center trace shows the
effects of (1S,3R)-ACPD (recorded during
the fourth minute of bath application). The right trace
is from a DSI trial after the stimulation intensity had been increased
(ADJ. STIM. INTENSITY) to evoke IPSCs comparable
in amplitude to those recorded in control. Note that DSI remains
reduced after this manipulation. C, Combined data
summarizing the action of (1S,3R)-ACPD on
DSI from 10 experiments as in A. In the same graph
(separated by the break in the ordinate)
are data recorded from a different set of cells summarizing experiments
performed as in B. Data in control and recovery are
labeled CON and REC, respectively.
D, Summarized is the suppression of the IPSC amplitude
produced by bath-applied (1S,3R)-ACPD.
Data in graphs C and D were obtained from
the number of cells shown in parentheses
above the bars. Asterisks in the
figures indicate significant differences from control values
(Student's paired t test; p < 0.05). In this and other figures stimulus artifacts were blanked for
clarity in the display.
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The block of DSI induced by (1S,3R)-ACPD could
not be explained simply by the reduction in IPSC size because when,
still in (1S,3R)-ACPD, the stimulus intensity was
increased to produce an IPSC similar to the control IPSC, DSI did not
increase (Fig. 1B,C). DSI recovered when
(1S,3R)-ACPD was washed from the bath, however
(n = 5). Thus it appears that activation of mGluRs
mimics and occludes hippocampal CA1 DSI as it does cerebellar DSI
(Glitsch et al., 1996).
Both DSI and (1S,3R)-ACPD decrease the frequency
of TTX-insensitive mIPSCs in cerebellum (Llano et al., 1991; Llano and
Marty, 1995). In hippocampus, DSI does not block mIPSCs (Pitler and
Alger, 1994; Alger et al., 1996). We recorded mIPSCs during 1 min
intervals from six cells in TTX and then applied
(1S,3R)-ACPD (50 µM) and compared
the mIPSCs in (1S,3R)-ACPD with those in control.
There was no change in mIPSC frequency (control, 4.8 ± 1 Hz;
(1S,3R)-ACPD + TTX, 5.29 ± 1 Hz) or
amplitude (Fig. 2). That bath-applied
(1S,3R)-ACPD was active in these cells was
evident by the small inward currents, 30-60 pA (see, for example, Fig.
2), that it induced. Note that in experiments performed with Cs-based
electrode filling solutions and iontophoretic application of
(1S,3R)-ACPD, direct postsynaptic membrane
effects, such as these inward currents, were undetectably small (see
Figs. 4,6,7) and cannot account for the
effects we report.
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Figure 2.
(1S,3R)-ACPD does
not affect the amplitude or frequency of TTX-insensitive mIPSCs. The
top trace illustrates the actions of bath-applied
(1S,3R)-ACPD (duration of application is
indicated by the solid bar) on a continuous record of
spontaneous mIPSCs in the presence of 0.5 µM TTX.
(1S,3R)-ACPD produced an inward current
of ~30 pA. A1, Traces of mIPSCs on an expanded
time scale recorded during the control period before the application of
(1S,3R)-ACPD. A2,
Shown are mIPSCs during the sixth minute of
(1S,3R)-ACPD perfusion.
B1, Corresponding amplitude histograms of the
mIPSCs before (filled bars) and in the presence
of (1S,3R)-ACPD (open
bars). Measurements were taken for 1 min in each condition.
B2, Cumulative amplitude distributions obtained
in B1 for mIPSCs recorded in control
(solid line) and in the presence of
(1S,3R)-ACPD (dashed line)
for the experiment shown in A. C,
Averaged cumulative amplitude distributions of mIPSCs obtained from six
cells in control and then in
(1S,3R)-ACPD. D, Bar graph
shows mean mIPSC frequencies in control and in the presence of
(1S,3R)-ACPD (n = 6).
(1S,3R)-ACPD had no significant effect on
the frequency of mIPSCs. Individual amplitude distributions of events
in B2 and C in control and in
(1S,3R)-ACPD are not statistically
significant, as determined by Kolmogorov-Smirnov tests
(p < 0.005).
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Figure 3.
Group II mGluRs are not involved in CA1 DSI.
A1, Continuous trace of IPSCs showing several
DSI trials. Below the trace are averages of five
consecutive IPSCs recorded at the indicated time points before
(Pre-DSI) and after the voltage step
(DSI) in control and in the presence of the
specific group II mGluR agonist, DCG-IV, applied at 10 µM (duration of application is indicated by the
solid bar above the continuous trace). Next to the
averaged traces is a bar graph summarizing the data from five cells.
DSI is not significantly altered by DCG-IV. A2,
The graph shows that 1 µM DCG-IV suppressed mossy
fiber-CA3 field EPSPs (n = 7 slices) and hence is
active under our conditions. EPSPs above the graph are
averages of six consecutive responses recorded at the indicated time
points from one slice. B, The first trace
(left) shows a control DSI trial, and the trial to the
right is from the same cell during the eighth minute of
application of the group II mGluR agonist, L-CCG-I. Results
from six such experiments are shown in the bar graph located to the
right of the current traces. L-CCG-I had no
effect on DSI.
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Evidence against group II or group III mGluR involvement
in DSI
(1S,3R)-ACPD is an agonist at group I and
group II mGluRs; hence it was not clear which class was responsible for
IPSC suppression in CA1. In cerebellum the highly selective group II
agonist DCG-IV (0.5-5 µM) potently blocked IPSCs and
occluded DSI (Glitsch et al., 1996). In CA1 we found that bath
application of 10 µM DCG-IV to five pyramidal cells, in
which robust DSI of evoked IPSCs was present, affected neither the IPSC
amplitudes nor DSI (control DSI, 43 ± 4.7%; DCG-IV DSI, 46 ± 6.1%) (Fig. 3A1). We confirmed (Kamiya et
al., 1996) that 1 µM DCG-IV was effective in CA3,
however, reducing evoked field potentials by 79 ± 4.2%
(n = 7) (Fig. 3A2), and in a
separate study (Morishita and Alger, 1997b) we verified that 10 µM DCG-IV reduces CA3 IPSCs (see Poncer et al., 1995). The EC50 of L-CCG-I for phosphoinositide (PI)
hydrolysis caused by expressed mGluR1 is ~50 µM (Suzdak
et al., 1994). The EC50 of L-CCG-I for the
inhibition of forskolin-stimulated cAMP production by expressed mGluR4
is ~50 µM, whereas its EC50 in the same
assay when mediated by expressed mGluR2 is 0.3 µM. Thus
at low concentrations L-CCG-I is relatively selective for
mGluR2. We found that L-CCG-I, at 3 µM, had
no effect on either evoked IPSCs or DSI (n = 6; Fig. 3B). In one cell we then increased the dose of
L-CCG-I to 100 µM and found that both IPSCs
and DSI were reduced dramatically. The lack of effect of group II mGluR
agonists on IPSCs means that these receptors probably are not involved
in DSI.
The mGluR agonist, L-AP4, is selective for group III mGluRs
(mGluR4, mGluR6, mGluR7, and mGluR8). Although mGluR6 does not appear
to be present in hippocampus and the levels of mGluR4 and mGluR8 are
very low in CA1 (Testa et al., 1994; Shigemoto et al., 1997), mGluR7 is
present (Okamoto et al., 1994; Saugstad et al., 1994; Shigemoto et al.,
1997). L-AP4 bath-applied at 200 µM to six
cells reduced the IPSCs by a mean of 39 ± 4.9%. Gereau and Conn
(1995b) found that L-AP4 did not block IPSCs when
glutamatergic transmission was blocked by APV and CNQX, implying that
L-AP4 acted at another site, probably the excitatory nerve
terminals onto the interneurons. Our experiments were done in CNQX and
APV; hence this explanation could not account for our data.
Nevertheless, glutamate still was released in the presence of CNQX and
APV, so we considered whether or not synaptically released glutamate could affect IPSCs by activation of mGluRs on interneurons. Adenosine inhibits glutamate release without affecting GABA release (Lambert and
Teyler, 1991). We found that 50 µM adenosine did not
alter the ability of L-AP4 to reduce IPSCs (47 ± 14.3% reduction in control vs 46 ± 15.9% reduction in
adenosine; n = 4), a result that is explained most
easily as a direct inhibitory effect of group III mGluRs on GABAergic
interneurons, rather than as an indirect effect.
Despite its suppression of monosynaptic IPSCs, L-AP4
did not reduce DSI significantly (control DSI, 42 ± 4.7%;
L-AP4 DSI, 37 ± 4.0%) (Fig.
4A1,
A2, p = 0.2; n = 11), even when stimulus intensity was increased to restore IPSC
amplitudes to control levels (Fig. 4A). Moreover,
neither the group III mGluR antagonist MSOP, 200 µM
(control DSI, 48 ± 7.8%; MSOP DSI, 50 ± 7.8%;
n = 6), nor the antagonist M-AP4, 2.5 mM,
affected DSI (Fig. 4C, n = 4). As also shown
in Figure 4C, M-AP4 had no effect on iontophoretically applied (1S,3R)-ACPD-induced IPSC suppression,
although M-AP4, 1 mM, completely and reversibly blocked the
effects of 50 µM L-AP4 on the CA1 field EPSP
(Fig. 4B). These data argue against a role for
group III mGluRs in DSI.
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Figure 4.
Group III mGluRs are not involved in CA1 DSI.
A1, The first current trace
(left) illustrates two control DSI trials. The
center trace shows two DSI trials recorded from the same
cell during the fifth minute of application of the group III mGluR
agonist, L-AP4. The trials in the right
trace also were recorded in L-AP4 after the
stimulation intensity had been increased (ADJ. STIM.
INTENSITY) to elicit IPSCs comparable in amplitude to
those recorded in control. A2, The bar graph
summarizes results from 11 experiments similar to those in
A1. DSI was not affected significantly by
L-AP4. B, An experiment showing that the
suppression of CA1 field EPSPs by L-AP4 can be blocked by
M-AP4, under our conditions, and hence that M-AP4 is an effective group
III antagonist. EPSPs displayed above the graph are
averages of six consecutive responses recorded at the indicated time
points from one slice. Results from five experiments are summarized in
the bar graph to the right. The continuous trace in
C shows that M-AP4 (the duration of application is
indicated by the solid bar) blocks neither DSI
(filled arrows) nor the suppression of IPSCs
induced by iontophoresis of (1S,3R)-ACPD
(open arrows). Below the trace are IPSCs
recorded at the indicated time points before
(Pre-DSI) and during DSI
(DSI) as well as before (Pre-ACPD)
and after (ACPD) iontophoresis of
(1S,3R)-ACPD. Individual IPSCs are the
averages of five consecutive responses. The bar graph to the
right summarizes results from four experiments.
(1S,3R)-ACPD was iontophoresed by a 155
nA, 2 sec current. Asterisks denote significant
differences from control values.
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Group II and group III mGluRs produce their effects mainly by
inhibiting adenylate cyclase (Conn et al., 1994). We found (data not
shown) that bath application of 50 µM forskolin enhanced
monosynaptic IPSC amplitude (by 60 ± 14%; n = 8), as previously reported (Capogna et al., 1995). Forskolin had no
effect on DSI, however, which in these cells amounted to a depression
of 54 ± 3.6% in control and 45 ± 5.9% in forskolin
(p = 0.09). Because forskolin did occlude DSI
and the effects of the group II agonists in cerebellum (Glitsch et al.,
1996), our results are consistent with a lack of participation of group
II or group III mGluRs in hippocampal CA1 DSI, assuming that the
depression of synaptic transmission mediated by these receptors is
caused by cAMP reduction.
Group I mGluR agonists mimic and occlude DSI
The efficacy of (1S,3R)-ACPD and a high
concentration of L-CCG-I in reducing IPSCs and DSI
suggested that group I mGluRs (mGluR1 and mGluR5) could be responsible.
At low concentrations ( 10 µM) quisqualate is fairly
selective for group I (Suzdak et al., 1994). We tested the effects of
quisqualate at 2 (n = 3), 5 (n = 3) and 10 µM (n = 2) and found that each was
highly effective in reducing IPSC amplitudes (pooling results from
these experiments gave a mean suppression of IPSC amplitudes of 70 ± 5.6% from control) (Fig.
5D, n = 8) and
DSI from 48 ± 3.6% to 19 ± 3.7% (Fig. 5A,C, n = 7). DHPG, 100 µM, is quite specific
for group I mGluRs (Ito et al., 1992; Schoepp, 1994; Brabet et al.,
1995; Gereau and Conn, 1995b). DHPG reduced IPSCs (to 52.9 ± 4.4% of control, Fig. 5D) and DSI (from 51 ± 5.3% in
control to 17 ± 4.2% in DHPG) (Fig. 5B,C,
n = 6). Thus the activation of group I mGluRs can mimic and occlude DSI.
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Figure 5.
Group I mGluR agonists, L-quisqualate
and DHPG, reduce the amplitude of evoked monosynaptic IPSCs and occlude
DSI. A, The first trace (left) shows the
DSI of IPSCs recorded in the control saline. The center
trace shows IPSCs recorded during the 10th min of bath
application of L-quisqualate (QUIS). The
right trace shows a DSI trial still in
L-quisqualate after the stimulation intensity had been
increased (ADJ. STIM. INTENSITY) to elicit IPSCs
comparable to those in the control condition. B,
Illustrated are the effects of DHPG on IPSCs and DSI; trace sequences
are as in A. Both L-quisqualate and DHPG
suppressed IPSCs and occluded DSI, and the effects persisted even after
the stimulation intensity had been increased. C, A graph
summarizes the effects of quisqualate and DHPG on DSI.
D, A graph shows the effect of these agonists on IPSC
amplitudes. Asterisks indicate significant differences
from control values.
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(S)-MCPG reduces
(1S,3R)-ACPD-induced suppression of IPSCs
and DSI
The mGluR antagonist, L-AP3, blocks cerebellar DSI;
however, when bath-applied at 1 mM, L-AP3 had
no consistent effect on CA1 IPSCs or DSI. Of four cells it had no
apparent effect on DSI in three, and in one cell both the IPSC and DSI
were diminished. When tested on DSI and iontophoretic
(1S,3R)-ACPD-induced IPSC suppression in another
group of cells, L-AP3 had no significant effect on either
(n = 3; data not shown). Thus L-AP3
appeared to be an ineffective mGluR antagonist in CA1 in our hands.
We examined the effect of (S)-MCPG on
(1S,3R)-ACPD-induced IPSC suppression and DSI by
bath-applying it at concentrations from 0.5 to 5 mM.
(1S,3R)-ACPD was applied iontophoretically from a
pipette containing 25 mM (1S,3R)-ACPD
(see Materials and Methods). Evoked IPSCs were suppressed on alternate
trials by DSI or by iontophoretic (1S,3R)-ACPD.
(S)-MCPG caused a dose-dependent reduction in DSI,
decreasing it, for example, by 10 ± 6.9% at 0.5 mM
and by 57 ± 1.3% at 5 mM (Fig.
6A).
(S)-MCPG was more effective in blocking
(1S,3R)-ACPD suppression of IPSCs than DSI,
causing reductions of 42 ± 12.7% and 82 ± 16.8% at 0.5 and 5 mM, respectively, in the same cells.
(S)-MCPG had no significant effect on IPSC amplitudes even at 5 mM (control IPSC, 1269 ± 172 pA;
(S)-MCPG IPSC, 1039 ± 138 pA;
p = 0.1; n = 5). We also tested the
antagonist 4-carboxyphenylglycine (4CPG) because this has been proposed
to distinguish between mGluR1 and mGluR5 effects (Brabet et al., 1995).
At 200 µM (KB = 14.9 ± 7.7 µM for blocking mGluR1 effects in LLC-PK1 cells) (Brabet et al., 1995), 4CPG did not affect DSI (control DSI, 54 ± 9.2%; 4CPG DSI 62 ± 7.4%) (see Fig. 6B) and also did
not affect (1S,3R)-ACPD-induced IPSC depression
(control (1S,3R)-ACPD, 35 ± 8.3%; 4CPG
(1S,3R)-ACPD, 40 ± 8.3%). These results
suggest that mGluR5 rather than mGluR1 might be involved in IPSC
suppression (see Discussion).
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Figure 6.
Selective block of DSI and the
(1S,3R)-ACPD-induced suppression of IPSCs
by (S)-MCPG, but not 4CPG. The current trace
(CONTROL) in A illustrates the transient
suppression of IPSCs during DSI (filled arrows)
and after iontophoresis of (1S,3R)-ACPD
(open arrows). The trace to the right of
control, (MCPG) shows that both forms of IPSC
suppression are antagonized during the 12th min of application of
(S)-MCPG. The recovery trace shown to the far
right was taken 40 min after we started to wash
(S)-MCPG from the recording chamber. All current
traces in A were recorded from the same cell. To the
left, in the bottom part of A,
are IPSCs recorded at the indicated time points before
(Pre-DSI) and during (DSI)
as well as before (Pre-ACPD) and after
(ACPD) iontophoretic application of
(1S,3R)-ACPD. The bar graph in the
center summarizes the results from five cells. The bar
graph to the extreme right shows the dose dependence of
(S)-MCPG effects on DSI. B, Shown
is a continuous record in which the evoked IPSCs were subjected to the
same stimulating protocol as in A. Below
the record are IPSCs recorded at the indicated time points. Note that
4CPG (duration of application is indicated by the solid
bar) does not antagonize DSI or the
(1S,3R)-ACPD-induced suppression of
IPSCs. The bar graph illustrates the results from five cells. IPSCs in
A and B are averaged traces from five
consecutive responses. (1S,3R)-ACPD was
iontophoresed by a 155 nA, 2 sec current. Asterisks
indicate significant differences from the control values.
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(1S,3R)-ACPD does not block DSI by reducing
voltage-dependent Ca2+ currents in postsynaptic CA1
pyramidal cells
Activation of mGluRs can cause a modest reduction of
voltage-dependent Ca2+ current (VDCC) in CA1 cells
(10-30%) (Lester and Jahr, 1990; Swartz and Bean, 1992; Trombley and
Westbrook, 1992). Inasmuch as DSI induction depends on VDCCs in CA1
(Pitler and Alger, 1992; Lenz et al., 1997), it was conceivable that
the reduction of DSI by mGluRs was dependent on this effect. However,
(1) mGluR agonists had no consistent effect on clamp current during the
DSI-inducing voltage steps, i.e., in an arbitrary group of 17 cells,
the net current did not change in 10, decreased in the outward
direction in four, and increased in the outward direction in three; (2) adenosine, which causes a greater reduction in VDCC in CA1 cells than
does (1S,3R)-ACPD (Kavalali et al., 1997), had no
effect on DSI; and, finally, (3) reported mGluR effects on VDCCs are strictly dependent on the presence of GTP, or GTP S, in the recording electrode. Omitting GTP from our pipette solution decreased the magnitude of G-protein-dependent responses (Pitler and Alger, 1994).
Nevertheless, the (1S,3R)-ACPD reduction of DSI
in the absence of pipette GTP was not altered (n = 4;
data not shown). Thus the effect of (1S,3R)-ACPD
cannot be ascribed to any apparent action on postsynaptic VDCCs in
CA1 pyramidal cells. In view of its strong suppressant effect on IPSCs,
it seems most likely that (1S,3R)-ACPD occludes
DSI by reducing IPSCs by a presynaptic inhibition of GABA release,
although there are other possibilities.
Other similarities between
(1S,3R)-ACPD-induced IPSC suppression
and DSI
The previous data are consistent with a role for glutamate and
mGluR in DSI. To test the hypothesis further, we examined other properties of mGluR-induced IPSC suppression. DSI can be reduced by
250-300 µM NEM (Morishita et al., 1997) and by bath
application of the K+ channel blocker 4-AP, 50 µM (Alger et al., 1996). If an mGluR mediates the signal
for DSI, then NEM and 4-AP should reduce the (1S,3R)-ACPD-induced IPSC suppression. From the
actions of mGluR1 agonists and the lack of effect of DCG-IV in CA1, we
infer that the actions of (1S,3R)-ACPD are on
group I mGluRs in CA1. A limited-duration application (10 min) of NEM,
250 µM, blocked DSI at a time when IPSC amplitudes were
increased over control values, as previously reported. NEM also
consistently antagonized the effects of
(1S,3R)-ACPD on IPSCs (control IPSC suppression
by (1S,3R)-ACPD, 56 ± 10.6%; IPSC
suppression by (1S,3R)-ACPD in NEM, 6 ± 3.3%; n = 6; p < 0.01) (Figure
7A). NEM effects were not
reversible over the time course of our experiments (Morishita et al.,
1997). The (1S,3R)-ACPD-induced suppression of
IPSCs and DSI (Fig. 7B1) was reversed by 4-AP, and 4-AP reduced DSI of evoked IPSCs (Fig. 7B2)
(control DSI, 38 ± 4%; 4-AP DSI, 11 ± 2.9%;
n = 6), as previously reported (Alger et al.,
1996).
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Figure 7.
Agents that block DSI also block
(1S,3R)-ACPD-induced depression of evoked
monosynaptic IPSCs. A, N-ethylmaleimide
(NEM; duration of application is indicated by the
solid line) blocks IPSC suppression induced by
iontophoretic application of (1S,3R)-ACPD
(open arrows). Below the current trace
are IPSCs recorded before (Pre-ACPD) and after
(ACPD) iontophoresis of
(1S,3R)-ACPD at the indicated time points
before (CONTROL) and during (NEM)
application of NEM. B1,
(1S,3R)-ACPD-induced depression of IPSCs
is blocked by 4-aminopyridine (4-AP; duration of
application is denoted by the solid line). IPSCs shown
below the continuous trace were taken at the indicated
time points. 4-AP induced large spontaneous inward currents (e.g.,
filled diamond), presumed to be GABAD
responses (Perrault and Avoli, 1992). B2, 4-AP
blocks DSI of evoked IPSCs. IPSCs below the continuous
trace were taken before (Pre-DSI) and after
(DSI) the depolarizing steps at the indicated
time points. Individual IPSCs in A and B
are averages of five consecutive IPSCs. Iontophoresis of
(1S,3R)-ACPD (25 mM) in
A and B1 was accomplished by a
155 nA, 2 sec current. Large spontaneous inward currents in
B2 are truncated to fit the figure.
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|
DSI does not affect the normal paired-pulse depression (PPD) of IPSCs
that is present at a 200 msec interstimulus interval (Alger et al.,
1996; Morishita and Alger, 1997a). (1S,3R)-ACPD, 50 µM, reduced IPSCs by 56 ± 4.7%, and yet PPD,
which was 77 ± 2.8% in control, was 81 ± 6.9% during
(1S,3R)-ACPD application (Fig.
8, p = 0.5;
n = 7). Thus (1S,3R)-ACPD, like
DSI, reduced IPSC amplitude, but it did not alter PPD.
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Figure 8.
(1S,3R)-ACPD does
not significantly alter paired-pulse depression of evoked monosynaptic
IPSCs. A1, Continuous trace illustrating the
effects of bath-applied (1S,3R)-ACPD
(duration of application is indicated by the solid bar)
on paired-pulse depression (PPD) of IPSCs. Pairs of IPSCs were elicited
every 5 sec with an interstimulus interval of 200 msec.
Below the continuous trace are IPSCs elicited by the
first (filled circle) and second (open
circle) stimulus of the paired-pulse stimulation recorded at
the indicated time points. In the right records the
traces at 1 and 2 are overlapped (offset
for ease of comparison) after the first IPSC in 2 was
scaled up to match the amplitude of the first IPSC in 1.
Note that the ratio of second to first IPSCs does not change in
(1S,3R)-ACPD. A2,
Plots generated from the experiment in A1
illustrating the amplitudes of IPSCs arising from the first
(filled circles) and second (open
circles) stimulus and corresponding PPD ratio (IPSC2/IPSC1,
filled triangles). B, Average PPD ratio
obtained from seven cells recorded in control and then in the presence
of (1S,3R)-ACPD. The IPSCs illustrated in
A1 are averaged from five consecutive IPSC
pairs.
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|
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DISCUSSION |
We examined the general hypothesis that glutamate, or an analog,
might, via activation of an mGluR, act as a retrograde signal to
suppress IPSCs in hippocampal DSI. Our data do not support the
hypothesis that group II mGluRs mediate CA1 DSI (cf. Glitsch et al.,
1996). This was not surprising, because there is little evidence that
mGluR2 exists in CA1 (Shigemoto et al., 1997), and mGluR3 mRNA
expression is low (Testa et al., 1994). We confirmed that, although
active in CA3 (cf. Poncer et al., 1995; Morishita and Alger, 1997b),
DCG-IV does not depress monosynaptic evoked IPSCs or mIPSCs in CA1
(Gereau and Conn, 1995a), and we found that neither DCG-IV nor low
concentrations of L-CCG-I affected DSI. Forskolin, which
blocks cerebellar DSI (Glitsch et al., 1996), had no effect on CA1
DSI.
Both group I and group III mGluR agonists suppressed IPSCs; however,
only group I agonists occluded DSI, suggesting that only they mimic the
DSI mechanism. MSOP and M-AP4, effective group III antagonists, did not
block DSI. Moreover, because group III mGluRs reduce cAMP, as do group
II receptors, the results of Glitsch et al. (1996) also suggest that
forskolin should have reduced CA1 DSI if L-AP4-sensitive
receptors had been involved.
Gereau and Conn (1995a) reported that L-AP4 blocked only
polysynaptic, but not monosynaptic, IPSCs in CA1. In our hands
L-AP4 consistently reduced IPSCs in CNQX and APV, even when
adenosine was added to suppress glutamate release and further prevent
the activation of polysynaptic IPSCs. The differences in results
probably are explained by the activation of different interneurons in
the two studies.
(S)-MCPG, a weak competitive mGluR antagonist,
reduced DSI in a dose-dependent way. The efficacy of
(S)-MCPG in blocking PI hydrolysis either produced by
expressed group I mGluRs (Brabet et al., 1995) or measured in brain
tissue (Littman and Robinson, 1994) depends on the agonist and is
greater when (1S,3R)-ACPD, rather than glutamate,
is used. We found that (S)-MCPG was more potent in
reversing (1S,3R)-ACPD-induced IPSC reduction
than in reducing DSI. Indeed, Littman and Robinson (1994) show that 3 mM (S)-MCPG reduced
L-glutamate-induced PI hydrolysis in hippocampal tissue
suspensions by only ~20%, in good agreement with our data on DSI.
Although (S)-MCPG antagonizes both group I and group
III mGluRs (Manzoni et al., 1995) the evidence against group III mGluR involvement makes a role for group I mGluRs in DSI more likely. Alternatively, an undefined mGluR subtype could mediate the inhibition of interneurons. The signal could be a glutamate analog, and not glutamate itself. In any case, the block of DSI by
(S)-MCPG suggests that a glutamate-like substance
plays a role.
Additional tests of the mGluR hypothesis were based on previously
established properties of DSI that should be duplicated by any putative
DSI signal in CA1. The candidate mechanism should (1) not affect mIPSCs
(Pitler and Alger, 1994; Alger et al., 1996), (2) be blocked by agents
that block G-proteins, such as pertussis toxin (Pitler and Alger, 1994)
or NEM (Morishita et al., 1997), (3) be reduced by bath application of
50 µM 4-AP, and (4) not alter PPD (Alger et al., 1996;
Morishita and Alger, 1997a). As assessed by these criteria, mGluR
activation is a candidate mechanism for DSI induction. The
K+ channel blocker 4-AP reversed the depressant
action of (1S,3R)-ACPD on CA1 IPSCs and decreased
DSI. [4-AP prevents the trans-ACPD-induced depression of EPSCs in
cortical neurons (Sladeczek et al., 1993), suggesting that 4-AP
sensitivity may be a general property of mGluR-mediated synaptic
depression.] The sulfhydryl alkylating agent, NEM, enhances IPSCs and
abolishes DSI (Morishita et al., 1997), and NEM abolishes the
depressant action of (1S,3R)-ACPD on IPSCs,
implying that G-proteins are involved in both responses (cf. Shapiro et
al., 1994).
(1S,3R)-ACPD, like DSI, reduced IPSCs without
affecting PPD of IPSCs, whereas many mechanisms that reduce transmitter
release do affect PPD (Davies et al., 1990; Misgeld et al., 1995; Alger et al., 1996) by altering the probability of transmitter release by the
first pulse according to the inverse relationship between probability
of release by the first and second pulses of a pair (Martin, 1977).
When evoked GABA release is decreased by substituting Sr2+ for extracellular Ca2+, PPD
changes to paired- pulse facilitation (PPF) (Morishita and Alger,
1997a). Neither PPD nor Sr2+-induced PPF changed
during DSI; thus the DSI process does not lower the probability of
release at presynaptic terminals as other agents do. Baskys and Malenka
(1991) found that (1S,3R)-ACPD enhanced paired-pulse EPSC facilitation while depressing EPSCs, raising the
possibility that (1S,3R)-ACPD may suppress
glutamate and GABA release via different mechanisms, although the
effect on EPSCs was present only in young animals (<30 d).
Barnes-Davies and Forsythe (1995) reported that
(1S,3R)-ACPD reduced EPSCs at the calyx of Held
in rat auditory brainstem slices without affecting PPF or the
presynaptic action potential. Subsequently, Takahashi et al. (1996)
showed that (1S,3R)-ACPD reduced
Ca2+ entry into the calyx. It recently has been
reported that a DSI-like process occurs in a dissociated hippocampal
cell culture (Ohno-Shosaku et al., 1998). Despite having many
similarities to DSI in the hippocampal slice, DSI in tissue culture
altered the paired-pulse ratio. Why some forms of presynaptic
inhibition alter paired-pulse release and others do not is unknown. In
CA1, mGluR activation and DSI are similar in this regard, however.
Activation of mGluR can reduce voltage-dependent
Ca2+ currents (Lester and Jahr, 1990; Sahara and
Westbrook, 1993; Takahashi et al., 1996). DSI is dependent on
Ca2+ influx into the pyramidal cell through
voltage-dependent Ca2+ channels (Lenz et al., 1997),
and thus mGluR agonists could reduce DSI by decreasing postsynaptic
Ca2+ influx. On the other hand, the mGluR-induced
inhibition of Ca2+ currents is dependent on
postsynaptic G-proteins (Lester and Jahr, 1990; Sahara and Westbrook,
1993), and neither the (1S,3R)-ACPD-induced IPSC
reduction nor occlusion of DSI requires GTP in the recording electrode.
Thus mGluR effects on DSI probably are not caused by a reduction in
Ca2+ influx, although we cannot rule out a
contribution of this mechanism.
If a group I mGluR is involved in DSI and
(1S,3R)-ACPD-induced IPSC suppression, it is more
likely to be mGluR5 than mGluR1. Expression of mGluR1 mRNA in CA1 is
low (Testa et al., 1994) and antibody staining for mGluR1 is confined
to a discrete group of interneurons near the border of s. oriens and
the CA1 alveus, whereas expression of mGluR5 mRNA is very high and
antibody staining is dense and widely distributed in CA1.
(S)-MCPG was somewhat less potent in blocking
mGluR5a-induced than mGluR1a-induced PI hydrolysis in LLC-PKI cells
when glutamate was the agonist (Brabet et al., 1995); when
(1S,3R)-ACPD was the agonist,
(S)-MCPG was very effective at both receptors. In
contrast, 4CPG was a potent antagonist of
(1S,3R)-ACPD actions only on mGluR1a-, not
mGluR5a-, mediated effects; thus the combination of
(1S,3R)-ACPD and 4CPG can distinguish between
mGluR1a and mGluR5. Because IPSC suppression by
(1S,3R)-ACPD was blocked by
(S)-MCPG, but not by 4CPG, mGluR5 receptors may
inhibit GABA release in CA1.
Results of ultrastructural labeling studies have been inconsistent
regarding the localization of group I mGluRs, with one study finding
evidence for axonal localization of group I mGluRs (Romano et al.,
1995) and the other not (Shigemoto et al., 1997). If group I mGluRs are
not present on or near inhibitory nerve terminals, the group I mGluRs
known to exist on the somata and dendrites of the interneurons could be
responsible for the effects we report.
Implications of mGluR involvement in DSI
The hypothesis that glutamate acting via mGluRs is the retrograde
signal in hippocampal CA1 DSI can explain some puzzles. In cerebellum
there are two types of DSI (Alger and Pitler, 1995). One acts on
TTX-insensitive mIPSCs; the other is blocked when TTX is applied.
Because TTX blocks CA1 DSI, we infer that DSI in CA1 and the second
form of cerebellar DSI are identical. We suggest that glutamate, or an
analog, could be the universal DSI messenger. The different types of
DSI would be determined by the classes of mGluR on the interneurons and
the effector mechanisms to which they are coupled. The group II mGluRs
would be linked to the cAMP-dependent mechanism, which can block even
TTX-insensitive mIPSCs. The mGluRs hypothetically responsible for CA1
DSI instead would be linked to other mechanisms such that only
TTX-sensitive release processes are affected.
A simple model for our results is that glutamate, released from
pyramidal cell somatic-dendritic regions, acts directly on interneurons. Lledo et al. (1998) report that a
vesicle-fusion-dependent process presumably in pyramidal cell
somatic- dendritic regions is required for LTP. If glutamate were
packaged in vesicles in the dendrites, then this process also could be
involved in DSI. Alternatively, glutamate also can be released from
glial cells (Barres, 1991; Parpura et al., 1994) and affect neuronal
neurotransmitter release via mGluRs (Arague and Haydon, 1997). An
unknown signal from pyramidal cells could induce glutamate release from
glial cells or the numerous glutamate-containing terminals of nearby excitatory fibers and mediate DSI indirectly. It will be important to
test these implications of the mGluR hypothesis for DSI.
| |
FOOTNOTES |
Received Feb. 6, 1998; revised April 10, 1998; accepted April 16, 1998.
This work was supported by National Institutes of Health Grants NS30219
and NS22010 to B.E.A. We thank E. Elizabeth for expert typing and
editorial assistance. We also thank F. Le Beau, R. Lenz, S. Mason, L. Martin, and N. Varma for their comments on a draft of this
manuscript.
W.M. and S.A.K. contributed equally to this work.
Correspondence should be addressed to Dr. B. E. Alger, Department
of Physiology, University of Maryland School of Medicine, 655 West
Baltimore Street, Baltimore, MD 21201.
Dr. Kirov's present address: Children's Hospital, Department of
Neurology, Harvard Medical School, 300 Longwood Avenue, Room 211, Boston, MA 02115.
| |
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Top
Abstract
Introduction
