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The Journal of Neuroscience, July 15, 2001, 21(14):4943-4948
G q-Deficient Mice Lack Metabotropic Glutamate
Receptor-Dependent Long-Term Depression But Show Normal Long-Term
Potentiation in the Hippocampal CA1 Region
Thomas
Kleppisch1,
Viktor
Voigt1,
Rüdiger
Allmann1, and
Stefan
Offermanns2
1 Institut für Pharmakologie und Toxikologie,
Technische Universität München, 80802 München,
Germany, and 2 Pharmakologisches Institut, Abteilung
Molekulare Pharmakologie, Universität Heidelberg, 69120 Heidelberg, Germany
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ABSTRACT |
Long-term potentiation (LTP) and depression (LTD) are potential
cellular mechanisms involved in learning and memory. Group I
metabotropic glutamate receptors (mGluR), which are linked to heterotrimeric G-proteins of the Gq family (Gq
and G11), have been reported to facilitate both
hippocampal LTP and LTD. To evaluate their functional role in synaptic
plasticity, we studied LTD and LTP in the CA1 region of the hippocampus
from wild-type, G q( /), and G11(/)
mice. Basic parameters of the synaptic transmission were not altered in
Gq(/) and G11(/) mice. Moreover,
these mice showed normal LTP in response to a strong tetanus and to a
weak tetanus. However, LTD induced either by a group I mGluRs agonist
or by paired-pulse low-frequency stimulation (PP-LFS) was absent in
Gq(/) mice. Moreover, PP-LFS caused potentiation of
the synaptic transmission in these mice that was not affected by the
NMDAR antagonist AP-5. These results show that Gq plays a
crucial role in the mGluR-dependent LTD, whereas hippocampal LTP is not
affected by the lack of a single member of the Gq family.
Key words:
synaptic plasticity; hippocampus; metabotropic glutamate
receptor; GTP-binding protein; gene targeting; mouse
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INTRODUCTION |
Long-term potentiation (LTP) and
long-term depression (LTD) represent potential cellular mechanisms of
learning and memory (Bliss and Collingridge, 1993 ; Manahan-Vaughan and
Braunwell, 1999). Both forms of synaptic plasticity depend critically
on a rise in intracellular Ca2+ (Bear and
Malenka, 1994; Zucker, 1999). In the CA1 region, the Ca2+ increase results largely from
NMDAR-mediated influx (Morris et al., 1986; Dudek and Bear, 1992;
McHugh et al., 1996). Metabotropic glutamate receptors (mGluRs) have
emerged as another important element in synaptic plasticity (for
review, see Bortolotto et al., 1999).
A role of mGluRs was first implied by the finding that receptor
antagonists inhibit hippocampal LTP (Reymann and Matthies, 1989; Bashir
et al., 1993a). In view of contradicting reports (Manzoni et al., 1994;
Selig et al., 1995) (for review, see Bortolotto et al., 1999),
Bortolotto et al. (1994) suggested that the stimulation of mGluRs
activates intracellular signaling molecules supporting the induction of
LTP until their activity is reversed. Fitting with this scheme, LTP is
strengthened by prestimulating mGluRs (McGuiness et al., 1991; Otani et
al., 1993). Remarkably, selective activation of group I receptors is
sufficient to facilitate LTP in response to a weak tetanus (Cohen and
Abraham, 1996; Cohen et al., 1998). The function of class I mGluRs in
LTP is further emphasized by studies in mice lacking the
mGluR5 highly expressed in CA1 pyramidal cells
(Lujan et al., 1996). mGluR5-deficient mice show
an impairment of LTP confined to the NMDA receptor component of
synaptic transmission (Lu et al., 1997; Jia et al., 1998).
Similarly, LTD in the CA1 region is shown to exhibit a component
depending on the function of mGluRs (Bashir et al., 1993b; Manahan-Vaughan, 1997; Oliet et al., 1997; Nicoll et al., 1998; Otani
and Connor, 1998). Based on the effects of mGluR antagonists, Manahan-Vaughan (1997) suggested that LTD in the hippocampus requires synergistic activity of group I and II. Fitting with this idea, Overstreet et al. (1997) have reported that
(±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid, an
agonist of group I and II mGluRs, induces LTD in the CA1 region.
However, others have shown that mere stimulation of class I receptors
is sufficient to generate LTD in various regions of the hippocampus
(Palmer et al., 1997; Camodeca et al., 1999; Fitzjohn et al., 1999;
Huber et al., 2000).
Thus, there is compelling evidence that group I mGluRs play a
fundamental role in hippocampal synaptic plasticity. The group I
receptors mGluR1 and mGluR5
couple to G-proteins of the Gq family, Gq and G11, both expressed
in hippocampal pyramidal cells (Mailleux et al., 1992; Milligan, 1993;
Friberg et al., 1998; Tanaka et al., 2000). Like
mGluR5,
Gq/G11 are primarily
localized in the postsynaptic extrajunctional membrane (Tanaka et al.,
2000). The function of these G-proteins in hippocampal synaptic
plasticity remains elusive. To gain new insight, we analyzed LTP and
LTD in mice lacking Gq or
G11. Mutant mice exhibited normal LTP. However, mGluR-dependent LTD was absent in Gq
(/) mice showing a critical role of Gq in
this form of synaptic plasticity.
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MATERIALS AND METHODS |
Field EPSP recordings in hippocampal slices.
Transverse hippocampal slices (400 µm thick) from wild-type,
Gq(/) and
G11(/) mice were prepared, and field
EPSPs (fEPSPs) in the CA1 region were recorded as described
previously (Kleppisch et al., 1999). The stimulus intensity was
adjusted to elicit ~40-50% of the maximal fEPSP amplitude. LTP was
induced using either a relatively strong 100 Hz tetanus (3 × 30 pulses, 100 Hz, 5 sec pause between trains) or a weak theta burst
(10 × 4 pulses with 100 Hz, 200 msec pause between bursts) in
slices pretreated with the group I mGluR-selective agonist
3,5-dihydroxyphenylglycine (DHPG; 5 µM for 5 min) (Ito et al., 1992; Schoepp et al., 1994). LTD was induced either
by application of DHPG (50 µM for 5 min) or by
a paired-pulse low-frequency stimulation (600 or 900 pulse pairs with 1 or 3 Hz, interpulse interval 50 msec) adapted from a recently published
protocol (Kemp and Bashir, 1997; Huber et al., 2000). The strength of
synaptic transmission was assessed through the fEPSP slope. LTP and LTD were expressed as percentage of the fEPSP during the baseline recording. All data shown for the time course of the fEPSP slope are
mean ± SEM. Statistical analysis was performed using the
Student's t test for two independent means. p
values of <0.05 were considered significant.
Animals. Gq(/) and
G11(/) mice originated from a cross
between C57BL/6 mice and chimeras with a contributing 129/Sv background
that were established by means of the conventional gene-targeting
method (Offermanns et al., 1997a,b, 1998). The phenotype of
Gq(/) mice includes impaired motor
coordination and defective platelet activation, whereas
G11(/) mice have no overt dysfunction.
Therefore, homozygous offspring from Gq(+/) mice and a G11-deficient lineage was used in
the present study. To minimize a possible impact of the undefined
genetic background, we used littermates as control.
Immunoblotting. For Western analysis, hippocampal tissue
samples were homogenized, and cholate extracts were separated on 10%
SDS-polyacrylamide gel and blotted onto nitrocellulose membranes. The
blots were probed with an
Gq/2fG11 antibody
(Santa Cruz Biotechnology, Santa Cruz, CA) recognizing a common
epitope at the C terminus of Gq and
G11. Bound antibodies were detected using the
ECL technique (Amersham Pharmacia Biotech, Arlington Heights, IL).
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RESULTS |
Gq is the predominant G-protein of the Gq
family expressed in the murine hippocampus
Gq has been reported to represent the
dominating subtype in the rat hippocampus (Milligan, 1993). The
expression of the Gq family members
Gq and G11 in the murine
hippocampus was studied by immunoblotting tissue extracts from
wild-type G11(/) and Gq(/) mice with a common
Gq/G11 specific
antibody. For the wild type, two bands were detected: one at 43 kDa
corresponding to the G11 subunit and a second
more prominent corresponding to the Gq subunit
with a slightly lower apparent molecular weight than
G11 (Fig. 1,
central lane). These data show that Gq
is the principal form of the Gq family expressed
in the murine hippocampus. The identity of the
Gq/11 bands was confirmed using immunoblots of
hippocampal extracts from G11(/) and
Gq(/) animals. These blots yielded only
single bands corresponding to the remaining G-protein -subunit (Fig.
1, left and right lanes). Remarkably, the
concentration of G11 was not altered in the
hippocampus of Gq(/) mice compared with
the wild type.
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Figure 1.
Gq is the predominant form of the
Gq family members expressed in the murine hippocampus.
Immunoblots with hippocampal tissue using a common antibody against the
C terminus of Gq and G11. Lanes were
loaded with protein extracts from the hippocampus of wild-type
(central), G11(/)
(left), and Gq(/)
(right) mice, respectively.
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Mice lacking Gq or G11 exhibit normal
synaptic transmission in the CA1 region
Gq(/) and
G11(/) mice had no gross anatomical
abnormalities in the brain, and the cellular layers in the hippocampus were regularly arranged (data not shown). To evaluate whether the gene
deletions resulted in an universal defect of synaptic transmission, we
examined the dependency of the fEPSP amplitude on the stimulus
intensity (I-O relation) and the paired-pulse facilitation
(PPF). The I-O relation in the two mutants,
Gq(/) and
G11(/), was not significantly different
from that observed in the wild type (Fig.
2A). The PPF represents
a second important control parameter of the synaptic transmission, in
particular of the presynaptic function. Mice lacking
G11 or Gq exhibited normal PPF for interstimulus intervals ranging from 25 to 275 msec
(Fig. 2B). Thus, the fundamental characteristics of
the synaptic transmission were not altered in the mutant mice.
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Figure 2.
Mice deficient in Gq and
G11 exhibit normal I-O relation and PPF.
A, Shown is the relationship between the stimulation
intensity (input) ranging from 20 to 200 µA and the corresponding
fEPSP slope (output) for slices from wild-type ( ;
n = 18 slices), Gq(/) ( ;
n = 17 slices), and G11(/) ( ;
n = 15 slices) animals. All points represent the
mean ± SEM fEPSP in the corresponding genotype. B,
PPF was studied for paired-pulse intervals in the range from 25-275
msec. Illustrated are the mean ± SEM of PPF as percentage for the
wild type (; n = 14 slices),
Gq(/) (; n = 13 slices), and
G11(/) (; n = 13). The
inset shows representative fEPSP recordings for the
three genotype as indicated. Calibration: 50 msec, 0.5 mV.
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Mice lacking G11 or Gq show normal
LTP in the hippocampal CA1 region
Mice lacking the mGluR5 coupling to
Gq/11 exhibit impaired LTP in the CA1 region (Lu
et al., 1997; Jia et al., 1998). Initially, we studied the effect of
Gq or G11 deficiency
on LTP in the Schaffer collateral pathway using a relatively strong 100 Hz tetanus similar to that used in the study with
mGluR5-deficient mice. Under these conditions,
LTP was not significantly altered in the Gq(/) and in the
G11(/) mice compared with the wild type (Fig. 3). The fEPSP slopes 1 hr after
tetanus for the three genotypes were 134.8 ± 7.0% (wild type,
n = 8 slices), 129.0 ± 8.4%
(Gq(/), n = 9 slices), and
139.5 ± 3.9% (G11(/),
n = 8 slices) of the pretetanus control. Similarly, as
described for group I mGluRs, the functional relevance of
Gq/11 in LTP might depend on the tetanization strength (cf. Wilsch et al., 1998; Balschun et al., 1999). Therefore, we additionally tested a weak theta burst stimulation (10 × 4 pulses). Again, LTP induced with the theta burst was not different in
the wild type (127.5 ± 6.5%; n = 8 slices), the
Gq(/) (125.2 ± 6.4%;
n = 8 slices), and the
G11(/) mice (126.3 ± 6.9%;
n = 9 slices) (Fig. 4).
Thus, mice lacking Gq or
G11 do not show defective LTP in the CA1
region of the hippocampus.
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Figure 3.
LTP induced by a strong tetanus is normal in
Gq(/) and G11(/) mice. Average
potentiation of the fEPSP slope in slices from wild-type (;
n = 7 slices), Gq(/) (;
n = 9 slices), and G11(/) (;
n = 10 slices) animals after a 100 Hz tetanus
(3 × 30 pulses) indicated by the arrow. The fEPSP
slope was normalized to the mean fEPSP slope during the baseline
previous tetanization. Representative fEPSP recordings for the three
genotypes are shown in the inset. Calibration: 0.5 mV,
10 msec.
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Figure 4.
LTP induced by a weak theta burst is not altered
in Gq(/) and G11(/) mice. Average
potentiation of the fEPSP slope after a weak theta burst (10 × 4 pulses) in slices from wild-type (; n = 8),
Gq(/) (; n = 8), and
G11(/) (; n = 9) animals. The
fEPSP slope was normalized to the mean fEPSP slope during the baseline
previous application of the theta burst indicated by the
arrow. Representative fEPSP recordings for the three
genotypes are shown in the inset. Calibration: 0.5 mV,
10 msec.
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mGluR-dependent LTD is absent in the hippocampal CA1 region of mice
lacking Gq
The temporary inhibition of the fEPSP slope caused by DHPG was
less pronounced in the Gq(/) mice (data
not shown), suggesting a possible functional role in depression of
synaptic transmission. In view of the reports that selective group I
mGluR agonists including DHPG induce LTD, the effect of DHPG on the
fEPSP slope was studied in more detail. Therefore, a saturating
concentration of DHPG (50 µM) was transiently applied (5 min) to the slices from matched wild-type,
Gq(/), and
G11(/) mice (cf. Huber et al., 2000). As
demonstrated in Figure 5A,
DHPG induced LTD in the wild-type and
G11(/) mice with no difference between the
two genotypes. The fEPSPs slopes 50 min after treatment with DHPG
amounted to 77.0 ± 4.4% (wild type, n = 17 slices) and 83.1 ± 3.9% (G11(/), n = 16 slices) of the control baseline
(p > 0.05). In contrast to the
G11(/) mice,
Gq-deficient animals exhibited a complete loss
of DHPG-induced LTD (Fig. 5B), although the initial
transient inhibition of the synaptic transmission induced by DHPG was
reduced only partially. The long-lasting depression of the synaptic
transmission was reflected in the corresponding fEPSP slopes 50 min
after wash-out of DHPG amounting to 72.5 ± 5.4% (wild type,
n = 18 slices) and 101.3 ± 5.1%
(Gq(/), n = 17 slices) of
the baseline (p < 0.01). These findings clearly
indicate a role of Gq for the LTD in the hippocampal CA1 region. To substantiate this notion, we examined synaptic plasticity after paired-pulse low-frequency stimulation (PP-LFS) (Fig. 6). Hippocampal slices
from wild-type and G11(/) mice showed LTD
in response to a 1 Hz PP-LFS. The fEPSP slopes 50 min after application
were 88.9 ± 3.7% (wild type, n = 8 slices) and
89.9 ± 4.0% (G11(/),
n = 10 slices) of the baseline in control
(p > 0.05). Analogous to LTD induced by the
group I mGluR agonist DHPG, LTD after 1 Hz PP-LFS was absent in
hippocampal slices from Gq(/)
(p < 0.05). Moreover, the synaptic transmission in the Gq(/) mice was potentiated
(111.4 ± 5.6%; n = 9 slices). Two forms of
activity-dependent LTD coexist in the hippocampus, a mGluR- and a
NMDAR-mediated form. To further differentiate between the role of
Gq in these two forms, we blocked NMDARs with
AP-5 (50 µM). The fEPSP slopes 40 min after the
1 Hz PP-LFS amounted to 87.9 ± 3.3% (wild type,
n = 12 slices) and 118.7 ± 2.5%
(Gq(/), n = 9 slices)
(p < 0.05) (Fig.
7) of the control baseline. Thus, under
these conditions, hippocampal preparations from wild-type mice
exhibited significant LTD in response to a 1 Hz PP-LFS, whereas the
synaptic transmission in slices from Gq(/)
mice was again potentiated (Fig. 7).
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Figure 5.
LTD induced by stimulation of mGluR group I is
normal in slices from G11(/) mice but abolished in
slices from Gq(/) mice. Slices were treated with the
mGluR group I agonist DHPG (50 µM) for 5 min to induce
LTD. Shown is the time course of the fEPSP slope in slices from the
wild-type (; n = 17 slices) versus
G11(/) (; n = 15 slices)
(A) and the wild-type (; n = 18) versus Gq(/) (; n = 17)
(B) animals, respectively. Representative fEPSP
recordings for the genotypes as indicated are shown in the
corresponding insets. Calibration: 10 msec, 0.5 mV.
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Figure 6.
Low-frequency stimulation causes LTP instead of
LTD in Gq(/) mice. Shown is the time course of the
average fEPSP slope after 600 pulse pairs at 1 Hz (PP-LFS) in slices
from wild-type (; n = 8 slices),
Gq(/) (; n = 9 slices), and
G11(/) (; n = 10 slices)
animals. Representative fEPSP recordings for the different genotypes in
control (black) and 50 min after PP-LFS
(gray) are shown in the
inset. Calibration: 20 msec, 0.5 mV.
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Figure 7.
Altered synaptic plasticity of the
Gq(/) mice after low-frequency stimulation does not
depend on NMDAR function. Shown is the time course of the average fEPSP
slope after 900 pulse pairs at 1 Hz (PP-LFS) in slices from wild-type
(; n = 12 slices) and Gq(/)
(; n = 9 slices) animals. AP-5 (50 µM) was present throughout all experiments.
Representative fEPSP recordings in control (black) and
40 min after PP-LFS (gray) are shown in
the inset. Calibration: 20 msec, 0.5 mV.
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DISCUSSION |
Heptahelical mGluRs play an important role in synaptic plasticity
(for review, see Bortolotto et al., 1999). For example, LTP and LTD in
the hippocampus are facilitated by group I mGluRs (Palmer et al., 1997;
Cohen et al., 1998; Fitzjohn et al., 1999; Camodeca et al., 1999; Huber
et al., 2000). Individual elements in the signal transduction of these
receptors supporting the long-term changes of synaptic transmission
remain to be established. According to the general scheme, the effects
of group I mGluR are mediated by G-proteins of the
Gq family stimulating  -isoforms of
phospholipase C (PLC). It has been reported recently that in the
hippocampal CA3 region group I mGluRs can also signal independently of
G-proteins (Heuss et al., 1999). Here, we studied the functional role
of Gq/11 in hippocampal synaptic plasticity using
the model of mice carrying a null mutation of the
Gq and G11 gene,
respectively. These mice had no overt morphological abnormalities of
the brain and showed the normal arrangement of hippocampal cellular
layers. In addition, basic parameters of the synaptic transmission
(I-O relation and PPF) in the CA1 region were not altered.
Similar to expression data reported previously for the rat (Milligan,
1993), immunoblots demonstrated clearly that Gq
is the predominant form of this family expressed in the murine
hippocampus (Fig. 1). Expression of G11 in the
Gq-deficient mice was not altered compared
with the wild type, arguing against a possible compensatory
upregulation. A recent study also shows that within the mouse brain,
Purkinje and hippocampal pyramidal cells display the maximum expression
of Gq mRNA (Tanaka et al., 2000). The two
G-proteins Gq and G11
colocalize with the mGluR5, the major subtype
expressed in the CA1 region, at extrajunctional regions in pyramidal
cell dendrites (Mailleux et al., 1992; Lujan et al., 1996;
Tanaka et al., 2000), further supporting the view that perisynaptic stimulation of group I mGluR is mediated through these G-proteins.
Lu et al. (1997) reported that mice lacking the
mGluR5 exhibit reduced Schaffer collateral LTP
after four trains of a 100 Hz stimulation that is confined to the
NMDAR-dependent component. However, a 100 Hz tetanus induced equivalent
LTP in the wild-type, G11(/), and
Gq(/) mice (Fig. 3). In the same way as
reported for group I mGluRs (Wilsch et al., 1998; Balschun et al.,
1999), the functional relevance of Gq/11 in LTP
might be limited with the 100 Hz tetanus and become more prominent with
weak tetanization. However, LTP induced with a weak theta burst
stimulation (10 × 4 pulses) was also not altered in the
Gq(/) and
G11(/) mice (Fig. 4). It has been reported
that prestimulation of group I mGluRs facilitates LTP in the
hippocampal CA1 region of the rat through a PLC-dependent mechanism
(Cohen et al., 1998). However, pretreatment of mouse slices according
to the protocol of Cohen et al. (1998) only slightly increased LTP
(~15%) compared with the control. Again, no difference between the
wild-type, Gq-, and
G11-deficient mice could be observed under
these conditions (data not shown). Our data may suggest that LTP can be
supported by both Gq and
G11. This could be tested rigorously in mice
lacking the -subunits of both Gq and
G11. Unfortunately, a double mutant generated by
conventional gene targeting is not viable (Offermanns et al., 1998).
Alternatively, we cannot exclude that group I mGluRs support LTP in a
way independent of both G-proteins (cf. Heuss et al., 1999). Such a
mechanism could underlie the specific defect of the NMDA receptor
component of the fEPSP in mGluR5-deficient mice
(Lu et al., 1997).
In contrast to LTP, a significant part of LTD, which represents another
important form of synaptic plasticity in the hippocampus, was found to
be associated with the function of Gq. LTD in the CA1 region can be induced through direct stimulation of group I mGluRs
(Palmer et al., 1997; Fitzjohn et al., 1999) and by LFS (Bear and
Abraham, 1996; Kemp and Bashir, 1997; Huber et al., 2000). DHPG-induced
LTD was completely eliminated in Gq(/) mice but remained intact in G11(/) mice
(Fig. 5). It is generally thought that the members of group I, mGluR1
and mGluR5, couple to both Gq and
G11 without discriminating (Conn and Pin,
1997). However, our data show that these two G-proteins are not
generally redundant in their synaptic function. Whereas both
Gq and G11 might support a
function of group I mGluRs in LTP, their function in LTD correlates
with a signaling through Gq (but not through G11). Interestingly,
Gq(/), but not
G11(/) mice, exhibit defects in other
regions of the CNS (Offermanns et al., 1997a). The mechanisms
underlying this selectivity remain unclear. As recently shown, mGluR
class I-dependent LTD in the CA1 region requires a rapid postsynaptic
translation of pre-existing dendritic mRNA (Huber et al., 2000), which
might suggest that Gq regulates the neuronal
protein synthesis through a yet unknown mechanism.
LFS-induced LTD is more complex consisting of two mechanistically
separate components inhibited by antagonists of NMDA and mGlu
receptors, respectively (Dudek and Bear, 1992; Oliet et al., 1997;
Nicoll et al., 1998). LFS-induced LTD in the
Gq(/) mice was, therefore, expected to be
reduced just partially. Interestingly, a 1 Hz paired-pulse LFS, while
generating significant LTD in the wild-type and the
G11(/) mice, caused weak LTP in mice
lacking Gq (Fig. 6). Moreover, the NMDAR
antagonist AP-5 had no effect on PP-LFS-induced LTD in the wild type,
and Gq(/) mice again showed LTP in
response to 1 Hz paired-pulse LFS in the presence of AP-5 (Fig. 7).
Therefore, changes in NMDAR function are obviously not involved in the
conversion of LTD into slight LTP observed in mice lacking
Gq. Altered synaptic plasticity in the
G11(/) mice may result from unmasking
alternative signaling mechanisms mediated neither by
Gq-coupled receptors nor by NMDA receptors.
Besides the sustained depression, DHPG caused a pronounced short-term
depression (STD) of the synaptic transmission that reversed rapidly
after wash-out. It has been described recently that the selective mGluR
antagonist LY 341495 eliminates LTD but does not block completely this
transient inhibition induced by DHPG (Huber et al., 2000). Similar to
this observation, STD, unlike LTD, was reduced only partially in the
Gq knock-out mice (Fig. 5). STD was not
affected in the G11(/) animals. These
results might reflect that LTD and STD depend on different signaling
mechanisms or that the two G-proteins, Gq and
G11, can at least in part substitute each other
functionally in STD. In summary, our data show that LTP in the CA1
region of the hippocampus is intact despite a deficiency of
Gq or G11. However,
the loss of Gq abolished the mGluR-dependent component of LTD in the hippocampal CA1 region.
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FOOTNOTES |
Received Jan. 10, 2001; revised March 26, 2001; accepted March 28, 2001.
This research was supported by grants from Bundesministerium für
Bildung und Forschung, Fonds der Chemischen Industrie, and the
Deutsche Forschungsgemeinschaft.
Correspondence should be addressed to Dr. Thomas Kleppisch, Institut
für Pharmakologie und Toxikologie, Biedersteiner Straße 29, 80802 München, Germany. E-mail:
kleppisch{at}ipt.med.tu-muenchen.de.
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REFERENCES |
-
Balschun D,
Manahan-Vaughan D,
Wagner T,
Behnisch T,
Reymann KG,
Wetzel W
(1999)
A specific role for group I mGluRs in hippocampal LTP and hippocampus-dependent spatial learning.
Learn Mem
6:138-152[Abstract/Free Full Text].
-
Bashir ZI,
Bartolotto ZA,
Davies CH,
Beretta N,
Irving AJ,
Seal AJ,
Henley JM,
Jane DE,
Watkins JC,
Collingridge GL
(1993a)
Induction of LTP in the hippocampus needs synaptic activation of glutamate metabotropic receptors.
Nature
363:347-350[Medline].
-
Bashir ZI,
Jane DE,
Sunter DC,
Watkins JC,
Collingridge GL
(1993b)
Metabotropic glutamate receptors contribute to the induction of long-term depression in the CA1 region of the hippocampus.
Eur J Pharmacol
239:265-266[ISI][Medline].
-
Bear MF,
Abraham WC
(1996)
Long-term depression in hippocampus. Long-term depression in hippocampus.
Annu Rev Neurosci
19:437-462[ISI][Medline].
-
Bear MF,
Malenka RC
(1994)
Synaptic plasticity: LTP and LTD.
Curr Opin Neurobiol
4:389-399[Medline].
-
Bliss TVP,
Collingridge GL
(1993)
A synaptic model of memory: long-term potentiation in the hippocampus.
Nature
361:31-39[Medline].
-
Bortolotto ZA,
Bashir ZI,
Davies CH,
Collingridge GL
(1994)
A molecular switch activated by metabotropic glutamate receptors regulates induction of long-term potentiation.
Nature
368:740-743[Medline].
-
Bortolotto ZA,
Fitzjohn SM,
Collingridge GL
(1999)
Roles of glutamate receptors in LTP and LTD in the hippocampus.
Curr Opin Neurobiol
9:299-304[ISI][Medline].
-
Camodeca N,
Breakwell NA,
Rowan MJ,
Anwyl R
(1999)
Induction of LTD by activation of group I mGluR in the dentate gyrus in vitro.
Neuropharmacology
38:1597-1606[ISI][Medline].
-
Cohen AS,
Abraham WC
(1996)
Facilitation of long-term potentiation by prior activation of metabotropic glutamate receptors.
J Neurophysiol
76:953-962[Abstract/Free Full Text].
-
Cohen AS,
Raymond CR,
Abraham WC
(1998)
Priming of long-term potentiation induced by activation of metabotropic glutamate receptors coupled to phopholipase C.
Hippocampus
8:160-170[ISI][Medline].
-
Conn PJ,
Pin JP
(1997)
Pharmacology and functions of metabotropic glutamate receptors.
Annu Rev Pharmacol Toxicol
37:205-237[ISI][Medline].
-
Dudek SM,
Bear MF
(1992)
Homosynaptic long-term depression in area CA1 hippocampus and effects of N-methyl-D-aspartate receptor blockade.
Proc Natl Acad Sci USA
89:4363-4367[Abstract/Free Full Text].
-
Fitzjohn SM,
Kingston AE,
Lodge D,
Collingridge GL
(1999)
DHPG-induced LTD in area CA1 of juvenile rat hippocampus: characterization and sensitivity to novel mGlu receptor antagonists.
Neuropharmacology
38:1577-1583[ISI][Medline].
-
Friberg IK,
Young AB,
Standaert DG
(1998)
Differential localization of the mRNAs for the pertussis toxin insensitive G-protein alpha sub-units Gq, G11 and Gz in the rat brain, and regulation of their expression after striatal deafferentation.
Mol Brain Res
54:298-310[Medline].
-
Heuss C,
Scanziani M,
Gähwiler BH,
Gerber U
(1999)
G-protein-independent signaling mediated by metabotropic glutamate receptors.
Nat Neurosci
2:1070-1077[ISI][Medline].
-
Huber KM,
Kayzer MS,
Bear MF
(2000)
Role for rapid dentritic protein synthesis in hippocampal mGluR-dependent long-term depression.
Science
288:1254-1256[Abstract/Free Full Text].
-
Ito I,
Kohda A,
Tanabe S,
Hirose E,
Hayashi M,
Mitsunaga S,
Sugiyama H
(1992)
3,5-Dihydroxyphenylglycine: a potent agonist of metabotropic glutamate receptors.
NeuroReport
3:1013-1016[ISI][Medline].
-
Jia Z,
Lu Y,
Henderson J,
Taverna F,
Romano C,
Abramow-Newerly W,
Wojtowicz JM,
Roder J
(1998)
Selective abolition of the NMDA component of long-term potentiation in mice lacking mGluR5.
Learn Mem
5:331-343[Abstract/Free Full Text].
-
Kemp N,
Bashir ZI
(1997)
NMDA receptor-dependent and -independent long-term depression in the CA1 region of the adult rat hippocampus in vitro.
Neuropharmacology
36:397-399[ISI][Medline].
-
Kleppisch T,
Pfeifer A,
Klatt P,
Ruth P,
Montkowski A,
Fässler R,
Hofmann F
(1999)
Long-term potentiation in the hippocampal CA1 region of mice lacking cGMP-dependent kinase is normal and susceptible to inhibition of nitric oxide synthase.
J Neurosci
19:48-55[Abstract/Free Full Text].
-
Lu YM,
Jia Z,
Janus C,
Henderson JT,
Gerlai R,
Wojtowicz JM,
Roder JC
(1997)
Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP.
J Neurosci
17:5196-5205[Abstract/Free Full Text].
-
Lujan R,
Nusser Z,
Roberts JDB,
Shigemoto R,
Somogyi P
(1996)
Perisynaptic location of metabotropic glutamate receptors mGluR1 and mGluR5 on dendrites and dendritic spines in the rat hippocampus.
Eur J Neurosci
8:1488-1500[ISI][Medline].
-
Mailleux P,
Mitchell F,
Vanderhaegen JJ,
Milligan G,
Erneux C
(1992)
Immunohistochemical distribution of neurons containing the G-proteins Gq/G11 in the adult brain.
Neurosci
51:311-316[ISI][Medline].
-
Manahan-Vaughan D
(1997)
Group 1 and 2 metabotropic glutamate receptors play differential roles in hippocampal long-term depression and long-term potentiation in freely moving rats.
J Neurosci
17:3303-30311[Abstract/Free Full Text].
-
Manahan-Vaughan D,
Braunwell K-H
(1999)
Novelty acquisition is associated with induction of hippocampal long-term depression.
Proc Natl Acad Sci USA
96:8739-8744[Abstract/Free Full Text].
-
Manzoni OJ,
Weisskopf MG,
Nicoll RA
(1994)
Metabotropic glutamate receptors inhibiting excitatory synapses in the CA1 area of rat hippocampus.
Eur J Neurosci
6:1050-1054[ISI][Medline].
-
McGuiness N,
Amwyl R,
Rowan M
(1991)
Trans-ACPD enhances long-term potentiation in the hippocampus.
Eur J Pharmacol
197:231-232[ISI][Medline].
-
McHugh TJ,
Blum KI,
Tsien JZ,
Tonegawa S,
Wilson MA
(1996)
Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mice. Impaired hippocampal representation of space in CA1-specific NMDAR1 knock-out mice.
Cell
87:1339-1349[ISI][Medline].
-
Milligan G
(1993)
Regional distribution and quantitative measurement of the phosphoinositidase C-linked guanine nucleotide binding proteins G11 and Gq in rat brain.
J Neurochem
61:845-851[ISI][Medline].
-
Morris RG,
Anderson A,
Lynch GS,
Baudry M
(1986)
Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP-5.
Nature
319:774-776[Medline].
-
Nicoll RA,
Oliet SHR,
Malenka RC
(1998)
NMDA receptor-dependent and metabotropic glutamate receptor-dependent forms of long-term depression coexist in CA1 hippocampal pyramidal cells.
Neurobiol Learn Mem
70:62-72[ISI][Medline].
-
Offermanns S,
Hashimoto K,
Watanabe M,
Sun W,
Kurihara H,
Thompson RF,
Inoue Y,
Kano M,
Simon MI
(1997a)
Impaired motor coordination and persistent multiple climbing fiber innervation of cerebellar Purkinje cells in mice lacking Gq.
Proc Natl Acad Sci USA
94:14089-14094[Abstract/Free Full Text].
-
Offermanns S,
Toombs CF,
Hu YH,
Simon MI
(1997b)
Defective platelet activation in Gq-deficient mice.
Nature
389:183-186[Medline].
-
Offermanns S,
Zhao LP,
Gohla A,
Sarosi I,
Simon MI,
Wilkie TM
(1998)
Embryonic cardiomyocyte hypoplasia and craniofacial defects in G alpha a/G alpha 11-mutatnt mice.
EMBO J
17:4304-4312[ISI][Medline].
-
Oliet SHR,
Malenka RC,
Nicoll RA
(1997)
Two distinct forms of long-term depression coexist in CA1 hippocampal pyramidal cells.
Neuron
18:969-982[ISI][Medline].
-
Otani S,
Connor JA
(1998)
Requirement of rapid Ca2+ entry and synaptic activation of metabotropic glutamate receptors for the induction of long-term depression in adult rat hippocampus.
J Physiol (Lond)
511:761-770[Abstract/Free Full Text].
-
Otani S,
Ben-Ari Y,
Roisin-Lallemand MP
(1993)
Metabotropic receptor stimulation coupled to weak tetanus leads to long-term potentiation and a rapid elevation of cytosolic protein kinase activity.
Brain Res
613:1-9[ISI][Medline].
-
Overstreet LS,
Pasternak JF,
Colley PA,
Slater NT,
Trommer BL
(1997)
Metabotropic glutamate receptor mediated long-term depression in developing hippocampus.
Neuropharmacology
36:831-844[ISI][Medline].
-
Palmer MJ,
Irving AJ,
Seabrook GR,
Jane DE,
Collingridge GL
(1997)
The group I mGlu receptor agonist DHPG induces a novel form of LTD in the CA1 region of the hippocampus.
Neuropharmacology
36:1517-1532[ISI][Medline].
-
Reymann KG,
Matthies H
(1989)
2-Amino-4-phosphonobutyrate selectively eliminates late phases of long-term potentiation in rat hippocampus.
Neurosci Lett
98:166-171[ISI][Medline].
-
Schoepp DD,
Goldsworthy J,
Johnson BG,
Salhoff CR,
Baker SR
(1994)
3,5-Dihydroxyphenylglycine is a highly selective agonist for phosphoinositide-linked metabotropic glutamate receptors in the rat hippocampus.
J Neurochem
63:769-772[ISI][Medline].
-
Selig DK,
Lee HK,
Bear MF,
Malenka RC
(1995)
Reexamination of the effects of MCPG on hippocampal LTP, and depotentiation.
J Neurophysiol
74:1075-1082[Abstract/Free Full Text].
-
Tanaka J,
Nakanawa S,
Kushiya E,
Yamasaki M,
Fukaya M,
Iwanaga T,
Simon MI,
Sakimura K,
Kano M,
Watanabe M
(2000)
Gq protein subunits G7q and G711 are localized at the postsynaptic extra-junctional membrane of cerebellar Purkinje cells and hippocampal pyramidal cells.
Eur J Neurosci
12:781-792[ISI][Medline].
-
Wilsch VW,
Behnisch T,
Jäger T,
Reymann KG,
Balschun D
(1998)
When are class I glutamate receptors necessary for long-term potentiation?
J Neurosci
18:6071-6080[Abstract/Free Full Text].
-
Zucker RS
(1999)
Calcium- and activity-dependent synaptic plasticity.
Curr Opin Neurobiol
9:305-313[ISI][Medline].
Copyright © 2001 Society for Neuroscience 0270-6474/01/21144943-06$05.00/0
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