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The Journal of Neuroscience, November 1, 2000, 20(21):7871-7879
Activation of Metabotropic Glutamate Receptor 5 Has Direct
Excitatory Effects and Potentiates NMDA Receptor Currents in Neurons of
the Subthalamic Nucleus
Hazar
Awad1, 3,
George W.
Hubert2, 4, 5,
Yoland
Smith2, 5,
Allan I.
Levey2, and
P. Jeffrey
Conn1
Departments of 1 Pharmacology and
2 Neurology, Graduate Programs in 3 Molecular
and Systems Pharmacology and 4 Neuroscience, and
5 Yerkes Regional Primate Research Center, Emory University
School of Medicine, Atlanta, Georgia 30322
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ABSTRACT |
The subthalamic nucleus (STN) is a key nucleus in the
basal ganglia motor circuit that provides the major glutamatergic
excitatory input to the basal ganglia output nuclei. The STN plays an
important role in normal motor function, as well as in pathological
conditions such as Parkinson's disease (PD) and related disorders.
Development of a complete understanding of the roles of the STN in
motor control and the pathophysiological changes in STN that underlie
PD will require a detailed understanding of the mechanisms involved in regulation of excitability of STN neurons. Here, we report that activation of group I metabotropic glutamate receptors (mGluRs) induces
a direct excitation of STN neurons that is characterized by
depolarization, increased firing frequency, and increased burst-firing activity. In addition, activation of group I mGluRs induces a selective
potentiation of NMDA-evoked currents. Immunohistochemical studies at
the light and
electron microscopic levels indicate that both subtypes
of group I mGluRs (mGluR1a and mGluR5) are localized postsynaptically
in the dendrites of STN neurons. Interestingly, pharmacological studies suggest that each of the mGluR-mediated effects
is attributable to activation of mGluR5, not mGluR1, despite the
presence of both subtypes in STN neurons. These results suggest that
mGluR5 may play an important role in the net excitatory drive to the
STN from glutamatergic afferents. Furthermore, these studies raise the
exciting possibility that selective ligands for mGluR5 may provide a
novel approach for the treatment of a variety of movement disorders
that involve changes in STN activity.
Key words:
metabotropic glutamate receptor; subthalamic
nucleus; basal ganglia; Parkinson's disease; burst firing; NMDA
receptor; mGluR1; mGluR5
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INTRODUCTION |
The basal ganglia (BG) are a set of
subcortical nuclei that play a critical role in motor control and are a
primary site of pathology in a number of movement disorders, including
Parkinson's disease (PD), Tourette's syndrome, and Huntington's
disease. Recent studies reveal that a key nucleus in the BG motor
circuit, the subthalamic nucleus (STN), plays an especially important
role in BG function. The STN is an excitatory glutamatergic nucleus in
the BG and provides the major excitatory input to the BG output nuclei,
the substantia nigra pars reticulata (SNr) and the internal globus
pallidus. Normal motor function requires an intricate balance between
excitation of the output nuclei by glutamatergic neurons from the STN
and inhibition of the output nuclei by GABAergic projections from the
striatum (for review, see Wichmann and DeLong, 1997 ).
Interestingly, recent studies suggest that the major pathophysiological
change that occurs in response to loss of nigrostriatal dopamine
neurons in PD patients is an increase in activity of STN neurons.
The resultant increase in synaptic excitation of GABAergic projection
neurons in the output nuclei leads to a "shutdown" of
thalamocortical projections and produces the motor impairment characteristic of PD (DeLong, 1990). Conversely, hyperkinetic disorders
such as Huntington's disease (Reiner et al., 1988; Albin et al., 1990)
and Tourette's syndrome (Albin et al., 1989; Leckman et al., 1997) are
associated with decreases in STN activity. These discoveries have led
to a major interest in development of novel strategies to treat these
disorders by altering neuronal STN activity or STN-induced excitation
of BG output nuclei. Interestingly, surgical lesions (Bergman et al.,
1990; Aziz et al., 1991; Guirdi et al., 1996) and high-frequency
stimulation of the STN (Benazzouz et al., 1993; Limousin et al.,
1995a,b) are highly effective in treatment of PD. Development of a
detailed understanding of the mechanisms involved in regulation of STN
activity could lead to development of novel therapeutic agents that
alter STN activity without surgical intervention.
Recent studies suggest that metabotropic glutamate receptors (mGluRs)
play an important role in regulating excitability of neurons in a wide
variety of brain regions, including BG structures (Conn and Pin, 1997).
If mGluRs are involved in regulating excitation of STN neurons, this
could provide a critical component of regulation of STN activity by
glutamatergic afferents. Thus, it will be important to
determine whether mGluRs are postsynaptically localized in these
neurons and whether activation of mGluRs alters STN activity. To date,
eight mGluR subtypes have been cloned from mammalian brain and are
classified into three major groups based on sequence homologies, second
messenger coupling, and pharmacological profiles (for review, see Conn
and Pin, 1997). Group I mGluRs (mGluR1 and mGluR5) couple primarily to
Gq, whereas group II (mGluR2 and mGluR3) and
group III mGluRs (mGluRs 4, 6, 7, and 8) couple to
Gi/Go. We now report that
activation of the group I mGluR mGluR5 has a dramatic excitatory effect
and selectively increases NMDA receptor currents in STN neurons.
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MATERIALS AND METHODS |
Slice preparation for electrophysiology. Experiments
were performed in STN neurons from 10- to 14-d-old Sprague Dawley rats. Rats were decapitated, the brains were removed, and a block of tissue
containing the STN was isolated on ice. The tissue was mounted and
immersed in an oxygenated sucrose-artificial CSF (ACSF) solution
containing (in mM): 3 KCl, 1.9 MgSO4,
1.2 KH2PO4, 2 CaCl2, 187 sucrose, 20 glucose, 26 NaHCO3, 0.5 pyruvate, and 0.005 glutathione, equilibrated with 95% O2 and 5%
CO2, pH 7.4. Saggital slices (300 µm) were
prepared using a manual VibroSlice (Stoelting, Chicago, IL) and then
incubated at room temperature in ACSF containing (in mM):
124 NaCl, 2.5 KCl, 1.3 MgSO4, 1 NaH2PO4, 2 CaCl2, 20 glucose, 26 NaHCO3, 0.5 pyruvate, and 0.005 glutathione,
equilibrated with 95% O2 and 5%
CO2, pH 7.4. In experiments requiring potassium channel blockade the ACSF had the following composition (in
mM): 105.4 NaCl, 19.6 NaOAc, 2.5 KCl, 1.3 MgCl2, 0.1 CaCl2, 0.1 CdCl2, 2 BaCl2, 6 CsCl, 20 glucose, 26 NaHCO3, 3 4-aminopyridine (4-AP), and
25 tetraethylammonium-Cl.
Electrophysiological recordings. After a 2 hr incubation,
the slices were transferred to a recording chamber mounted on the stage
of an Olympus Optical (Tokyo, Japan) microscope and continuously perfused at 1-2 ml/min with oxygenated ACSF containing 50 µM picrotoxin and 0.5 µM tetrodotoxin
(except when firing was studied). Recordings were made with visualized
patch-clamp techniques using Nomarski optics with a water immersion
40× objective. Whole-cell patch-clamp recordings were made using patch
electrodes pulled from borosilicate glass on a Narishige (Tokyo, Japan)
vertical puller. Electrodes were filled with (in mM): 140 potassium gluconate, 10 HEPES, 10 NaCl, 0.2 EGTA, 2 MgATP, and 0.2 NaGTP. Internal solutions used in experiments requiring potassium
channel block contained 140 mM cesium methylsulfonate in
place of potassium gluconate. Signals were recorded using a Warner
PC-501A patch-clamp amplifier (Warner Instrument Corp., Hamden, CT) and
a pClamp data acquisition and analysis system (Axon Instruments, Foster
City, CA).
For measurement of NMDA and kainate-evoked currents, NMDA (100 µM-1 mM) with glycine (100 µM)
or kainate (100 µM) was pressure-ejected into the slice
from a low-resistance pipette using a Picospritzer (General Valve,
Fairfield, NJ) at pressures ranging from 5 to 20 psi and for durations
of 50-200 msec. Currents were recorded from a holding potential of
 60 mV. Slices were bathed in ACSF containing 0.5 µM
tetrodotoxin to block synaptic transmission. Agonists and antagonists
of mGluRs were then applied by bath infusion for 5 min. NMDA receptor
(NMDAR) and kainate receptor current amplitude was measured from
baseline to peak of the current.
Animal perfusion and preparation of tissue for
immunohistochemistry. Five male Sprague Dawley rats were deeply
anesthetized with ketamine (20 mg/kg) and transcardially perfused with
cold, oxygenated Ringer's solution followed by 500 ml of 4%
paraformaldehyde and 0.1% glutaraldehyde in phosphate buffer (PB, 0.1 M), pH 7.4, followed by 300 ml of cold PB. The brain was
removed from the skull and stored in PBS (0.01 M), pH 7.4, before being sliced on a vibrating microtome into 60 µm transverse
sections. These sections were then treated with 1.0% sodium
borohydride for 20 min and rinsed in PBS.
Immunohistochemistry. The sections were preincubated at room
temperature in a solution containing 10% normal goat serum (NGS), 1.0% bovine serum albumin (BSA), and 0.3% Triton X-100 in PBS for 1 hr. They were then transferred to solutions containing each of four
primary antibodies raised against synthetic peptides corresponding to
either the C terminus of mGluR1a (Chemicon, Temecula, CA) or to
residues 1116-1130 of mGluR1a (Dr. Carmelo Romano, Washington University School of Medicine, St. Louis, MO) or to the C terminus of
mGluR5 (Upstate Biotechnology, Lake Placid, NY; Dr. Carmelo Romano).
Antibodies were diluted at 0.5-1.0 mg/ml in a solution containing
1.0% NGS, 1.0% BSA, and 0.3% Triton X-100 in PBS. The tissue was
incubated in this solution overnight at room temperature. The sections
were rinsed in PBS and incubated for 1 hr at room temperature in a
secondary antibody solution containing biotinylated goat-anti-rabbit
IgGs (Vector Laboratories, Burlingame, CA) diluted 1:200 in the primary
antibody diluent solution. After rinsing, sections were put in a
solution containing 1:100 avidin-biotin-peroxidase complex (Vector).
The tissue was then washed in PBS and 0.05 M Tris buffer
before being transferred to a solution containing 0.01 M
imidazole, 0.0005% hydrogen peroxide, and 0.025% 3,3-diaminobenzidine tetrahydrochloride (DAB; Sigma, St. Louis, MO) in Tris for 7-10 min.
Sections were then mounted on gelatin-coated slides, dried, and
coverslipped with Permount.
For immunohistochemical analysis at the electron microscopic level, the
sections were treated with cryoprotectant for 20 min and transferred to
a 80°C freezer for an additional 20 min. The sections were then
thawed and treated with successively decreasing concentrations of
cryoprotectant and finally PBS. The immunocytochemical procedure was
the same as that used for studies at the light level, except that
Triton X-100 was not used, and the incubation in the primary antibody
was performed at 4°C for 48 hr. After DAB revelation, the sections
were processed for the electron microscope. They were first washed in
0.1 M PB for 30 min and then post-fixed in 1.0% osmium
tetroxide for 20 min. Afterward, they were washed in PB and dehydrated
by a series of increasing concentrations of ethanol (50, 70, 90, and
100%). Uranyl acetate (1.0%) was added to the 70% ethanol to enhance
contrast in the tissue. Next, the sections were exposed to propylene
oxide and embedded in epoxy resin (Durcupan; Fluka, Buchs, Switzerland)
for 12 hr. They were then mounted on slides, coverslipped, and heated
at 60°C for 48 hr.
Five blocks (three for mGluR1a and two for mGluR5) were cut from the
STN and mounted on resin carriers to allow for the collection of
ultrathin sections using an ultramicrotome (Ultracut 2; Leica, Nussloch, Germany). The ultrathin sections were collected on
single-slot copper grids, stained with lead citrate for 5 min to
enhance contrast, and examined on a Zeiss (Thornwood, NY) EM-10C
electron microscope. Electron micrographs were taken at 10,000 and
31,500× magnifications to characterize the nature of immunoreactive
elements in the STN.
Drugs. All drugs were obtained from Tocris Cookson (Ballwin,
MO), except that (+)-2-aminobicyclo[3.1.0]-hexane-2,6-dicarboxylate monohydrate (LY354740) was a gift from D. Schoepp and J. Monn (Eli
Lilly, Indianapolis, IN), methylphenylethynylpyridine (MPEP) and
7-hydroxyiminocyclopropan-[b]chromen-1a-carboxylic acid
ethyl ester (CPCCOEt) were gifts from R. Kuhn (Novartis, Basel,
Switzerland), and
(S)-(+)-2-(3'-carboxy-bicyclo[1.1.1]pentyl)-glycine
(CBPG) was purchased from Alexis (San Diego, CA). All other materials were obtained from Sigma.
Data analysis. Values are expressed as mean ± SEM.
Statistical significance was assessed using Student's t test.
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RESULTS |
Group I mGluRs mediate depolarization of STN neurons
Previous studies suggest that STN neurons express multiple mGluR
subtypes, including receptors belonging to each of the major groups of
mGluRs (groups I-III) (Testa et al., 1994, 1998; Bradley et al., 1998,
1999). We took advantage of highly selective agonists of each of the
mGluR groups to determine whether activation of these receptors has
effects on membrane properties of STN neurons. Unless otherwise stated,
all studies were performed in the presence of tetrodotoxin (TTX; 0.5 µM) to block action potential firing. The group I
mGluR-selective agonist 3,5-dihydroxyphenylglycine (DHPG)
(Schoepp et al., 1994) (100 µM) induced a robust
depolarization of STN neurons (17.1 ± 1.1 mV; p < 0.001; Fig. 1A,C)
that was accompanied by an increase in membrane input resistance (Fig. 1B). In voltage-clamp mode, this could be seen as an
inward current with an accompanying decrease in membrane conductance
(data not shown). DHPG-induced depolarization was seen in
23 of 24 cells, indicating a relatively homogeneous population of
neurons. The dose-response relationship for DHPG-induced
depolarization of STN neurons revealed an EC50 of
~30 µM (Fig. 1D), which is
consistent with the EC50 value of DHPG at
activation of group I mGluRs (Schoepp et al., 1994).
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Figure 1.
Group I mGluR-mediated depolarization of STN
neurons. A, Representative current-clamp traces of
membrane potential changes in response to DHPG (100 µM),
LY354740 (100 nM), and L-AP-4 (1 mM) from a holding potential of 60 mV. B,
Corresponding change in membrane input resistance accompanying the
change in membrane potential. C, Mean data ± SEM
of membrane potential changes, showing a significant depolarization by
the group I-selective agonist DHPG (**p < 0.001).
D, Dose-response curve of DHPG-mediated changes in
membrane potential.
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In contrast with DHPG, the group II selective mGluR agonist LY354740
(100 nM) (Monn et al., 1997) had no effect on membrane potential (Fig. 1A,C) or input resistance (Fig.
1B). Likewise, the group III-selective agonist
L(+)-2-amino-4-phosphonobutyric acid (L-AP-4)
(1 mM) (Conn and Pin, 1997) had no effect
on the membrane potential or input resistance of STN neurons when
examined in the presence of the NMDA receptor antagonists
D-AP-5 (20 µM) and
MK801 (10 µM) (Fig.
1A-C). L-AP-4 (1 mM) did induce a slight depolarization of STN
neurons when applied in the absence of NMDA receptor antagonists (data
not shown). This is consistent with previous reports that
L-AP-4 is a weak NMDA receptor agonist (Davies and Watkins, 1982).
In other neuronal populations, activation of group I mGluRs can induce
cell depolarization by inhibiting a leak potassium current
(Guérineau et al., 1994) or by increasing an inward cation current (Crépel et al., 1994; Guérineau et al., 1995; Pozzo Miller et al., 1995). The finding that the DHPG-induced depolarization or inward current in STN neurons is accompanied by a decrease in
membrane conductance suggests that this effect is more likely mediated
by inhibition of a leak potassium current. To determine whether the
DHPG-induced current has a reversal potential consistent with mediation
by inhibition of a potassium current, we performed an analysis of the
I-V relationship of the DHPG-induced current in
voltage-clamp mode. I-V relationships were determined in
the presence and absence of 100 µM DHPG by a
series of voltage steps ranging from 120 to 30 mV in increments of
10 mV. I-V plots were determined in a total of five cells.
A representative leak-subtracted I-V plot in the presence
and absence of DHPG (100 µM) is shown in Figure
2A. A subtraction of
the predrug I-V plot from that in the presence of DHPG
yielded an I-V plot of the DHPG-induced current alone (Fig.
2B). DHPG induced a net outward current at hyperpolarized potentials (greater than 80 mV) and an inward current
at potentials in the range of the resting potential (Fig. 2B). The reversal potential of the DHPG-induced
current is approximately 80 mV.
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Figure 2.
Ionic basis of DHPG-induced current.
A, Leak-subtracted I-V plot in normal
K+ conditions in the presence and absence of DHPG
(100 µM). B, Subtracted
I-V plot representing DHPG-induced current alone,
showing reversal potential of approximately 80 mV. C,
Representative leak-subtracted I-V plot in the presence
of potassium channel block and cesium. D, Subtracted
I-V plot representing DHPG-induced current alone,
showing reversal potential of 30 mV. E, Mean data ± SEM of DHPG-induced inward current amplitude (picoamperes) in
voltage-clamp mode in normal potassium conditions, potassium block and
cesium, and in the presence of cadmium (100 µM)
(**p < 0.01).
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A reversal potential in a hyperpolarized range coupled with the
reduction in membrane conductance is consistent with the hypothesis that DHPG-induced membrane depolarization is partially attributable to
inhibition of a leak potassium current. However, the reversal potential
is somewhat more depolarized than the predicted equilibrium potential
for potassium (105 mV). This, coupled with the nonlinear I-V curve of the DHPG-induced current, suggests that other
factors may also play a role in this membrane depolarization. In some other systems, group I mGluR activation can also activate inward cation
currents (Crépel et al., 1994; Guérineau et al., 1995; Pozzo Miller et al., 1995). It is possible that a similar effect occurs
in STN neurons. To determine whether the DHPG-induced current is solely
a potassium current, we performed ion substitution experiments. Voltage-clamp experiments were performed under conditions of potassium channel block by replacement of a K+ ion
with a Cs+ ion and inclusion of 4-AP and
tetraethylammonium in the external bathing solution.
DHPG-induced inward current amplitude at 60 mV was significantly
reduced (10.8 ± 2.3 pA; n = 6) compared with that
in control conditions (36.2 ± 8.1 pA; n = 4;
p < 0.01; Fig. 2E). However, the
current was not completely blocked, and the residual current is
probably mediated by ions other than potassium. Consistent with this,
the leak-subtracted I-V plot in the presence of potassium
channel block has a reversal potential of 30 mV and shows that DHPG
causes an inward current at potentials more negative than 30 mV and
outward current at potentials more positive than 30 mV
(n = 3; Fig. 2C,D).
The simplest interpretation of the data presented above is that DHPG
induces depolarization of STN neurons by actions on postsynaptically localized group I mGluRs. However, it is possible that DHPG acts by
inducing release of another neurotransmitter that then depolarizes STN
neurons. Because all of the studies presented above were performed in
the presence of TTX, it is unlikely that DHPG acts by increasing cell
firing and thereby increasing neurotransmitter release. However, this
does not rule out the possibility that DHPG directly depolarizes presynaptic terminals, which could lead to calcium influx and neurotransmitter release. To rule out this possibility, we performed experiments in the presence of cadmium (100 µM) in the
bathing solution to block Ca+ channel
activity. Consistent with an effective block of neurotransmitter release, this concentration of cadmium completely eliminated
EPSCs elicited in the STN by stimulation of the internal capsule
(data not shown). However, the amplitude of the DHPG-induced current was not significantly different than that seen in control (31.1 ± 6.9 pA; n = 4; Fig. 2E).
When measured in the absence of TTX, the DHPG-induced depolarization
was accompanied by a dramatic increase in action potential firing (Fig.
3A). This is consistent with a
recent report that group I mGluR agonists increase extracellular single
unit firing of STN neurons (Abbott et al., 1997). This increase in cell
firing was completely eliminated by hyperpolarizing current injection to hold the membrane potential at the predrug level (Fig.
3A). This suggests that the increase in firing frequency was
strictly attributable to the DHPG-induced depolarization rather than
being partially mediated by other changes in membrane properties that allow the cells to fire at a higher frequency. There was no effect of
DHPG on other membrane properties of the cell, including spike width,
spike amplitude, and the shape or amplitude of
afterhyperpolarizations (data not shown). However, DHPG did induce
an increase in the incidence of burst firing, a property of STN neurons
previously described by Beurrier et al. (1999) (Fig. 3B).
Oscillatory activity underlying burst firing was not seen in any of 15 cells examined at a resting potential of 60 mV before DHPG treatment
but was seen in 7 of 26 cells (~27%) during the DHPG-induced
depolarization. In the absence of TTX, oscillatory activity was
accompanied by burst firing (Fig. 3B). When studied in the
presence of TTX, the DHPG-induced oscillatory activity underlying burst
firing was seen, indicating that such activity may not be dependent on
synaptic transmission and may be an intrinsic membrane property of STN neurons (Fig. 3C). Furthermore, burst firing was not seen in
any cells treated with the group II agonist LY354740 (n = 6) or the group III mGluR agonist L-AP-4
(n = 9) when the cell membrane was held at 60 mV
before drug application.
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Figure 3.
Postsynaptic effects of group I mGluR activation
in STN neurons. A, Representative current-clamp traces
of firing rate before drug application (at 50 mV) and dramatic
increase in the presence of DHPG (100 µM) that is
countered by current injection to return membrane potential to the
predrug level. B, DHPG-mediated switch to burst-firing
mode (from a holding potential of 60 mV), which is countered by
hyperpolarizing current injection to maintain membrane potential at the
predrug level. C, DHPG-mediated membrane oscillations in
the presence of TTX are also countered by hyperpolarizing current
injection. Action potentials are truncated in A and
B. Scale bars in C also apply to
B.
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Group I mGluRs potentiate NMDA-evoked currents
The data presented above suggest that activation of group I mGluRs
can exert a direct excitatory effect on STN neurons that could
contribute to the overall excitatory drive to this important nucleus in
the BG motor circuit. In some other brain regions, activation of mGluRs
can also potentiate excitatory synaptic responses by potentiating
currents through glutamate-gated cation channels. To determine the
effects of mGluR agonists on the responses of STN neurons to activation
of ionotropic glutamate receptors, we used pressure-evoked application
of constant amounts of NMDA or kainate onto the cell. Stable baseline
NMDA- or kainate-evoked currents were obtained before perfusion of the
slice with mGluR agonists. Representative NMDA-evoked current traces
are shown before, during, and after mGluR agonist application (Fig.
4A). DHPG (100 µM) caused a reversible potentiation of
NMDA-evoked current amplitude (39.1 ± 9.2%; n = 10; p < 0.05; Fig. 4B). In contrast,
the group II- and group III-selective mGluR agonists LY354740 and
L-AP-4 had no effect on NMDA-evoked currents
(Fig. 4A,B). None of the group-selective mGluR
agonists had any effects on kainate-evoked currents in STN neurons
(Fig. 4C).
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Figure 4.
Activation of group I mGluRs potentiates
NMDA-evoked currents in STN neurons but has no effect on kainate-evoked
currents. A, Representative voltage-clamp traces of
NMDA-evoked currents in predrug, agonist, and wash conditions. Only the
group I-selective agonist caused a reversible potentiation of
NMDA-evoked currents. The group II and III agonists had no effect on
NMDA-evoked currents. B, Mean data ± SEM of
percent potentiation of NMDA-evoked currents by DHPG over predrug
current amplitude. DHPG caused a significant potentiation compared with
vehicle (*p < 0.05). C, Mean
data ± SEM of percent predrug kainate-evoked current amplitude
showing no difference compared with vehicle. D, Mean
data ± SEM of percent potentiation of NMDAR currents by DHPG in
normal K+ at 60 and 80 mV, cesium and potassium
channel block at 60 mV, and in the presence of
Cd2+ (100 µM).
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One concern that should be considered with studies of modulation of
NMDA-evoked currents in brain slices is that it is impossible to obtain
complete voltage control of the entire dendritic region of the STN
neurons. Thus, it is possible that DHPG-induced potentiation of the
NMDA-evoked current is attributable to depolarization of dendritic
regions in which we have not achieved adequate voltage control. If so,
the DHPG-induced depolarization may relieve the voltage-dependent
magnesium block of the NMDA receptor and thereby cause NMDA-evoked
currents to be potentiated. To test for this possibility, we performed
a series of experiments to determine the effect of DHPG on NMDA-evoked
currents under conditions in which the DHPG-induced depolarization is
blocked. First, experiments were performed in normal
K+ concentrations when holding at the
reversal potential of the DHPG-induced current (80 mV). Also, we
determined the effect of DHPG in the presence of conditions that block
voltage-dependent potassium channels and thereby reduce the
DHPG-induced depolarization. Under both conditions, DHPG-induced inward
current was either reduced or absent. In contrast, neither
manipulation significantly altered DHPG-induced potentiation of
NMDA-evoked currents (Fig. 4D). In addition,
experiments were performed in the presence of cadmium (100 µM) to ensure that the response was not caused
by calcium-dependent release of another neurotransmitter from
presynaptic terminals. As with the studies of DHPG-induced inward
currents, cadmium had no significant effect on DHPG-induced
potentiation of NMDA-evoked currents (Fig. 4D).
mGluR1 and mGluR5 are postsynaptically localized in
STN neurons
DHPG is an agonist at both mGluR1 and mGluR5, suggesting that
either of these mGluR subtypes could mediate the responses described above. We performed immunocytochemical studies with mGluR1a and mGluR5
antibodies at the electron microscopic level to determine whether both
of these receptors are localized at postsynaptic sites in STN neurons.
At the light microscopic level, the STN showed strong neuropil labeling
for mGluR1a and mGluR5 (Figs.
5A, 6 A). In general, the
immunoreactivity was found predominantly in dendritic processes, whereas the level of labeling in cell bodies was very low. In sections
immunostained for mGluR1a, labeled dendrites were found in the cerebral
peduncle (Fig. 5A), which is consistent with previous Golgi
studies showing that the dendrites of neurons located along the ventral
border of the STN extend ventrally into the cerebral peduncle (Iwahori,
1978; Afsharpour, 1985).
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Figure 5.
Immunostaining for mGluR1a in
the STN. A, Low-power light micrograph of mGluR1a in the
STN. B, C, High-power electron micrographs of
mGluR1a-immunoreactive dendrites (Den) that form
asymmetric synapses (arrowheads) with unlabeled
terminals. Note that the dendrite in B contains vesicles
(arrows). D, High-power electron
micrograph of mGluR1a-immunoreactive terminal that forms an asymmetric
synapse (arrowhead) with an immunoreactive dendrite.
CP, Cerebral peduncle. Scale bars: A, 500 µm; B-D, 0.5 µm.
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Figure 6.
Immunostaining for mGluR5 in
the STN. A, Low-power light micrograph of mGluR5
immunostaining in the STN. B, Low-power electron
micrograph of mGluR5-immunoreactive dendrites (Den).
C, High-power electron micrograph of a small
mGluR5-immunoreactive dendrite that forms an asymmetric synapse
(arrowhead) with the unlabeled terminal.
D, High-power electron micrograph of a large
mGluR5-immunoreactive dendrite that forms a symmetric synapse
(arrow) with an unlabeled terminal. The open
arrowhead points to a puncta adherentia. CP,
Cerebral peduncle. Scale bars: A, 500 µm;
B, 1 µm; C, D, 0.5 µm.
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To determine the exact nature of the immunoreactive neuronal elements,
we performed further analysis at the electron microscopic level. Both
antibodies primarily labeled dendritic processes, which formed
symmetric and asymmetric synapses with unlabeled axon terminals (Figs.
5B-D, 6B-D). In general, the labeling
was seen throughout the dendrites, instead of being associated
selectively with the plasma membrane (Figs. 5B-D,
6B-D). It is worth noting that such a pattern of
labeling was also detected for mGluR5 in the SNr using both immunogold
and immunoperoxidase techniques (Hubert and Smith, 1999). In addition
to dendrites, mGluR1a immunoreactivity was occasionally seen in a few
myelinated and unmyelinated axonal segments as well as a few axon
terminals (Fig. 5D). Cell bodies displayed light
intracytoplasmic labeling with either antibody.
Immunohistochemical studies were repeated with additional anti-mGluR1a
(Romano et al., 1996) and anti-mGluR5 (Reid et al., 1995; Romano et
al., 1995) antibodies and showed similar results confirming our
findings of the postsynaptic localization of both of these receptor
subtypes in the STN (data not shown). This is consistent with previous
in situ hybridization studies (Testa et al., 1994) as well
as studies of mGluR localization at the light level (Testa et al.,
1998).
Effects of DHPG in STN neurons are mediated by mGluR5
The postsynaptic localization of both mGluR1a and mGluR5 in STN
neurons suggests that either or both of these receptors could be
involved in mediating the effects of DHPG. We used newly available pharmacological tools that distinguish between these two group I mGluR subtypes to further characterize the group I-mediated effects
in STN. Interestingly MPEP (10 µM), a highly selective noncompetitive antagonist at mGluR5 (Bowes et al., 1999; Gasparini et
al., 1999), blocked DHPG-induced membrane depolarization (4.2 ± 0.27 mV; p < 0.001; n = 3; Fig. 7
A,B). In contrast, the
mGluR1-selective noncompetitive antagonist CPCCOEt (100 µM) (Annoura et al., 1996; Casabona et al.,
1997; Litschig et al., 1999), had no effect on DHPG-mediated
depolarization of STN neurons (18.8 ± 3.0 mV; n = 3; Fig. 7A,B) at concentrations that have been shown to be
effective at blocking mGluR1a in recombinant (Litschig et al., 1999)
and native (Casabona et al., 1997) systems. These data suggest that DHPG-induced depolarization of STN neurons is mediated by mGluR5 rather
than mGluR1. Consistent with this, CBPG (100 µM), a partial agonist of mGluR5 with mGluR1
antagonist activity (Mannaioni et al., 1999), mimics DHPG-induced
depolarization of STN neurons. As with DHPG, the response to CBPG is
blocked by MPEP but not by CPCCOEt (Fig. 7B).
View larger version (29K):
[in this window]
[in a new window]
|
Figure 7.
mGluR5 mediates group I mGluR-evoked
depolarization of STN neurons. A, Membrane potential
traces showing depolarization with DHPG (100 µM), which
is blocked by the mGluR5-selective antagonist MPEP (10 µM). Membrane depolarization is not blocked by the
mGluR1-selective antagonist CPCCOEt (100 µM).
B, Mean data ± SEM of change in membrane potential
showing a significant inhibition of DHPG-mediated depolarization of STN
neurons by MPEP (10 µM) compared with DHPG alone
(**p < 0.001). MPEP also significantly blocks
depolarization mediated by the mGluR5-selective agonist CBPG (100 µM) (*p < 0.05).
|
|
Pharmacological analysis of mGluR-mediated potentiation of NMDA
receptor currents suggests that this response is also mediated by
mGluR5. As with the depolarization, MPEP blocks DHPG-induced potentiation of NMDA-evoked currents (2.3 ± 3.2%;
p < 0.05; n = 5), whereas CPCCOEt is
without effect on this potentiation (44.2 ± 18.9%;
n = 6; Fig. 8
A,B).
View larger version (29K):
[in this window]
[in a new window]
|
Figure 8.
mGluR5 mediates group I mGluR-induced potentiation
of NMDA-evoked currents. A, Current traces of
NMDA-evoked currents before, during, and after application of DHPG (100 µM). The potentiation is blocked by MPEP (10 µM) but not CPCCOEt (100 µM).
B, Mean data ± SEM of percent potentiation of
NMDA-evoked currents by DHPG over predrug conditions. MPEP (10 µM) significantly blocks potentiation of NMDA-evoked
current compared with DHPG alone (*p < 0.05).
|
|
| |
DISCUSSION |
The data presented reveal that group I mGluRs are postsynaptically
localized on neurons in the STN and that activation of these receptors
leads to a direct depolarization of STN neurons. In most cells, the
DHPG-induced depolarization was accompanied by an increase in firing
frequency with no obvious effects on the recently characterized stable
oscillations of STN neuronal firing (Bevan and Wilson, 1999). However,
in approximately one-third of the cells examined, DHPG induced a switch
in the firing pattern from the characteristic single-spike firing mode
to a burst-firing mode that was recently characterized in detail by
Beurrier et al. (1999). In addition, DHPG induced a selective increase
in NMDA receptor currents in STN neurons. These combined effects of
group I mGluR activation could provide an important component of the
net excitatory drive elicited by activity of the major excitatory
afferents to the STN from the cortex or thalamus. However, it is
important to note that activation of group I mGluRs has also been shown
to induce presynaptic effects on glutamate release in some brain
regions (Gereau and Conn, 1995; Manzoni and Bockaert, 1995;
Rodriguez-Moreno et al., 1998). If group I mGluRs have similar effects
in the STN, the net effect of group I mGluR activation in this region
will ultimately depend on a combination of presynaptic and postsynaptic effects.
Immunohistochemistry studies revealed that both mGluR1a and mGluR5 are
postsynaptically localized in STN neurons. Interestingly, pharmacological analysis suggested that each of the responses studied
was mediated by mGluR5, with little or no contribution of mGluR1. This
finding suggests that although STN neurons contain both group I mGluR
subtypes, there is a segregation of function of these two receptors. It
is possible that mGluR1 also plays important roles in regulating STN
functions that were not measured in the present studies. Future studies
of the roles of mGluR1 in these cells may shed important light on the
functions of expression of multiple subtypes of closely related
receptors by a single neuronal population.
Implications of mGluR5 actions for treatment of PD
One of the most interesting implications of the finding that
mGluR5 is involved in regulating activity and NMDA receptor currents in
STN neurons is the possibility that antagonists of this receptor could
provide novel therapeutic agents that could be useful for treatment of
PD. Traditional dopamine replacement strategies for PD treatment tend
to lose efficacy over time, and patients begin to experience serious
adverse effects, including motor fluctuations (Poewe and Granata,
1997). Because of this, a great deal of effort has been focused on
developing a detailed understanding of the circuitry and function of
the BG in the hopes of developing novel therapeutic approaches for the
treatment of PD. Interestingly, a large number of animal and clinical
studies reveal that loss of nigrostriatal dopamine neurons results in
an increase in activity of the STN and that an increase in STN-induced
excitation of the output nuclei is ultimately responsible for the motor
symptoms of PD (for review, see DeLong, 1990; Wichmann and DeLong,
1997). These findings suggest that pharmacological agents that reduce the excitatory drive to the STN or otherwise reduce STN activity could
provide a therapeutic effect in PD patients.
The data reported here suggest that mGluR5 may be a particularly
interesting candidate as a receptor that could regulate STN output. Of
particular interest is the finding that mGluR5 activation increases
burst firing of STN neurons. For instance, previous studies suggest
that a transition of STN neurons from single-spike activity to a
burst-firing mode is one of the characteristics of parkinsonian states
in rats and nonhuman primates (Hollerman and Grace, 1992; Bergman et
al., 1994; Hassani et al., 1996) as well as parkinsonian patients
(Benazzouz et al., 1996; Rodriguez et al., 1997). The finding that
membrane oscillations underlying burst firing occur in the presence of
TTX is consistent with the findings of Beurrier et al. (1999) and
suggests that burst firing is, in part, an intrinsic property of STN
neurons. However, these data do not rule out the possibility that
synaptic mechanisms also participate in induction of burst firing
(Plenz and Kitai, 1999). Consistent with the hypothesis that group I
mGluRs can increase the output of STN in vivo, Kaatz and
Albin (1995) recently reported that injection of group I mGluR agonists
into the STN induces rotational behavior. Furthermore, Kronthaler and
Schmidt reported that
(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1996) and (25,35,45)- -carboxycyclopropyl glycine (1998),
agonists of both group I and group II mGluRs, induce catalepsy in rats. These effects are not mimicked by a highly selective agonist of group
II mGluRs (Marino et al., 1999b; Bradley et al., 2000), suggesting that
it is likely mediated by mGluRs belonging to group I. Taken together,
these findings raise the exciting possibility that mGluR5 antagonists
could reduce STN activity and thereby provide a therapeutic benefit to
PD patients.
For antagonists of group I mGluRs to be effective in the
treatment of PD, mGluR5 must be physiologically activated by endogenous glutamate release onto STN neurons from various
glutamatergic afferents. We made several attempts to elicit slow
mGluR-mediated synaptic responses using single-pulse stimuli as well as
stimulus trains of varying frequencies and durations. Unfortunately, we were unable to reliably elicit mGluR-mediated EPSPs or EPSCs in our
slices (our unpublished findings). Although disappointing, this
is not surprising, because mGluR-mediated slow EPSPs have also been
difficult to measure in other brain regions, except those in which
there is a laminar or other organization in which glutamatergic
afferent pathways are not severed by slice preparation. In addition to
severing afferent projections during slice preparation, mGluR-mediated
slow EPSPs are often difficult to measure because of the small size of
the events as well as the distance between the recording site in the
soma and the distal dendrites where the slow EPSP is likely generated.
Because of this, failure to measure a slow EPSP does not imply that
mGluRs are not synaptically activated in vivo. Also, we
often elicited slow EPSPs that were not blocked by antagonists of known
receptors and could have occluded an mGluR-mediated slow EPSP
(our unpublished findings). Ultimately, the question of whether
mGluR5 in the STN is activated by endogenous glutamate may require
in vivo electrophysiological and/or behavioral studies in
which mGluR5 antagonists are injected into this structure.
Potential therapeutic effects of mGluR5 agonist actions in
the STN
In addition to the potential utility of mGluR5 antagonists in
treatment of PD, it is important to point out that the actions of
mGluR5 agonists could provide a therapeutic benefit in some other motor
disorders, such as Tourette's syndrome and Huntington's disease.
Tourette's syndrome is a relatively common neuropsychiatric disorder
that is characterized by motor and phonic tics that can include sudden
repetitive movements, gestures, or utterances. According to current
models, Tourette's syndrome is associated with an increase in striatal
dopamine or in the dopamine sensitivity of striatal neurons that has
effects that are opposite of those seen in PD patients (Albin et al.,
1989; Leckman et al., 1997). Huntington's disease is another
hyperkinetic disorder that is thought to be caused by a selective loss
of striatal spiny neurons that gives rise to the indirect pathway and,
consequently, a decrease in STN activity (Reiner et al., 1988; Albin et
al., 1990). On the basis of this, it is possible that selective mGluR5
agonists could provide a therapeutic benefit to patients suffering from these hyperkinetic disorders by increasing activity of STN neurons.
Roles of group I mGluRs in other basal ganglia nuclei
Interestingly, agonists of group I mGluRs have actions in other
areas of the basal ganglia motor circuit that could complement their
actions in the STN. For instance, group I mGluRs, and especially mGluR5, are heavily localized in the striatum (Shigemoto et al., 1993;
Tallaksen-Greene et al., 1998), where agonists of these receptors
induce excitatory effects similar to those described here in the STN
(Calabresi et al., 1993; Colwell and Levine, 1994; Pisani et
al., 1997). Furthermore, recent behavioral studies reveal that
injection of group I mGluR agonists into the striatum induces turning
behavior that is accompanied by an increase in activity of neurons in
the STN and BG output nuclei (Sacaan et al., 1991, 1992; Kaatz and
Albin, 1995; Kearney et al., 1997). Group I mGluRs are also present in
the SNr (Hubert and Smith, 1999). Recent physiological studies from our
laboratory suggest that activation of these receptors has direct
excitatory effects and decreases evoked IPSCs (Marino et al., 1999a) in
SNr neurons. Taken together, these data suggest that group I mGluRs
function at multiple levels of the BG circuit to lead to a net increase
in activity of neurons in the output nuclei. Thus, in addition to the
STN, both antagonists and agonists of group I mGluRs could act at the
levels of the striatum and SNr to provide a therapeutic benefit in the
treatment of PD or hyperkinetic disorders, respectively.
| |
FOOTNOTES |
Received May 26, 2000; revised July 26, 2000; accepted Aug. 3, 2000.
This work was supported by grants from the National Institutes of
Health National Institute of Neurological Disorders and Stroke, the
Tourette's Syndrome Foundation, and the US Army Medical Research and
Material Command. We thank Dr. Carmelo Romano (Washington University)
for supplying anti-mGluR1a and anti-mGluR5 antibodies, Dr. Darryle
Schoepp and Dr. James Monn (Eli Lilly) for supplying LY354740, Dr.
Rainer Kuhn (Novartis) for supplying MPEP and CPCCOEt, and Stephanie
Carter for valuable technical assistance.
Correspondence should be addressed to Dr. P. Jeffrey Conn, Emory
University, Department of Pharmacology, Rollins Research Center, 1510 Clifton Road, Atlanta, GA 30322. E-mail: Pconn{at}emory.edu.
| |
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TOP
ABSTRACT
INTRODUCTION
