Department of Anatomy and Structural Biology, University of Otago, Dunedin, New Zealand
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Kerr, J.N.D. and J. R. Wickens. Dopamine D-1/D-5 Receptor Activation Is Required for Long-Term Potentiation in the Rat Neostriatum In Vitro. J. Neurophysiol. 85: 117-124, 2001. Dopamine and glutamate are key neurotransmitters involved in learning and memory mechanisms of the brain. These two neurotransmitter systems converge on nerve cells in the neostriatum. Dopamine modulation of activity-dependent plasticity at glutamatergic corticostriatal synapses has been proposed as a cellular mechanism for learning in the neostriatum. The present research investigated the role of specific subtypes of dopamine receptors in long-term potentiation (LTP) in the corticostriatal pathway, using intracellular recording from striatal neurons in a corticostriatal slice preparation. In agreement with previous reports, LTP could be induced reliably under Mg2+-free conditions. This Mg2+-free LTP was blocked by dopamine depletion and by the dopamine D-1/D-5 receptor antagonist SCH 23390 but was not blocked by the dopamine D-2 receptor antagonist remoxipride or the GABAA antagonist picrotoxin. In dopamine-depleted slices, the ability to induce LTP could be restored by bath application of the dopamine D-1/D-5 receptor agonist, SKF 38393. These results show that activation of dopamine D-1/D-5 receptors by either endogenous dopamine or exogenous dopamine agonists is a requirement for the induction of LTP in the corticostriatal pathway. These findings have significance for current understanding of learning and memory mechanisms of the neostriatum and for theoretical understanding of the mechanism of action of drugs used in the treatment of psychotic illnesses and Parkinson's disease.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Activity-dependent synaptic
plasticity is a widely used model for learning and memory mechanisms of
the brain (Bliss and Collingridge 1993). Although most
extensively studied in the hippocampus, activity-dependent synaptic
plasticity has also been described in several other brain areas
including the neostriatum. The neostriatum is a brain region involved
in certain types of learning including reward-related (Beninger
1983
) and motor (Graybiel 1995
) learning. It
receives inputs from all regions of the cerebral cortex
(McGeorge and Faull 1989
) via an extensive glutamatergic
projection (McGeer et al. 1977
). The neostriatum also
receives a major dopaminergic projection from the substantia nigra,
which terminates in close proximity to the corticostriatal inputs
(Smith et al. 1994
). A number of models have proposed
activity-dependent synaptic plasticity in the corticostriatal pathway
as a mechanism for learning-related functions of the neostriatum
(Beninger 1983
; Groves 1983
;
Miller 1981
; Wickens 1990
). These models
assume that synaptic plasticity in the corticostriatal pathway is
regulated by the dopamine inputs from the substantia nigra.
The corticostriatal pathway is of critical importance for the function
of the neostriatum. Corticostriatal inputs to the neostriatum synapse directly on the spiny projection neurons (Somogyi et al. 1981), which are the output neurons of the neostriatum
(Preston et al. 1980
). Thus the corticostriatal synapses
are the direct connection between the input and output of the
neostriatum. Furthermore the spiny projection neurons are relatively
quiescent, and their firing activity occurs in response to excitation
by cortical inputs (Wilson and Groves 1981
;
Wilson et al. 1983
). Thus the efficacy of the
corticostriatal synapse is a major determinant of the action potential
activity of the spiny projection neurons, and plasticity in these
synapses is a candidate mechanism for the learning functions of the neostriatum.
Both long-term potentiation (LTP) and long-term depression (LTD) have
been described in the corticostriatal pathway. LTD can be induced by
high-frequency stimulation (HFS) of the cortical afferents to the
neostriatum (Calabresi et al. 1992b; Lovinger et
al. 1993
; Wickens et al. 1996
, 1998
), and the
requirements for its induction have been extensively characterized
(Calabresi et al. 1992a
,b
, 1994
, 1995
). In contrast to
LTD, neostriatal LTP cannot be induced reliably by HFS in standard
solutions. It was first reported after HFS in slices bathed in
Mg2+-free fluid (Walsh 1991
). This
form of LTP was subsequently shown to be blocked by
N-methyl-D-aspartate (NMDA) receptor antagonists (Calabresi et al. 1992c
), suggesting that the unmasking
of LTP in Mg2+-free fluid was due to removal of
the voltage-dependent Mg2+ block of the NMDA
channels (Nowak et al. 1984
).
In addition to occurring in Mg2+-free conditions,
striatal LTP can be induced in normal bathing solutions if dopamine is
applied in pulses timed to coincide with cortical HFS (Wickens
et al. 1996). A similar phenomenon occurs in response to
substantia nigra stimulation in the intact animal (Reynolds and
Wickens 2000
) but not in dopamine-depleted animals, suggesting
that LTP can be induced under more physiological conditions and that it
is a dopamine-dependent phenomenon. There are also indications that
Mg2+-free LTP is blocked by chronic dopamine
depletion by 6-hydroxydopamine (Centonze et al. 1999
).
These findings suggest a possible link between the induction of
neostriatal LTP under Mg2+-free conditions and
LTP associated with endogenous dopamine release or direct application
of dopamine.
The present experiments used intracellular recording techniques to investigate the role of specific dopamine receptor subtypes in corticostriatal LTP. We report a stimulation protocol that reliably induces LTP of the corticostriatal pathway in Mg2+-free conditions. We also show that this form of LTP is blocked reliably by a dopamine D-1/D-5 receptor antagonist but not by a dopamine D-2 receptor antagonist or GABAA receptor antagonist. Finally, we show that LTP is prevented by dopamine depletion but can be restored by a dopamine D-1 receptor agonist.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Male Wistar rats (190-240 g) were deeply anesthetized with
ether and decapitated. The brain was quickly removed and chilled in
ice-cold artificial cerebrospinal fluid (ACSF, see following text).
After cooling for 3 min, the brain was removed from solution, the
hemispheres were separated, and a block of brain tissue was prepared by
sectioning one hemisphere in a horizontal plane 45° to the base of
the brain. The block containing the neostriatum and overlying cortex
was fixed to the stage of a Campden vibroslice, and 400-µm slices
were cut in which the cortex, neostriatum, and corticostriatal
connecting fibers were preserved (Arbuthnott et al.
1985; Kawaguchi et al. 1989
). Slices were
maintained at room temperature before being transferred to a recording
chamber in which they were superfused with ACSF containing (in mM) 124 NaCl, 2.5 KCl, 2.0 MgSO4, 2.5 CaCl2, 1.25 NaH2PO4, 26 NaHCO3, and 11 glucose that was gassed with 95%
O2-5% CO2 mixture and maintained at a
temperature of 35 ± 0.1°C (mean ± SD). During
slice preparation, an ACSF solution in which sucrose (248 mM) was
substituted for NaCl was used to maximize the yield of good impalements
(Aghajanian and Rasmussen 1989
). Slices were allowed to
equilibrate in the recording chamber for at least 1 h before use.
Intracellular records were obtained from neostriatal cells using glass
microelectrodes filled with 2 M potassium acetate solution (95-120
M). For inclusion in the study, cells were required to meet the
following criteria: resting membrane potential more negative than
80
mV and stable throughout the recording period (at least 50 min) without
use of holding current; action potential overshoot greater than 10 mV;
and, action potential onset delayed at least 50 ms from the onset of a
just-suprathreshold current pulse. Cells were rejected from the study
at the start of the experiment if they did not meet these criteria.
These criteria were adopted after extensive preliminary work had shown
that less stringent criteria resulted in greater variability in both
cellular properties and LTP. A total of 29 cells meeting these
inclusion criteria were used in the present study.
Electrophysiological traces were recorded using an Axoprobe 1A intracellular amplifier (Axon Instruments). Traces were digitized at a sampling rate of 10 kHz per channel using pClamp software (Axon Instruments) and saved to hard disk for analysis off-line. Postsynaptic potentials (PSPs) were evoked by stimulation of the deeper layers of the cortex and adjacent white matter (bipolar electrodes, monophasic constant current pulses, 0.1 ms, 150 µA max). Stimulus intensity was adjusted to give initial postsynaptic potential (PSP) amplitudes of 10-15 mV. After a 10-min baseline period in normal solution, perfusion was switched to a Mg2+-free solution. During exchange of Mg2+-free for normal solution, PSPs were recorded for 20 min by which time the PSP amplitude and waveform had stabilized. Thus recordings were made for at least 30 min before HFS.
The cortical stimulus current used during HFS was the same as that used for test pulses and thus was not a suprathreshold stimulus. To ensure a conjunction of both presynaptic activity and action potential firing of the postsynaptic cell, HFS of the cortex (trains of 50 pulses at 100 Hz repeated 6 times at 10-s intervals) was paired with depolarization of the postsynaptic neuron using an intracellular current pulse. Prior to HFS, the depolarizing current pulse for each cell was adjusted to an intensity that ensured action potential firing in response to cortical stimulation (520-ms pulse, 0.2-1.2 nA). Test responses were recorded for at least 20 min following HFS. No intracellular holding current was used to maintain the membrane potential, and cells were discarded if the membrane potential changed during the recording period. Only one cell per slice was used to avoid effects of prior HFS on synaptic plasticity.
Measurements of PSP peak amplitude and slope were made using in-house programs based on Axograph 2.0 software (Axon Instruments). Peak PSP values were measured from the resting membrane potential to the maximum depolarization during the PSP. The PSP slope was the maximum rate of rise, obtained from the maximum value of slope of the moving regression line fitted to eight consecutive sample points (corresponding to 0.8 ms) between onset and peak of the PSP.
Measurements of cellular properties (input resistance and action potential characteristics) were made shortly after impalement and repeated 10 min before and 20 min after HFS. Input resistance was determined from the slope of a regression line fitted to the membrane potentials produced by a series of subthreshold depolarizing current pulses. Threshold for action potential firing was defined as the point on the voltage trajectory at which the rate of depolarization exceeded 8 mV/ms. Action potential amplitude was defined as the difference between threshold and the peak of the action potential waveform. Action potential duration was measured at the voltage midway between threshold and peak potentials. The amplitude of the afterhyperpolarization potential (AHP) was defined as the difference between threshold and the minimum of the hyperpolarization that followed each action potential. Threshold was used as the baseline for AHP measurements rather than resting membrane potential because the equilibrium potential for AHPs is more depolarized than the hyperpolarized resting membrane potential of spiny projection neurons.
Remoxipride (10 µM, Sigma), SCH 23390 (10 µM, RBI), SKF 38393 (5 µM, RBI), and picrotoxin (50 µM, Sigma) were dissolved to their
desired final concentration in the Mg2+-free
superfusing fluid. Dopamine-depleted slices were prepared from animals
injected with alpha-methyl para tyrosine (AMPT, 300 mg/kg ip, RBI)
2.5 h before slice preparation. The administration of AMPT
depletes up to 86% of the releasable stores of dopamine (White
et al. 1993) by inhibiting tyrosine hydroxylase, an enzyme catalyzing the rate limiting step in the production of dopamine (Cumming et al. 1994
). Previous work has shown that the
protocol used in the present experiments abolishes dopamine release
within 45 min (Williams and Millar 1990
). All animals in
the AMPT group showed reduced motor activity (consistent with dopamine
depletion) prior to slice preparation, and recording was completed
within 5 h of the AMPT injection.
Statistical analysis of synaptic plasticity was based on the percentage change in response from baseline values (average of 5 min of test responses prior to HFS). Between-group differences were tested for statistical significance using a one-way ANOVA followed by Student-Newman multiple comparison procedure. Statistical analysis of cellular properties used a two-tailed t-test for independent samples (between group comparison) and a paired t-test (within group comparison of cellular properties 10 min before and 20 min after HFS). The probability level for statistical significance was set at P = 0.05.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Switching of the ACSF to a Mg2+-free solution was associated with an increase in the slope and peak of the test responses. These changes reached a steady state and stabilized within 20 min of changeover from normal to Mg2+-free ACSF. In these slices, cortical HFS paired with depolarization of the postsynaptic cell reliably induced a long-term increase in both the slope and peak of the cortically evoked test responses, which we refer to as Mg2+-free LTP. Averaging across all cells tested (n = 6), there was an increase in the PSP peak amplitude (22.3 ± 3.4%) and slope (15.3 ± 2.9%) measured 20 min after HFS. These findings are illustrated in Fig. 1.
|
To test whether the Mg2+-free LTP was due to potentiation of a reversed inhibitory postsynaptic potential (IPSP), LTP was measured in the presence of picrotoxin, a GABAA receptor antagonist. The group average (n = 3) showed an increase in the PSP peak amplitude (40.8 ± 5.1%) and slope (28.4 ± 5.4%) measured 20 min after HFS that was not significantly different from the LTP seen in the Mg2+-free control group (data not shown).
Subtype-specific dopamine receptor antagonists were used to test
whether dopamine receptors play a role in
Mg2+-free LTP. The D-1/D-5 antagonist SCH 23390 (10 µM) abolished Mg2+-free LTP (Fig.
2). In slices treated with SCH 23390, there was no change in the group average (n = 5)
measures of PSP peak amplitude (1.6 ± 2.2%) or slope
(
3.3 ± 1.6%) measured 20 min after HFS.
|
To determine whether dopamine D-2 receptors play a role in Mg2+-free LTP, the D-2 receptor antagonist remoxipride was also tested (Fig. 3). Averaging across all slices tested (n = 4), remoxipride (10 µM) did not prevent LTP of the PSP peak amplitude (26.9 ± 6.7%) or slope (24.7 ± 3.4%) measured 20 min after HFS.
|
Group average data for the control (Mg2+-free), dopamine D-1/D-5 receptor antagonist (SCH 23390) and dopamine D-2 receptor antagonist (remoxipride) are shown in Fig. 4. The difference between Mg2+-free control and SCH 23390 groups was significant (P < 0.05). There was no significant difference between Mg2+-free control and remoxipride groups. Although the magnitude of Mg2+-free LTP appeared to be greater in the remoxipride-treated slices, this difference was not significant. Thus dopamine D-1/D-5 receptor activation, but not D-2 receptor activation, was found to be a requirement for neostriatal LTP in Mg2+-free conditions.
|
The blockade of Mg2+-free LTP by a dopamine
D-1/D-5 receptor antagonist suggests that endogenous dopamine may be
involved in this form of LTP. The requirement for endogenous dopamine
was tested in slices depleted of releasable dopamine by pretreatment with AMPT. Pretreatment of slices with AMPT blocked
Mg2+-free LTP (Fig.
5, A and C).
Averaging across all slices tested (n = 6), there was
no change in the PSP peak amplitude (9.4 ± 10.2%) or slope
(
13.2 ± 10.2%) measured 20 min after HFS. The difference
between the Mg2+-free control group and the
AMPT-treated group was significant (P < 0.05).
|
Application of the dopamine D-1 receptor agonist SKF 38393 restored the ability of AMPT-treated slices to show Mg2+-free LTP (Fig. 5, B and C). There was LTP of PSP peak amplitude (20.5 ± 7.8%) and slope (18.4 ± 6.6%) measured 20 min after HFS (n = 5). The difference between the control (dopamine-depleted) group and the SKF 38393 (dopamine-depleted) group was significant (P < 0.05).
An apparent short-term facilitation of both PSP slope and peak was observed in slices exposed to SCH23390 (Fig. 2). This short-term facilitation was not significantly different in magnitude from the initial potentiation seen in control slices, slices exposed to Remoxipride, or AMPT-treated slices exposed to SKF 38393 (Fig. 4). Short-term facilitation was, however, completely abolished in slices from AMPT-treated animals (Fig. 5).
Changes (or the absence of changes) in postsynaptic response measures (slope and peak of the PSP) could be secondary to changes in cellular properties other than synaptic efficacy. This possibility was tested by measuring selected cellular properties 10 min before and 20 min after HFS. No significant changes were observed in resting membrane potential, input resistance, action potential threshold, action potential amplitude and duration, or AHPs (Figs. 1C, 2C, and 3C and Table 1).
|
Between-group differences in the induction of Mg2+-free LTP could also in theory be secondary to differences in cellular properties affecting neuronal excitability. However, there were no significant between group differences in cellular properties as a result of treatment with SCH 23390, remoxipride, AMPT, or AMPT plus SKF 38393 (Table 1). To exclude possible differences in the level of depolarization during HFS, the intensity of the applied current and the responses of the postsynaptic cell to HFS plus depolarization were also compared between groups. There were no significant differences between groups in the intensity of the current pulse used during HFS, the number of action potentials fired, or the level of depolarization produced in the postsynaptic neuron during HFS (data not shown).
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The main finding of the present study was that dopamine D-1/D-5
receptor activation is a necessary requirement for
Mg2+-free LTP in the neostriatum. The present
result is in agreement with previous studies showing that LTP could
reliably be induced by HFS of the corticostriatal pathway in slices
bathed in Mg2+-free solution (Calabresi et
al. 1992c; Walsh 1991
). In addition, we found
that Mg2+-free LTP was blocked by the dopamine
D-1/D-5 receptor antagonist SCH 23390 and not blocked by the dopamine
D-2-selective antagonist remoxipride. To our knowledge, this is the
first study showing that dopamine D-1/D-5 receptor activation is
necessary for Mg2+-free LTP in the neostriatum.
The slices treated with SCH 23390 showed an apparent short-term
facilitation that was not evident in other groups. This may be an early
phase of Mg2+-free LTP that is unmasked by the
prevention of the later phase of LTP in the presence of SCH 23390. Previously a role of dopamine D-1/D-5 receptors in the persistence of
LTP has been described in the hippocampal CA1 area, where Frey
et al. (1991) showed that the presence of SCH 23390 resulted in
prevention of late LTP stages (more than 1-2 h). This effect in the
hippocampus occurs over a longer time course than that described in the
present experiments (hours rather than minutes) but may involve similar
cellular mechanisms.
At the doses of SCH 23390 used in the present study (10 µM), it is not possible to rule out an effect on other monoamine receptors such as those for serotonin. However, Mg2+-free LTP was also blocked in slices which were dopamine depleted by pretreatment with AMPT, which does not lead to depletion of serotonin. The only difference between these treatments was the complete abolition of short-term facilitation in the AMPT group, which indirectly suggests a possible link between short-term facilitation and serotonergic effects of SCH 23390; this might warrant further experimental investigation.
It has been reported recently that Mg2+-free LTP
was blocked after chronic dopamine depletion with 6-hydroxydopamine
(Centonze et al. 1999). Treatment with 6-hydroxydopamine
has also been shown to cause loss of synapses in the striatum
(Ingham et al. 1998
), and this may affect the synapses
that are normally potentiated in Mg2+-free LTP.
The present results show, however, that in slices acutely depleted of
endogenous dopamine by pretreatment with AMPT, HFS in
Mg2+-free solutions similarly failed to induce
LTP. Together with the previous result, these findings suggest that
endogenous dopamine release at the time of HFS is a necessary
requirement for Mg2+-free LTP.
Another important finding of the present study is that after acute
dopamine depletion with AMPT, Mg2+-free LTP is
restored to control levels by bath application of the dopamine D-1
receptor agonist SKF 38393. We are not aware of any previous reports
showing that dopamine D-1 receptor activation restores LTP in
dopamine-depleted slices. Together with the effects of dopamine
depletion and dopamine D-1/D-5 receptor antagonists, the effects of the
D-1 receptor agonist strongly implicate dopamine D-1/D-5 receptors in
Mg2+-free LTP. The neostriatal dopamine D-1/D-5
receptors are G-protein-coupled receptors that activate adenylyl
cyclase leading to intracellular accumulation of cyclic AMP (cAMP).
Thus Mg2+-free LTP probably involves elevation of
cAMP and triggering of related biochemical cascades present in
neostriatal neurons. Elevation of cAMP by direct activation of adenylyl
cyclase (Colwell and Levine 1995) or dopamine D-1/D-5
receptors (Price et al. 1999
) causes enhancement of
responses to glutamatergic agonists. In contrast, the dopamine D-2
receptor is negatively coupled to adenylyl cyclase. We found that the
dopamine D-2 receptor antagonist, remoxipride, did not block
Mg2+-free LTP. These results are compatible with
dopamine D-1/D-5 receptor mediated activation of adenylyl cyclase being
necessary for the enhancement of synaptic transmission in
Mg2+-free LTP.
The magnitude of Mg2+-free LTP was not reduced in
the presence of the GABAA antagonist, picrotoxin.
This finding is important because previous studies have not ruled out
the possibility that Mg2+-free LTP included a
component of LTP of feed-forward inhibitory IPSPs (Calabresi et
al. 1992c; Walsh 1991
). At the hyperpolarized resting membrane potentials typical of spiny neostriatal neurons, IPSPs
may be depolarizing because the equilibrium potential of GABAA-activated conductances is more depolarized
(Misgeld et al. 1982
). This made it necessary to test if
the changes in cortically evoked test responses were due to changes in
feedforward IPSPs. The finding that Mg2+-free LTP
was not blocked or reduced in magnitude by the
GABAA antagonist picrotoxin shows that
Mg2+-free LTP is not due to changes in
GABAA mediated IPSPs. It implies that the LTP is
due to changes in excitatory postsynaptic potentials.
In the present study, LTP could reliably be induced by HFS in
Mg2+-free solution in all cells tested. The
reliability of induction of this form of LTP is consistent with a
previous study in which longer HFS trains were applied.
Calabresi et al. (1992c) described LTP in
Mg2+-free solution after 900 suprathreshold
stimulus pulses (applied as 3 trains of 300 pulses at 100 Hz). In
contrast, Walsh (1993)
found that a somewhat milder
induction protocol involving 400 subthreshold stimulus pulses (applied
as 4 trains of 100 pulses at 100 Hz) did not reliably induce LTP but
induced short-term potentiation lasting from 5 to 45 min. In the
present study, LTP lasting for as long as recordings were continued (at
least 20 min and up to 40 min) was elicited by HFS consisting of a
total of 300 subthreshold stimulus pulses (applied as 6 trains of 50 pulses at 100 Hz) in conjunction with suprathreshold depolarization of
the postsynaptic neuron. These results show that
Mg2+-free LTP is a robust phenomenon that is
readily reproduced in different laboratories despite marked differences
in HFS protocols.
Previous work has shown that the induction of
Mg2+-free LTP in the neostriatum can be blocked
by NMDA receptor antagonists (Calabresi et al. 1992c).
In normal bathing solutions, NMDA receptor-operated channels play a
minor role in corticostriatal synaptic transmission (Kita
1996
). This is because at hyperpolarized membrane potentials such channels are closed by a magnesium block (Nowak et al.
1984
) and, as in the present and previous studies (Jiang
and North 1991
), the resting membrane potential of the
neostriatal neurons is strongly hyperpolarized. Thus it is necessary to
consider whether the facilitation of LTP in
Mg2+-free is due to the greater influx of calcium
postsynaptically in Mg2+-free solution. In
Mg2+-free conditions, HFS of cortical afferents
paired with suprathreshold current injection as used in the present
study can be expected to produce influx of calcium via NMDA channels.
This failed to produce LTP in slices that had been dopamine depleted by
pretreatment with AMPT or slices in which dopamine D-1/D-5 receptors
were blocked by a selective antagonist. Thus the present results show
that activation of NMDA channels per se is not sufficient for induction of Mg2+-free LTP.
Calabresi et al. (1997) have shown abnormal induction of
LTP in slices made from mice lacking dopamine D-2 receptors. In slices made from dopamine D-2 receptor knockout mice, HFS of the
corticostriatal pathway under conditions that would normally induce LTD
produced LTP. In contrast to the present results showing blockade of
Mg2+-free LTP in wild-type rats, the abnormal
form of LTP seen in the D-2 receptor-deficient mice was not blocked by
SCH 23390. A potentially important factor in these differences is that
D-2 receptor-deficient mice have abnormal dopamine function throughout life. Dopaminergic receptor mechanisms can be disrupted by abnormal dopamine receptor stimulation during development. For example, rats
given 6-OHDA lesions as neonates show a substantial sub-sensitivity to
both D-2 and D-1 antagonists as adults (Duncan et al.
1987
). Thus it is plausible that in the D-2 receptor-deficient
mice, the dose of SCH 23390 used by Calabresi et al.
(1997)
may not produce effective D-1 blockage in dopamine
receptor knockout animals.
Another possible cause of the difference in response to SCH 23390 in
the present experiments and in the D-2 receptor-deficient mice
(Calabresi et al. 1997) is that the neurons in the
present study were relatively polarized (
95 mV in comparison to
85
mV in the D-2 receptor-deficient mice). No holding current was used in
the present experiments, and the resting membrane potential reflects
the selection criteria used, the quality of the impalement, the ionic
composition of the extracellular fluid, and the effects of the ionic
composition of the intracellular electrode solution (Nisenbaum
and Wilson 1995
). Furthermore during the plasticity-inducing HFS, depolarizing current was applied to ensure suprathreshold depolarization of the recorded cells. This minimizes any potential interaction between resting membrane potential and the production of
LTP. In addition, because there was no significant difference in
resting membrane potential between the groups in the present experiments (Table 1), the polarized resting membrane potential is
unlikely to have influenced the results.
While showing that activation of NMDA channels is not sufficient for
LTP induction, the present results do not exclude a complex modulatory
effect of dopamine D-1/D-5 receptor activation on NMDA receptor-mediated channels, which may also be necessary for LTP induction. Previous work has shown that dopamine application leads to
an enhancement of NMDA receptor-mediated responses that is apparently
mediated by dopamine D-1/D-5 receptors (Cepeda et al. 1992,
1993
; Levine et al. 1996
). Such enhancement of
NMDA receptor-mediated channels may be necessary for LTP to occur in
Mg-free solutions, suggesting that both dopamine D-1/D-5 receptor
activation and NMDA receptor-mediated channel activation may be
necessary. Futher experiments are needed to investigate this possibility.
An alternative explanation for the facilitation of striatal LTP in
Mg2+-free conditions is that these conditions
favor dopamine release; an effect that itself is mediated by activation
of presynaptic NMDA receptors (Desce et al. 1992;
Krebs et al. 1991a
,b
; Roberts and Sharif
1978
) presumably located on dopaminergic nerve terminals. The
dopaminergic terminals on spiny projection neurons synapse in close
proximity to the glutamatergic corticostriatal terminals (Freund
et al. 1984
; Hersch et al. 1995
; Smith et
al. 1994
; Yung et al. 1995
). Thus glutamate
released from corticostriatal terminals during cortical HFS might act
directly on adjacent dopaminergic terminals to cause dopamine release.
Spillover of glutamate under Mg2+-free conditions
favors NMDA-mediated release of endogenous dopamine. A model in which
Mg2+-free conditions favor LTP by facilitating
endogenous dopamine release is compatible with the present findings as
well as previous results showing that in the absence of exogenous
dopamine NMDA receptor activation is necessary for
Mg2+-free LTP (Calabresi et al.
1992c
) and that pulsatile application of exogenous dopamine
facilitates LTP under physiological conditions (Wickens et al.
1996
). To confirm this possibility, further experiments are
needed to measure endogenous dopamine release in response to HFS in
Mg2+-free and control conditions.
In summary, the present study has confirmed previous reports that
Mg2+-free LTP is a reliable and robust phenomenon
in the neostriatum. It has extended understanding of this phenomenon by
showing that Mg2+-free LTP is dopamine dependent
and requires activation of dopamine D-1/D-5 receptors but not dopamine
D-2 receptors. Furthermore it has shown that LTP can be restored in
dopamine-depleted slices by the application of a dopamine D-1/D-5
agonist. These results are significant for current understanding of
learning and memory mechanisms of the neostriatum and are compatible
with behavioral evidence that D-1/D-5 receptors are important in
reward-related learning (Sutton and Beninger 1999;
Wickens and Kotter 1995
). The results are also
significant for theoretical understanding of the mechanism of the
therapeutic effect of dopamine receptor antagonist drugs used in the
treatment of psychotic illnesses (Miller et al. 1990
)
and dopamine receptor agonists in the treatment of Parkinson's disease
(Rascol et al. 1999
).
![]() |
ACKNOWLEDGMENTS |
---|
We thank Prof. W. C. Abraham and Dr. D. Plenz for helpful comments on the manuscript.
This work was supported by the New Zealand Neurological Foundation, the New Zealand Health Research Council, the New Zealand Schizophrenia Fellowship, the HS and JC Anderson Trust, and the New Zealand Lottery Grants Board.
Present address of J.N.D. Kerr: Unit of Neural Networks Physiology, LSN/NIMH, National Institutes of Health, Bethesda, MD 20892-4075.
![]() |
FOOTNOTES |
---|
Address for reprint requests: J. R. Wickens, Dept. of Anatomy and Structural Biology, School of Medical Sciences, University of Otago, PO Box 913, Dunedin, New Zealand (E-mail: jeff.wickens{at}stonebow.otago.ac.nz).
Received 8 June 2000; accepted in final form 12 September 2000.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|