Depotentiation in the Dentate Gyrus of Freely Moving Rats is Modulated by D1/D5 Dopamine Receptors

Alexander Kulla and Denise Manahan-Vaughan

Institute for Physiology of the Charite, Synaptic Plasticity Group, Humboldt University, Tucholskystrasse 2, 10117 Berlin, Germany


    Abstract
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Notes
 References
 
Hippocampal depotentiation comprises a reversal of tetanization- induced long-term potentiation (LTP) which occurs following low-frequency stimulation. In the CA1 region, it has been reported that agonist activation of D1/D5 dopamine receptors enhances LTP expression and inhibits depotentiation. The role of these receptors in synaptic plasticity in the dentate gyrus (DG) has not been characterized. This study therefore investigated the role of D1/D5 receptors in LTP and depotentiation in the DG of freely moving rats. Male Wistar rats underwent chronic implantation of a recording electrode in the DG granule cell layer, a bipolar stimulating electrode in the medial perforant path and a cannula in the ipsilateral cerebral ventricle (to enable drug administration). The D1/D5 agonist Chloro-PB dose-dependently inhibited depotentation in the DG. This effect was prevented by the D1/D5 antagonist SCH 23390. Neither D1/D5 agonist nor antagonist had an effect on LTP expression or basal synaptic transmission. These results highlight differences between D1/D5 receptor-involvement in LTP and depotentiation in the CA1 region and DG, and indicate that whereas D1/D5 receptor activation may not be a critical factor in LTP induction in the DG, a differential role for these receptors in the expression of depotentiation, in this hippocampal subfield, may exist.


    Introduction
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Notes
 References
 
Synaptic plasticity is believed to comprise the cellular mechan- ism which underlies information storage in the form of memory in the mammalian brain (Bear, 1996Go). The dopaminergic system is intrinsically involved in both short- (Goldman-Rakic, 1995Go; Bach et al., 1999Go; Wilkerson and Levin, 1999Go) and long- term memory (Schultz et al., 1993Go; Izquierdo et al., 1998Go). Furthermore, dopaminergic modulation of multiple forms of hippocampus-dependent learning, such as spatial navigation (Gasbarri et al., 1996Go) and passive avoidance (Bernabeu et al., 1997Go), has been demonstrated. Long-term potentiation (LTP), which is a form of synaptic plasticity that is widely believed to be responsible for cellular information storage, is a persistent use-dependent enhancement of synaptic efficacy which typically occurs in the hippocampus following tetanic stimulation of afferent pathways (Bliss and Lomo, 1973Go). Depotentiation (or reversal) of LTP may serve to return potentiated synapses to their previous level of activation (following transduction of an LTP signal) or to shut-down erroneous LTP induction, thereby free- ing a synaptic population to undergo renewed LTP. Both hippocampal LTP and depotentiation may be regulated by the dopaminergic system (Otmakhova and Lisman, 1996Go, 1998Go).

Depotentiation is induced by means of repetitive low- frequency stimulation (LFS) of afferent fibres in the hippo- campus (Barrionuevo et al., 1980Go; Staubli and Lynch, 1990Go; Fuji et al., 1991). Depotentiation has been widely reported in the CA1 region both in vitro (Fuji et al., 1991; Wagner and Alger, 1996Go; Abraham and Huggett, 1997Go; Holland and Alger, 1998) and in vivo (Barrionuevo et al., 1980Go; Staubli and Lynch, 1990Go; Staubli and Chun, 1996Go). However, until recently, little was known about the occurence of depotentiation in the dentate gyrus.

In freely moving rats, dentate gyrus depotentiation occurs in two phases: a transient depression of evoked responses to below pre-tetanization values which persists for ~60 min following LFS, and a recovery of this response to a stable level of synaptic transmission which comprises a significant reversal of LTP (Kulla et al., 1999Go). As is the case for depotentiation in the CA1 region in vivo (Staubli and Chun, 1996Go), the magnitude of reversal of LTP by LFS is inversely proportional to the time-interval between tetanization and LFS. Thus, application of LFS up to 5 min post-tetanization gives rise to depotentiation in the dentate gyrus in vivo, whereas LFS given at time points later than 5 min post-tetanization has no significant effect on the magnitude of LTP (Kulla et al., 1999Go).

It has been reported that pharmacological antagonism of D1/D5 dopamine receptors, which are positively coupled to adenylyl cyclase, inhibits LTP expression (Frey, 1990, 1991), whereas D1/D5 receptor agonist application enhances LTP in the CA1 region (Otmakhova and Lisman, 1996Go). On the other hand, pharmacological activation of D1/D5 dopamine receptors inhibits depotentiation in this hippocampal subfield (Otmakhova and Lisman, 1998Go). In addition, recent work by this group (Kulla et al., 1999Go) has shown that metabotropic glutamate receptors (mGluRs), which are negatively coupled to adenylyl cyclase, modulate depotentiation in the dentate gyrus in vivo. These findings strongly support a role for adenylyl cyclase-coupled neurotransmitter systems in the modulation of hippocampal depotentiation. The role of D1/D5 dopamine receptors in LTP and depotentiation in the dentate gyrus of freely moving rats has not been characterized. Given the significance of the dentate gyrus as a ‘gate’ for information flow through the trisynaptic circuit of the hippocampus, clarification of this issue is of particular interest. This study therefore investigated the role of the adenylyl cyclase-coupled D1/D5 dopamine receptors in LTP and depotentiation in the dentate gyrus of freely moving rats.


    Materials and Methods
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Notes
 References
 
Electrode Implantation

Male Wistar rats (7–8 weeks old) underwent electrode implantation into the dentate gyrus as described previously (Manahan-Vaughan et al., 1998Go). Briefly, under sodium pentobarbitone anaesthesia (Nembutal, 40 mg/kg, i.p., Serva, Germany), animals underwent implantation of a monopolar recording and a bipolar stimulating electrode (made from 0.1 mm diameter, Teflon-coated, stainless steel wire). A drill hole was made (1.5 mm diameter) for the recording electrode (2.8 mm posterior to bregma, 1.8 mm lateral to the midline) and a second drill hole (1 mm diameter, 6.9 mm posterior to bregma and 4.1 mm lateral to the midline) for the stimulating electrode. The dura was pierced through both holes and the recording and stimulating electrode lowered into the dentate gyrus granule cell layer and the medial perforant path respectively. Recordings of evoked field potentials via the implanted electrodes were taken throughout surgery. A cannula was also implanted into the lateral cerebral ventricle, through which drug application was made. Once verification of the location of the electrodes was complete, the entire assembly was sealed and fixed to the skull with dental acrylic (Paladur, Heraeus Kulzer GmbH, Germany). The animals were allowed 7–10 days to recover from surgery before experiments were conducted. Through- out experiments the animals could move freely. Experiments were consistently conducted at the same time of day (commencing 09.00 h). Baseline experiments to confirm stability of evoked responses were routinely carried out (at least 24 h) before LTP or depotentiation experiments were conducted. Where possible, the animals served as their own controls. Thus, basal synaptic transmission (in the absence of injection) was monitored over a 24 h period in all animals to confirm stability of evoked responses. Subsequently, a control experiment (e.g. depotentiation or basal synaptic transmission) was carried out in the presence of vehicle injection and ~1 week later the same experiment was carried out in the same animal in the presence of a drug injection.

Measurement of Evoked Potentials

Responses were evoked by stimulating at low frequency (0.025 Hz, 0.1 ms stimulus duration, 10,000 Hz sample rate). For each time-point, five evoked responses were averaged. Both field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude were monitored. The amplitude of PS was measured from the peak of the first positive deflection of the evoked potential to the peak of the following negative potential. fEPSP slope was measured as the maximal slope through the five steepest points obtained on the first positive deflection of the potential. By means of input/output curve determination the maximum PS amplitude was found, for each individual animal, and all potentials employed as baseline criteria were evoked at a stimulus intensity which produced 40 % of this maximum.

LTP was induced by a tetanus of 200 Hz (10 bursts of 15 stimuli, 0.2 ms stimulus duration, 10 s interburst interval). Depotentiation was generated using LFS at 5 Hz (600 pulses). The stimulus amplitude for both protocols was the same as that used for recordings.

Compounds and Drug Treatment

The D1/D5 agonist (±)-6-chloro-PB hydrobromide (Chloro-PB) was obtained from Research Biochemicals International, USA. The D1/D5 antagonist, R-(+)-7-chloro-8- hydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine (SCH 23390), was obtained from Tocris Cookson Ltd, Bristol, UK. For injection, drugs were first dissolved in 5 µl sodium hydroxide solution (1 mM), and then made up to a 100 µl volume with 0.9% sodium chloride. Compounds or vehicle were injected in a 5 µl volume over a 6 min period via a Hamilton syringe. Agonist injection was carried out 30 min prior to tetanization, and antagonist injection occurred a further 30 min prior to agonist application, to enable diffusion from the lateral cerebral ventricle to the hippocampus to occur (Manahan-Vaughan et al., 1998Go).

Throughout the experiments, injections were administered following measurement of the baseline for 30 min. In LTP experiments, a tetanus was applied 30 min following injection, with measurements then taken at t = 2, 5, 10, 15 and then 15 min intervals up to 4 h, with additional measurements taken after 24 h. LFS to induce depotentiation was given 5 min after tetanization had occurred, and the experimental protocol for measuring evoked responses was then followed as above.

Data Analysis

The fEPSP or PS data were obtained by averaging the response to stimulating the perforant path, to obtain five sweeps at 0.025 Hz, every 5 or 15 min as described above. The data were then expressed as a mean percentage of the average pre-injection baseline value ± SEM. Statistical significance was estimated using analysis of variance (ANOVA) with repeated measures, followed by post-hoc Student's t-tests. The probability level interpreted as statistically significant was P < 0.05.


    Results
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Notes
 References
 
Robust Depotentiation Occurs in the Dentate Gyrus of Freely Moving Rats

Robust LTP in the dentate gyrus was induced by means of 200 Hz high-frequency tetanization (HFT, 10 bursts of 15 stimuli, 0.2 ms stimulus duration) of the medial perforant path (Fig. 1Go). When LFS (5 Hz, 600 pulses) was given 5 min following application of HFT, persistent depotentiation occurred (Fig. 2Go). As reported previously (Kulla et al., 1999Go), depotentiation occurred in two phases: an initial depression which was below basal pre-HFT values for both PS and fEPSP and which endured for ~60 min, and a second phase which developed 60 min post-LFS and which involved a stabilization of evoked potentials to comprise a significant depotentiation of evoked responses (Fig. 2Go).



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Figure 1.  Robust long-term potentiation occurs in the dentate gyrus of freely moving rats, which is unaffected by application of the D1/D5 receptor agonist, 6-chloro-PB. (A,B) High-frequency tetanization (HFT; 200 Hz, n = 6) results in a robust long-term potentiation of both PS (A) and fEPSP (B). Application of Chloro-PB (40 nmol) prior to HFT has no effect on the profile of LTP expressed (n = 6). Line breaks indicate a change in timescale. (C) Original analog traces showing the field potentials evoked from the dentate gyrus before HFT, 5 min and 24 h following application of HFT in the presence of Chloro-PB (40 nmol). Vertical scalebar corresponds to 4 mV; horizontal scalebar corresponds to 3 ms.

 


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Figure 2.  The D1/D5 receptor agonist Chloro-PB inhibits depotentiation in the dentate gyrus of freely moving rats. The D1/D5 receptor antagonist SCH 23390 has no effect. (A,B) Low-frequency stimulation (LFS) at 5 Hz when given 5 min post-HFT in the presence of vehicle injection (n = 9) results in a significant reversal of LTP of both PS (A) and fEPSP (B). Application of Chloro-PB (40 nmol) prior to HFT and LFS results in a significant inhibition of depotentiation. Line breaks indicate a change in timescale. Administration of SCH23390 (30 nmol) has no effect on the expression of depotentiation. (C) Original analog traces showing the field potentials evoked from the dentate gyrus before HFT, 2 min post-HFT, 5 min post-LFS and 24 h post-LFS in the presence of Chloro-PB (40 nmol). Vertical scalebar corresponds to 5 mV; horizontal scalebar corresponds to 4 ms.

 
The D1/D5 Receptor Agonist 6-Chloro-PB Dose-dependently Inhibits Depotentiation in the Dentate Gyrus of Freely Moving Rats

When Chloro-PB was applied 30 min before the HFT and LFS protocols were applied, a dose-dependent effect on depoten- tiation was seen. Neither 20 nmol (n = 7) nor 30 nmol (n = 7) Chloro-PB influenced the expression of depotentiation (Fig. 3BGo). Five minutes after LFS, PS and fEPSP values were respectively 125 ± 11% and 89 ± 3% in control animals (n = 9). Where 20 nmol Chloro-PB was injected PS and fEPSP values were respectively 96 ± 20% and 87 ± 3% 5 min post-LFS. In the 30 nmol group, PS was 107 ± 11% and fEPSP 90 ± 3% 5 min post-LFS. Twenty-four hours following LFS, PS and fEPSP values were 147 ± 7% and 109 ± 5% respectively in control animals. Where 20 nmol Chloro-PB was injected, PS and fEPSP values were respectively 127 ± 15% and 107 ± 7% 5 min post-LFS. In the 30 nmol group, PS was 142 ± 13% and fEPSP was 114 ± 3% at 5 min post-LFS.



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Figure 3.  The inhibition of depotentiation by the D1/D5 receptor agonist 6-chloro-PB is dose-dependent. (A,B) LFS (5 Hz) when given 5 min post-HFT in the presence of Chloro-PB at a concentration of 50 nmol (n = 7) does not affect depotentiation of either PS (A) or fEPSP (C) compared to vehicle-injected controls (n = 7). Application of Chloro-PB (60 nmol) prior to HFT and LFS results in a transient enhancement of depotentiation. This effect is not significant at 24 h post-LFS, however. Line breaks indicate a change in timescale. (C) Dose–response curve for the agonist effect of Chloro-PB (20–120 nmol) on depotentiation in the dentate gyrus of freely moving rats. The values represent the magnitude of depotentiation for PS (i) and fEPSP (ii) observed at 24 h post-LFS. In control (depotentiated) animals 4 h following application of LFS, PS amplitude was 147 ± 7% and fEPSP slope was 109 ± 5%.

 
When the concentration of Chloro-PB was increased to 40 nmol (n = 6), however, a significant inhibition of depoten- tiation was obtained (Fig. 2Go). This effect was still significant 24 h after LFS was given (t-test: P < 0.05, compared to vehicle-injected controls, n = 9). ANOVA confirmed a statistical significance between the drug and control groups. For PS values, the statistical results were: within-factor: F(1,31) = 148.64, P < 0.001; between-factor: F(1,31) = 17.55, P < 0.001. For EPSP values, the ANOVA results were: within-factor: F(1,31) = 62.59, P < 0.001; between-factor: F(1,31) = 15.06, P < 0.001.

Further increasing the concentration of Chloro-PB to 50 nmol (n = 7) did not enhance the inhibitory effects of the com- pound. Rather, at this concentration no significant effects on depotentation were seen (Fig. 3Go). Twenty-four hours following LFS, PS and fEPSP values were 164 ± 22% and 106 ± 6% respectively. These values did not differ significantly from vehicle-injected controls (n = 7).

Increasing the concentration of Chloro-PB to 60 nmol (n = 7) revealed possible non-specific effects of the drug at this concentration. Thus, depotentiation was slightly enhanced when Chloro-PB at a concentration of 60 nmol was applied prior to HFT and LFS (Fig. 3Go). This effect was transient and no longer significant 24 h following LFS. Application of this concentration of Chloro-PB was accompanied by signs of behavioral distress in the animals.

The D1/D5 Receptor Agonist 6-Chloro-PB Has No Effect on Long-term Potentiation in the Dentate Gyrus of Freely Moving Rats

As the concentration of 40 nmol Chloro-PB was effective in inhibiting depotentiation, we tested this concentration against induction of LTP (n = 6, Fig. 1Go). No effect on the profile of LTP was seen, however, compared to vehicle-injected controls. Furthermore, this concentration of Chloro-PB had no effect on the profile of basal synaptic transmission (n = 6) compared to vehicle-injected controls (n = 6, Fig. 4Go).



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Figure 4.  Neither the D1/D5 receptor agonist Chloro-PB nor the D1/D5 receptor antagonist SCH 23390 affect basal synaptic tranmission in the dentate gyrus of freely moving rats. (A,B) Test-pulse stimulation when given in the presence of either Chloro-PB (40 nmol, n = 6) or SCH 23390 PB (30 nmol, n = 6) does not affect either basal PS amplitude (A) or fEPSP slope (B) compared to vehicle-injected controls (n = 6). Line breaks indicate a change in timescale.

 
The D1/D5 Receptor Antagonist SCH 23390 Dose-dependently Prevents the Inhibitory Effects of Chloro-PB on Depotentiation in the Dentate Gyrus of Freely Moving Rats

To confirm that the inhibitory effects seen following application of 20 nmol Chloro-PB were mediated by D1/D5 dopamine re- ceptors, we examined the effect of carrying out this experiment in the presence of the selective D1/D5 receptor antagonist SCH 23390. A dose-dependent inhibition of the effects of Chloro-PB was found (Fig. 5Go). Whereas SCH 23390 at a concentration of 20 nmol (n = 10) partially inhibited the effects of Chloro-PB on depotentiation, a complete antagonism of the effects were seen with a concentration of 30 nmol SCH 23390 (n = 10). Twenty- four hours following application of LFS in the presence of SCH 23390 and 6-chloro-PB, PS and fEPSP values were 132 ± 10% and 107 ± 4%. These values were statistically significant from vehicle-injected controls where only LFS was given.



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Figure 5.  The D1/D5 receptor antagonist SCH 23390 dose-dependently prevents the inhibitory effects of Chloro-PB on depotentiation in the dentate gyrus of freely moving rats. (A,B) Application of the D1/D5 dopamine receptor antagonist SCH 23390 (20 nmol, n = 10), partially impairs the inhibition of depotentiation of both PS (A) and fEPSP (B) induced in the presence of Chloro-PB (40 nmol). Administration of SCH 23390 in a concentration of 30 nmol (n = 10) completely prevents the inhibitory effects of Chloro-PB on depotentiation. Line breaks indicate a change in timescale.

 
ANOVA confirmed a statistical significance between the SCH 23390 30 nmol/Chloro-PB and 6-chloro-PB-injected groups. For PS values, the statistical results were: within-factor: F(1,38) = 28.61, P < 0.001; between-factor: F(1,38) = 23.79, P < 0.001. For EPSP values, the ANOVA results were: within-factor: F(1,38) = 104.45, P < 0.001; between-factor: F(1,38) = 10.99, P < 0.001.

The D1/D5 Receptor Agonist SCH 23390 Has No Effect on Long-term Potentiation or Depotentiation in the Dentate Gyrus of Freely Moving Rats

The concentration of SCH 23390 (30 nmol) which was effective in preventing the inhibitory effects of Chloro-PB on depoten- tiation was tested against LTP (n = 6, Fig. 6Go). No effect on the profile of LTP was seen, however, compared to vehicle-injected controls (n = 6). Raising the concentration of SCH 23390 to either 60 or 120 nmol did not result in an alteration of the profile of LTP expression. Five minutes after HFT, PS and fEPSP values were respectively 226 ± 8% and 128 ± 12% in control animals (n = 9). When 60 nmol SCH 23390 was injected, PS and fEPSP values were respectively 204 ± 7% and 123 ± 5% 5 min post-LFS. In the 120 nmol group, PS was 234 ± 11% and fEPSP was 124 ± 4% 5 min post-LFS. Twenty-four hours following LFS, PS and fEPSP values were 212 ± 22% and 123 ± 9% respectively in control animals. Where 60 nmol SCH 23390 was injected, PS and fEPSP values were respectively 200 ± 20% and 112 ± 7% 5 min post-LFS. In the 120 nmol group, PS was 220 ± 17% and fEPSP was 117 ± 6% at 5 min post-LFS.



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Figure 6.  The D1/D5 receptor antagonist SCH 23390 has no effect on long-term potentiation in the dentate gyrus of freely moving rats. (A,B) HFT (200 Hz, n = 6) results in a robust long-term potentiation of both PS (A) and fEPSP (B). Application of SCH 23390 (30 nmol) prior to HFT has no effect on the profile of LTP expressed (n = 6). Line breaks indicate a change in timescale. (C) Original analog traces showing the field potentials evoked from the dentate gyrus before HFT, 5 min and 24 h following application of HFT in the presence of SCH 23390 (30 nmol). Vertical scalebar corresponds to 4 mV; horizontal scalebar corresponds to 3 ms.

 
The concentration of SCH 23390 which inhibited the effects of Chloro-PB on depotentiation, had no independent effects on the expression of depotentiation (Fig. 2Go). Twenty-four hours following application of LFS in the presence of SCH 23390 (30 nmol), PS and fEPSP values were 148 ± 20% and 107 ± 3% respectively (n = 7). Control values for PS and fEPSP 24 h post-LFS were 149 ± 14% and 106 ± 4% respectively (n = 9). SCH 23390 (30 nmol) also had no effect on the profile of basal synaptic transmission (n = 6) compared to vehicle-injected controls (n = 6, Fig. 4Go).


    Discussion
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Notes
 References
 
The results of this study demonstrate that depotentiation of tetanus-induced LTP is inhibited by a D1/D5 dopamine receptor agonist in the dentate gyrus of freely moving rats. LTP or basal synaptic transmission is unaffected by the D1/D5 receptor agonist. Whereas a D1/D5 receptor antagonist prevents the agonist-induced inhibition of depotentiation, the antagonist has no independent effects on the expression of depotentiation, LTP or basal synaptic transmission. These data indicate a modulatory role for D1/D5 dopamine receptors in depotentiation in the dentate gyrus in vivo, but also suggest that D1/D5 dopamine receptor activation is neither critical for the induction of depotentiation, nor for the expression of LTP.

In contrast to reports with regard to the hippocampal CA1 region, pharmacological manipulation of D1/D5 dopamine receptors did not result in alteration of the expression of LTP in the dentate gyrus. It has been reported that whereas application of D1/D5 dopamine receptor agonists enhance LTP expression in the CA1 region (Otmakhova and Lisman, 1996Go), antagonists of these receptors inhibit LTP (Frey et al., 1990Go, 1991Go). In the dentate gyrus application of either an agonist or an antagonist of D1/D5 dopamine receptors elicited no change in tetanus- induced LTP. Thus, in the dentate gyrus D1/D5 dopamine receptor activation is not a critical factor in the induction of LTP. The contrast of this finding, with those reported for the CA1 region, may be perhaps be explained by the relatively lower expression of D1/D5 dopamine receptors in the dentate gyrus (Huang et al., 1992Go) as compared with the CA1 region, a different complement of D1 and D5 receptors in this hippo- campal subfield (Huang et al., 1992Go; Meador-Woodruff, 1992; Tarazi et al., 1999Go), by intrinsic differences in the receptor systems involved in modulation of LTP in the distinct hippo- campal regions, or alternatively, by variations arising as a result of the experimental preparation used (e.g. hippocampal slice versus recordings from the intact animal). Region-dependent differences between the CA1 and dentate gyrus LTP have been demonstrated with regard to other cAMP-dependent neuro- transmitter systems. For example, it has been reported that CA1 LTP is {alpha}1-adrenoceptor dependent (Izumi and Zorumski, 1999Go), whereas LTP in the dentate gyrus is modulated by ß-adreno- ceptors (Bramham et al., 1997Go; Seidenbecher et al., 1997Go). Furthermore 5-HT2C receptors appear to modulate dentate gyrus but not CA1 LTP (Tecott et al., 1998Go).

Interestingly, despite a lack of effect on LTP, agonist activa- tion of D1/D5 dopamine receptors resulted in inhibition of depotentiation in the dentate gyrus. Similar findings have been reported for depotentiation in the CA1 region (Otmakhova and Lisman, 1998Go), where it was shown that these effects were mediated via adenylyl cyclase and cAMP-dependent protein kinase A. Interestingly, a role for adenylyl cyclase-coupled mGluRs in hippocampal synaptic plasticity has also been reported. Whereas, pharmacological antagonism of group 2 mGluRs (which are negatively coupled to adenylyl cyclase) has no effect on LTP in the dentate gyrus (Manahan-Vaughan et al., 1998Go) or CA1 region (Manahan-Vaughan, 1997Go), inhibition of depotentiation (Kulla et al., 1999Go) and long-term depression (Manahan-Vaughan, 1997Go) by group 2 mGluR antagonism occurs. Conversely, agonist activation of group 2 mGluRs inhibits maintenance of LTP, enhances depotentiation (Kulla et al., 1999Go) and facilitates the expression of long-term depression in the dentate gyrus (Manahan-Vaughan, 1998Go). Furthermore, it has been shown that agonist activation of ß-adrenoceptors, which like D1/D5 dopamine receptors are positively coupled to adenylyl cyclase, results in inhibition of depotentiation only under specific physiological conditions in vitro (Otmakhova and Lisman, 1998Go).

Therefore, it would appear that differential effects on depotentiation and LTP are elicited by neurotransmitter receptors which are coupled to adenylyl cyclase. This finding could perhaps be explained by the relative distribution and expression of the respective receptor types. For example, D1/D5 dopamine receptors are localized on dendritic spines close to excitatory synapses but are largely absent from cell bodies (Smiley et al., 1994Go; Bergson et al., 1995Go), ß-Adrenoceptors are localized predominantly on cell bodies and dendrites (Palacios and Kuhar, 1980Go; Aoki et al., 1987Go), whereas group 2 mGluRs are more randomly localized on neuronal structures (Lujan et al., 1997Go). Thus, whereas D1/D5 dopamine receptors and ß-adrenoceptors demonstrate a mainly postsynaptic distribution (Palacios and Kuhar, 1980Go; Strader et al., 1983Go; Jaber et al., 1996Go), group 2 mGluRs are expressed predominantly pre- synaptically (Shigemoto et al., 1997Go). Alternatively, the varying effects of these adenylyl cyclase-coupled receptors on LTP and depotentiation may perhaps be explained by the different effector mechanisms which mediate their influence on neuronal function. Thus, elevation of adenylyl cyclase via activation of D1/D5 dopamine receptors leads, for example, to opening of L-type voltage-dependent calcium channels (Liu et al., 1992Go) and promotion of non-selective cation channel opening (Aosaki et al., 1998Go). ß-Adrenoceptor activation causes, for example, enhanced neuronal excitability via inhibition of a slow calcium-activated potassium current (McCormick et al., 1991Go), whereas stimulation of group 2 mGluRs leads to inhibition of L- and N-type voltage-gated calcium channels (Chavis et al., 1995Go).

In conclusion, contrary to reports with regard to the CA1 region, D1/D5 dopamine receptors do not appear to play a critical role in the expression of LTP and depotentiation in the dentate gyrus. However, the finding that agonist activation of D1/D5 dopamine receptors results in an inhibition of dentate gyrus depotentiation, whereas pharmacological manipulation of D1/D5 dopamine receptors has no effect on LTP, suggests a differential role for these receptors in the modulation of distinct forms of synaptic plasticity in this hippocampal subfield. Dopamine is released in response to reward stimuli (Schultz et al., 1993Go). One could speculate therefore, that dopamine release in this context could serve to inhibit depotentiation and thereby reinforce LTP expression. This event could have particular significance should LTP prove to be the cellular mechanism underlying information storage in the mammalian brain.


    Notes
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Notes
 References
 
This work was supported by a Deutsche Forschungsgemeinschaft grant (SFB 515/ B8) to D.M.-V.

Address correspondence to Dr Denise Manahan-Vaughan, Institute for Physiology of the Charite, Synaptic Plasticity Group, Humboldt University, Tucholskystrasse 2, 10117 Berlin, Germany. Email: denise.manahan-vaughan{at}charite.de.


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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Notes
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