Cerebral Cortex Advance Access originally published online on September 29, 2007
Cerebral Cortex 2008 18(6):1326-1334; doi:10.1093/cercor/bhm164
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β-Adrenoreceptors Comprise a Critical Element in Learning-Facilitated Long-Term Plasticity
1 Learning and Memory Research, Medical Faculty, Ruhr University Bochum, 44780 Bochum, Germany, 2 International Graduate School for Neuroscience, Ruhr University Bochum, 44780 Bochum, Germany
Address correspondence to Denise Manahan-Vaughan, PhD, Learning and Memory Research, Medical Faculty, Ruhr University Bochum, FNO 1/116, Universitaetsstrasse 150, 44780 Bochum, Germany. Email: dmv-igsn{at}rub.de.
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Abstract |
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A novel spatial environment consists of several different types of information that may be encoded by cellular information storage mechanisms such as long-term potentiation (LTP) and long-term depression (LTD). Arousal, mediated, for example, by activation of the noradrenergic system, is a critical factor in information acquisition and may enhance the encoding of novel spatial information. Using electrophysiological recordings of hippocampal responses in freely moving rats during spatial learning, we investigated the role of the β-adrenoreceptor in Schaeffer collateral–CA1 synaptic plasticity. We found that novel exploration of spatial context facilitates induction of LTD that is inhibited by intracerebroventricular application of the β-adrenoreceptor antagonist, propranolol. Long-lasting homosynaptic LTD, that was electrically induced by low-frequency stimulation, was unaffected by the antagonist. Although application of a β-adrenoreceptor agonist (isoproterenol) did not affect electrically induced LTD, agonist application facilitated short-term depression (STD) into LTD and mimicked the augmentation, through spatial exploration, of STD into LTD. Exploration of a novel empty environment facilitated LTP that was prevented by application of propranolol. These results suggest that β-adrenoreceptors may facilitate encoding of spatial information through synaptic plasticity in the hippocampus and that noradrenaline is a key factor in effective information acquisition.
Key Words: beta-adrenergic receptor • CA1 • long-term depression • long-term potentiation • noradrenaline • novelty exploration • spatial learning
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Introduction |
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The hippocampus unequivocally participates in formation of learning and memory. Hippocampal encoding and storage of information is dependent on changes in synaptic strength (Martin et al. 2000
; Kemp and Manahan-Vaughan 2007a) that are bidirectional (Bear 1996). The type of information encoded is dependent on the type of plasticity expressed in the synapse (Manahan-Vaughan and Braunewell 1999; Kemp and Manahan-Vaughan 2004, 2007a). The term metaplasticity has been introduced to describe the influence of the prior history of a synapse on the synaptic efficacy (Abraham and Bear 1996). This implies that different behavioral states of an animal and the activation of different neurotransmitter systems influence the direction and probability of long-term plasticity subsequently induced at the synapse. Thus, neuromodulation plays an important role in setting the scene for encoding memories. In particular, the integrity of the noradrenergic system has been shown to be important for novelty exploration (Delini-Stula et al. 1984) as well as for memory retrieval (Devauges and Sara 1991; Murchison et al. 2004) and reconsolidation (Roullet and Sara 1998).
The hippocampus receives a noradrenergic input that stems exclusively from the locus coeruleus (Loy et al. 1980). Although the major innervation is found in the dentate gyrus and the concentration of noradrenaline there is twice the concentration found in the hippocampus proper, the distribution of β-adrenoreceptors is equal in all areas of the hippocampus (Crutcher and Davis 1980). Novelty exploration causes an enhanced activity of the locus coeruleus and enhanced release of noradrenaline in the hippocampus (Sara et al. 1994). Direct application of noradrenaline (Lacaille and Harley 1985; Stanton and Sarvey 1985; Harley 1991) to slices increases cell excitability recorded in dentate gyrus by a mechanism involving β-adrenoreceptors (Kitchigina et al. 1997). More recently, it has become apparent that increasing the level of noradrenaline via locus coeruleus stimulation in vivo potentiates hippocampal synaptic responses 24 h after stimulation (Walling and Harley 2004), suggesting that this system is also involved in memory mechanisms. In line with this, it has been observed that facilitation of long-term potentiation (LTP) in the dentate gyrus through novel exploration involves the β-adrenoreceptor system (Straube, Korz et al. 2003). Furthermore, injection of a β-adrenergic antagonist directly into area CA1 impairs long-term memory of a water maze spatial task (Ji et al. 2003).
Facilitation of hippocampal LTP by exploration of novel space has been reported by various studies (Li et al. 2003; Straube, Korz, and Frey 2003; Davis et al. 2004; Kemp and Manahan-Vaughan 2004). A distinct time window for facilitation of LTP exists. If novelty exploration happens after high-frequency stimulation (HFS), it has a detrimental effect on LTP (Xu et al. 1998; Abraham et al. 2002), whereas HFS given during exploration of novel space facilitates LTP (Kemp and Manahan-Vaughan 2004, 2007b). However, our previous studies have shown that acquisition of other novel features of an environment, such as spatial context, is associated with the facilitation of long-term depression (LTD) (Manahan-Vaughan and Braunewell 1999; Kemp and Manahan-Vaughan 2004; Lemon and Manahan-Vaughan 2006). Given the importance of the noradrenergic system for novelty-induced behavior and novelty-facilitated LTP in the dentate gyrus, it is feasible that spatial novelty-induced plasticity in CA1 is directed by β-adrenoreceptors. The hitherto uncharacterized role of β-adrenoreceptors in the expression of homosynaptic and learning-facilitated LTD was therefore the subject of this study.
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Materials and methods |
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Electrophysiology
Seven- to eight-week-old male Wistar rats (Charles River, Germany) were anesthetized (52 mg/kg pentobarbital) and underwent chronic implantation of a monopolar recording electrode in CA1 stratum radiatum (AP: –2.8; ML: 1.8) and a bipolar stimulation electrode in the Schaffer collaterals (AP: –3.1; ML: –3.1). To enable injections, a guide cannula was placed in the ipsilateral cerebral ventricle as described previously (Manahan-Vaughan 1997). Experiments commenced 7–10 days after surgery. During all experiments, the animals could move freely in the recording chamber (40 x 40 x 50 cm) and had free access to food and water. To allow the animals to acclimatize, they were transferred to the experiment room the day before the experiment took place.
The head stage was connected to an amplifier and stimulator via a flexible cable with a swivel connector. Recordings were analyzed and stored on computer, and the electroencephalogram was monitored throughout experiments.
To evoke field excitatory post-synaptic potentials (fEPSPs), a biphasic pulse was given with half-wave duration of 0.2 ms. For recordings, the stimulation intensity was set to produce a fEPSP, which was 40% of the maximal obtainable slope value. The intensity was found on the basis of an input–output curve (maximal stimulation 900 µA). Each recording consisted of an average of 5 consecutive pulses at 0.025 Hz. To ensure stability of recordings, all animals were first tested in a baseline experiment over the same time period as subsequent experiments.
To induce LTD, a low-frequency stimulation (LFS) consisting of 900 pulses at 1 Hz was given with a stimulus intensity that yielded potentials that were 70% of the maximal fEPSP slope observed during the input–output curve analysis.
A subthreshold LFS (subLFS, 600 pulses, stimulus intensity set as above) was applied to induce short-term depression (STD). LTP (>24 h) was obtained by stimulation with high-frequency tetanization (HFT). This was comprised of 4 bursts of 100 pulses at 100 Hz, with a 5-min interburst interval. For short-term potentiation (STP), 1 or 2 bursts were used. Animals participating in LTP experiments had a minimum age of 12 weeks as it has been observed that application of HFT in younger animals causes epileptiform seizures.
Novelty Exploration
In the experiments involving learning-induced plasticity, a holeboard (39.8 x 39.8 cm) was inserted into the recording chamber immediately after the first hour of recording and left there while subLFS or subthreshold HFT (subHFT) was applied. Animals were allowed to explore the holeboard for 10 min before it was removed. The holeboard had 4 holes (5.5 cm in diameter and 5 cm deep), one in each corner, and in each hole, a small a object was placed. The objects were different in shape, color, texture, and size, but none of them were larger than the holes. When subthreshold HFS (subHFS) was applied, the holes were empty (empty holeboard). To ensure maximal familiarization with the recording chamber and external environment, the individual rats were assigned a particular recording chamber where all experiments with the animal were carried out.
The terms "electrically induced" plasticity and "learning-facilitated" plasticity were used to distinguish between synaptic plasticity induced exclusively by electrical stimulation and plasticity induced by the combination of novel spatial exploration with mild electrical stimulation (that would normally not induce long-lasting plasticity).
Drugs
The β-adrenoreceptor antagonist propranolol or the agonist isoproterenol (Biotrend, Germany) was dissolved in isotonic saline (0.9% NaCl) solution and injected in a 5 µl volume. Throughout plasticity experiments, the used amounts of drugs were 2 and 20 µg for propranolol and isoproterenol, respectively. These concentrations were chosen on the basis of baseline experiments, as they did not influence basal synaptic transmission (Fig. 1). In control experiments, a vehicle injection of 5 µl saline was given. All injections were given via the intracerebral ventricle in the ipsilateral lateral ventricle via the implanted cannula.
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Data Analysis
For each time point, 5 consecutively evoked responses at 40 s intervals were averaged. The first 30 min of recording (6 time points) served as baseline, and the results were expressed as the mean percentage ± the standard error of the mean of the average baseline value. Recordings were made every 5 min until 30 min after LFS/HFT and then every 15 min until 4 h had elapsed. The following day, an additional 1 h of recordings were obtained. For analysis of difference between groups, a 2-way analysis of variance (ANOVA) was applied. Statistical differences between individual time points were assessed with t-test. Level of significance was set at P < 0.05.
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Results |
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Learning-Facilitated LTD Is Dependent on β-Adrenoreceptors
Initially, we evaluated the effects of pharmacological agonism and antagonism of β-adrenoreceptors to establish concentrations that were subthreshold for effects on basal synaptic transmission. The general β-adrenoreceptor antagonist propranolol was tested in 2 concentrations (Fig. 1A). The lowest concentration of 2 µg did not significantly change basal synaptic transmission (ANOVA: F1,26 = 1.57, P = 0.2210; vehicle experiment compared with drug experiment, n = 10 in both groups). However, by raising the concentration of the drug to 5 µg (n = 4), a depression of the fEPSPs occurred (ANOVA: F1,26 = 158.51, P < 0.0001). The effect became evident 1 h after the injection (P = 0.0434, t-test). The recordings obtained the following day revealed that the synaptic transmission had not recovered (P = 0.0411, t-test comparing the vehicle experiment with the drug experiment at t = 24 h).
We then examined if pharmacological activation of β-adrenoreceptors could alter baseline responses. Three doses of the agonist isoproterenol were tested: 10 µg (n = 6), 20 µg (n = 7), and 30 µg (n = 12). None of these concentrations resulted in a significant alteration of baseline recordings (Fig. 1B). However, signs of discomfort, such as panting, increased activity, and piloerection, were observed by application of 30 µg isoproterenol. Therefore, we chose to use 20 µg isoproterenol in our experiments.
SubLFS (1 Hz, 600 pulses) when given alone induced STD that returned to baseline levels after approximately 1 h (Fig. 2A). However, when a novel spatial environment, consisting of a holeboard, that contained a spatial distribution of slightly concealed objects was introduced to the control group, during subLFS, LTD occurred that lasted for at least 24 h (n = 11).
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Injection of the β-adrenoreceptor agonist, isoproterenol (20 µg, n = 6), did not change the profile of learning-facilitated LTD. ANOVA revealed no statistical difference between the isoproterenol group and the controls (F1,24 = 227, P > 0.05). However, animals treated with the β-adrenoreceptor antagonist, propranolol (2 µg, n = 10), showed an impairment of LTD. As early as 10 min after induction, less depression was evident (77.1 ± 6.6% of pre-LFS level compared with 55.3 ± 4.4% in control group; t-test: P = 0.0062).
Eight days later, the experiment was repeated with the now "familiar" holeboard (Fig. 2B). This time, all groups were given a vehicle injection. The control group and isoproterenol group showed the previously observed habituation to the holeboard and the accompanying lack of induction of LTD. However, in the propranolol group, reexposure to the familiar holeboard facilitated LTD.
LTD Induced by LFS Is Not Modulated by β-Adrenoreceptors
LFS (900 pulses at 1 Hz) induces a long-lasting LTD (>24 h) under control conditions (Fig. 3, n = 9). When LFS was given in the presence of the β-adrenoreceptor agonist, isoproterenol (20 µg, n = 6), LTD occurred that was not significant from that elicited in vehicle-treated animals (Fig. 3; ANOVA between factor: F1,24 = 0.54, P = 0.465).
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Similarly no effect was found when LFS was given in the presence of the β-adrenoreceptor antagonist, propranolol (2 µg, n = 9). (ANOVA between factor: F1,24 = 3.70, P > 0.05, compared with vehicle-injected controls.)
β-Adrenoreceptor Activation Facilitates STD into LTD
As learning-facilitated LTD requires activation of β-adrenoreceptors, does this imply that activation of these receptors is critical for the facilitation of LTD? To address this question, in the next experiment, we investigated whether β-adrenoreceptor activation could positively modulate STD.
SubLFS induced synaptic depression in control animals that returned to baseline levels after 90 min (n =9; t-test: P = 0.196, LFS-treated animals compared with baseline experiment (Fig. 4). When the animals were treated with the β-adrenoreceptor agonist, isoproterenol (20 µg, n = 9), STD was enhanced into LTD (ANOVA: F1,24 = 31.4, P < 0.0001). LTD was still evident in the isoproterenol group 24 h after LFS (71.4 ± 8.3%). Thus, activation of β-adrenoreceptors facilitates LTD in the CA1 region.
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LTP Induced by Novelty Exploration Is Dependent on β-Adrenoreceptors
Exploration of a novel empty holeboard facilitates LTP in the CA1 region, where reexposure to the holeboard does not (Kemp and Manahan-Vaughan 2004). Here, we found that subHFT, which produces STP in controls (n = 14), induces LTP (n = 7, Fig. 5) by exploration of the empty holeboard (ANOVA: F1,24 = 139.1, P < 0001). Twenty-four hours after induction, LTP was still present in the novel holeboard group. When subHFS was given in the presence of the β-adrenoreceptor antagonist, propranolol (2 µg, n = 7), a complete inhibition of learning-facilitated LTP occurred (Fig. 5; ANOVA: F1,24 = 172.9, P < 0.0001). When compared with the response to subHFT alone, no significant change was evident (ANOVA:F1,24 = 2.48, P = 0.1162).
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Attenuation of LTP by β-Adrenoreceptor Antagonist Application
We also investigated the effect of β-adrenoreceptor antagonist treatment on HFT-induced LTP. Application of 4 trains of 100 Hz induces a robust LTP in animals, which received a vehicle injection (Fig. 6, n = 12). No decline was seen in the 24 h post-HFT measurement where the average was 149.0 ± 13.9%. The concentration of propranolol we used in this study blocks novelty-induced LTP in the dentate gyrus (Straube, Korz et al. 2003). HFT in the presence of the β-adrenoreceptor antagonist, with propranolol (2 µg, n = 12), resulted in an impairment of LTP under familiar conditions (Fig. 6, ANOVA: F1,24 = 159.72, P > 0.0001). By 24 h post-HFT, there was no longer any significant potentiation in the propranolol group (P = 0.2915, t-test.). Propranolol blocked the induction of LTP. The effect was evident from the first recording after HFT. (106.9 ± 4.1% in propranolol-treated animals vs. 153.2 ± 11.5% after vehicle injection, P = 0017, t-test).
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When HFT was given in the presence of the β-adrenoreceptor agonist, isoproterenol (20 µg, n = 10), the induction and expression of LTP was unaffected (Fig. 6, ANOVA: F1,24 = 3.14; P = 0.077).
Synaptic Potentiation Is Not Facilitated by β-Adrenoreceptor Activation
Although we observed no effect of isoproterenol on the persistent LTP induced by 4 bursts of 100 Hz, β-adrenoreceptor activity may modulate weaker forms of potentiation. To induce STP, we reduced the number of bursts in our HFT protocol (Fig. 7). Two bursts at 100 Hz generated STP in vehicle-injected animals that had an initial magnitude of 129.0 ± 15.5% of baseline values (n = 8). By 2 h after HFT, fEPSP values were not significantly different from the corresponding values in a baseline experiment (t-test: P = 0.108). The profile was not significantly changed by prior application of 20 µg isoproterenol (n = 7) (ANOVA: F1,24 = 0.05, P = 0.824). Thus, in this experiment, no modulation of STP was observed.
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Discussion |
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The results of this study indicate that both learning-facilitated LTD and learning-facilitated LTP in the hippocampal CA1 region critically require β-adrenoreceptor activation. On the other hand, LTD induced exclusively by electrical afferent stimulation is not impaired by β-adrenoreceptor antagonism, although activation of β-adrenoreceptors lowers the threshold for the induction of LTD. In contrast, LTP, induced by a strong tetanus alone, is prevented by antagonism of β-adrenoreceptors, although pharmacological activation of β-adrenoreceptors does not change the profile of LTP. These data support that changes in arousal, which are triggered by exploration of a novel environment and result in β-adrenoreceptor activation, facilitate synaptic plasticity. This may serve as a means to tag hippocampal information as salient enough to be stored in the form of LTP or LTD. These data also suggest that different mechanisms may underlie the persistence of learning-facilitated and electrically induced synaptic plasticity. Furthermore, β-adrenoreceptors may drive the bidirectionality of synaptic plasticity elicited solely by electrical stimulation.
Synaptic Plasticity as a Memory Mechanism
As reported previously, the type of novel information determines the direction of change of long-term plasticity (Manahan-Vaughan and Braunewell 1999; Kemp and Manahan-Vaughan 2004, 2005, 2007a, 2007b; Lemon and Manahan-Vaughan 2006). Thus, LTD induction is correlated to distinct features of spatial learning, such as learning of novel object–place configurations. This hypothesis is supported by a recent study using knockout mice with a deletion of the transcription factor Serum response factor (SRF) (Etkin et al. 2006). Here it was found that these mice have a selective impairment of LTD induction (whereas induction of LTP is spared) and exhibit selective learning deficits of novel contextual learning, whereas learning of novel odor discrimination is normal. The ability to form spatial working memory is also correlated to LTD induction: a clear correlation has been demonstrated between spatial memory, assessed in a spontaneous alteration task, and the magnitude of LTD (Nakao et al. 2002). Taken together, these studies support an independent role for a LTD mechanism in encoding of certain types of information in hippocampus.
Induction of LTP, on the other hand, is correlated to encoding of space per se. Thus, a novel empty holeboard facilitates LTP. Also exploration of a novel recording chamber facilitates LTP in CA1 (Li et al. 2003). This is not limited to area CA1 but has also been observed in dentate gyrus. For instance, exploration of a novel recording chamber facilitates LTP in dentate gyrus (Straube, Korz et al. 2003; Straube, Korz, and Frey 2003).
The Noradrenergic System and Novel Information Processing in the Hippocampus
Substantial evidence supports a role for the noradrenergic system in the processing of novel information. Novel stimuli initiate firing of locus coeruleus cells (Sara et al. 1995; Vankov et al. 1995). Furthermore, novelty exploration enhances the excitability of granule cells in dentate gyrus (Kitchigina et al. 1997), whereas novelty-facilitated LTP in dentate gyrus requires functional β-adrenoreceptors (Straube and Frey 2003; Straube, Korz, and Frey 2003). This concurs with the theory of noradrenaline functioning as a gating mechanism for hippocampal processing (Bouret and Sara 2005). The contribution of β-adrenoreceptors to expression of LTD has not previously been investigated. We show here that the β-adrenoreceptor antagonist, propranolol, inhibits expression of learning-facilitated LTD, which indicates a requirement for β-adrenoreceptors in this form of LTD in the CA1 region. Interestingly, this finding suggests that antagonism of β-adrenoreceptors blocks familiarization to a novel environment as well as the associated LTD. Upon reexposure to the "familiar" environment, the propranolol-treated animals behave as if they have never seen this environment before.
Although we did not conduct quantitative measurements of behavior in our study, these were done by others in a previous study using the same concentration of propranolol (Straube, Korz et al 2003). They reported that the drug did not influence a range of behavioral parameters including locomotory activity and stress hormone levels. This supports that the effects on learning and plasticity that we observed were not due to an effect of the drug on general behavior.
We could mimic the learning facilitation of LTD by injecting isoproterenol before subLFS under familiar conditions, which suggests that noradrenaline and β-adrenoreceptors comprise a central component of learning-facilitated plasticity. Here one could speculate that activation of the locus coeruleus and release of noradrenaline in the hippocampus is a necessary feature of the novel processing of spatial information.
β-Adrenoreceptors in LTD
β-Adrenoreceptors are Gs proteins coupled to the cyclic adenosine 3',5'-monophosphate (cAMP)/protein kinase A (PKA) cascade. LTD induced by LFS is dependent on the presence of specific subunits of PKA. Thus, induction of LTD is impaired in transgenic mice missing either the catalytic PKA subunit cβ1 or the regulatory subunit RIβ (Brandon et al. 1995; Qi et al. 1996). Interestingly, these mice exhibit no change in the overall level of PKA. On the other hand, changing the level of activated PKA with postsynaptic application of succinyl cAMP attenuates LTD (Mulkey et al. 1994; Kameyama et al. 1998). PKA isoforms may thus play a subtle role in LTD.
Our results indicate that activation of β-adrenoreceptors is necessary if LTD is to occur as a consequence of spatial context learning. An interesting corollary of this is that persistent homosynaptic LTD that is induced by prolonged LFS is both resistant to β-adrenoreceptor antagonism and agonism. These findings are in contrast to an in vitro study that reported that LFS (1 Hz, 900 pulses) induces LTD is inhibited by a concentration of isoproterenol that transiently facilitates baseline transmission (Katsuki et al. 1997). However, we used ligand concentrations that did not affect basal synaptic transmission and could therefore not have a direct effect on synaptic excitability and plasticity thresholds. Our findings suggest that the strong electrical stimulation, which evoked synaptic plasticity in this context, bypasses the need for β-adrenoreceptor activation. This may reflect the different physiological conditions during which information storage occurs—it is widely known that learning can be facilitated not only by arousal but also by fear, stress, and pain processes that recruit the noradrenergic system to differing degrees (Rochford and Dawes 1993; Debiec and LeDoux 2006; Srikumar et al. 2006).
β-Adrenoreceptor Antagonism Prevents Homosynaptic LTP
We found that in contrast to homosynaptic, electrically induced LTD, learning-facilitated LTP is inhibited by β-adrenoreceptor antagonism. A similar observation has been made in dentate gyrus where application of propranolol inhibited induction of LTP in freely moving animals (Straube and Frey 2003). In contrast, an in vitro study in mice reports that propranolol is ineffective in impeding the course of LTP induced in CA1 (Schimanski et al. 2007). Although, LTP was induced with 4 trains at 100 Hz. The intertrain interval was much shorter (i.e., 3 s.) This might be an issue in terms of the second messengers involved (see discussion below). The most notable difference between this study and our results is of course that one study was done in vitro and the other in awake animals. In isolated slices, a multitude of long-ranging monosynaptic and multisynaptic connections, all of which influence the efficacy of synaptic transmission, is disconnected. Furthermore, in awake animals, a tonic level of noradrenaline exists (Berridge and Waterhouse 2003) and other neuromodulators as for instance dopamine (Matsuda et al. 2006). Preparation of slices for in vitro experiments requires several hours of acclimatization in the recording chamber. At the time of recording, the presence of neuromodulators is presumably lower than basal levels found in awake animals (Matsuda et al. 2006).
We use intracerebroventricular injections, which ensures that hippocampal tissue is not disrupted. The caveat is that extrahippocampal structures such as the amygdala, where noradrenergic receptors are abundant, may also be influenced. Modulation of plasticity in the dentate gyrus by the amygdala is well-known (Frey et al. 2001; Akirav and Richter-Levin. 2002; Korz and Frey 2005). Although activation of β-adrenergic receptors in the amygdala does not directly influence LTP in the CA1 region (Vouimba et al. 2007), changes occurring downstream in networks connected to CA1 cannot be excluded.
Studies have reported that the requirement of PKA activation for the expression of LTP is dependent on the stimulation protocol (Woo et al. 2000, 2003). Multiple stimulation trains given with relatively long intertrain intervals (i.e., four 100 Hz train at 5 min intervals) do not induce LTP when PKA is either pharmacologically blocked (Frey et al. 1993) or PKA activity is reduced genetically. As mentioned above, β-adrenoreceptors stimulate cAMP formation. This suggests that the inhibition of LTP observed by β-adrenoreceptor antagonism could be due to an inhibition of PKA activation. On the other hand, synaptic potentiation induced with a single 100-Hz train is unaltered by PKA inhibition (Huang and Kandel 1994). Interestingly, animals exposed to an enriched environment express LTP in a PKA-dependent manner after stimulation with a single 100-Hz train (Duffy et al. 2001). Environmental enrichment increases the noradrenaline level in mice (Naka et al. 2002). Although, the animals are usually exposed to the enriched environment from an early age and they live in these environments over a long period, a tentative parallel may be drawn to our experiments. We did not investigate whether novelty exploration induces a PKA-dependent LTP facilitation, but it would be an interesting subject for further studies.
We did not find an enhancement of LTP by application of a β-adrenoreceptor agonist. However, this may derive from the fact that potent LTP had already been induced. In the dentate gyrus, weak HFT induced LTP in the presence of isoproterenol (Straube and Frey 2003). Thus, β-adrenoreceptor activation may play a permissive role where synaptic potentiation is weak (conferring perhaps a relevancy signal to this synaptic information). Another possible explanation could be that the 2 regions differ in their ratio of β1/β2 subtypes, with the dentate gyrus expressing the most β1-adrenoreceptors. Regional differences have previously been reported in a study comparing the role of β-adrenoreceptor contribution to LTP in CA1 and dentate gyrus (Swanson-Park et al. 1999). They found that LTP in dentate gyrus requires β-adrenoreceptor activation. However, in CA1 only, a slight enhancement of the induction phase could be obtained by activating β-adrenoreceptors. The contribution of β-adrenoreceptors to LTP is also dependent on the frequency of stimulation. Stimulation frequencies ranging from 5 to 10 Hz, which does not induce potentiation in CA1 in naive circumstances, elicit LTP in the presence of isoproterenol (Thomas et al. 1996; Katsuki et al. 1997; Gelinas and Nguyen 2005). Thus, the noradrenergic system may have a greater modulatory influence at the crossover point for LTD/LTP induction. It has been proposed that this system serves as a mechanism of network resetting to accommodate for adaptation of changes in the environment (Bouret and Sara 2005). Shifting of the crossover point for synaptic plasticity could be one way of initiating this network resetting.
β-Adrenoreceptor Antagonism Inhibits Learning-Facilitated LTP
Learning-facilitated LTP in the CA1 region was prevented by antagonism of β-adrenoreceptors. Our study is in contrast to a previous report (Li et al. 2003), where it was reported that novelty-facilitated LTP in CA1 is dependent on dopaminergic activation, whereas application of propranolol had no effect. However, there was a major difference in the relative order of behavioral and electrical stimulation compared with our study. In the previous study, they applied the electrical stimulation 5 min after novelty exploration was terminated, whereas we stimulated during the exploration phase. Locus coeruleus cells habituate rapidly (within seconds) to a novel stimulus (Kitchigina et al. 1997). Therefore, it can be presumed that the time window for noradrenergic intervention is narrow. After exploration is terminated and the animals have returned to their familiar surroundings, the noradrenaline concentration in CA1 may have returned to basal levels, which would explain the lack of a significant contribution to LTP induction reported by Li et al. (2003). When the electrical stimulation is applied while the locus coeruleus activity is at the highest (i.e., immediately after holeboard introduction), β-adrenoreceptors participate in LTP facilitation. Because β-adrenoreceptor activation alone does not mimic the merged effect of novelty exploration and subHFT, our results support that the NA system may mediate its effects on LTP indirectly via a β-adrenergic modulation of other neurotransmitter systems such as the dopaminergic system (Li et al. 2003; Lemon and Manahan-Vaughan 2006) or possibly the cholinergic system (Watabe et al. 2000).
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Conclusion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionConclusionReferences |
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Learning-facilitated induction of long-term plasticity in CA1 is regulated by β-adrenoreceptors. Pharmacological activation of β-adrenoreceptors is sufficient to mimic the behavioral effect on LTD facilitation, which suggests that novelty-induced LTD is crucially dependent on β-adrenoreceptor activation. However, although learning-facilitated LTP is blocked by propranolol, LTP facilitation does not occur by substituting holeboard exploration with application of isoproterenol. This suggests that whereas β-adrenoreceptor activation may be a critical component for information storage in LTD, LTP is enabled by this along with a number of other factors. This may reflect the different roles of LTP and LTD in the encoding of different types of information that together enable the creation of a map of a spatial environment.
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Acknowledgments |
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Conflict of Interest: None declared.
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References |
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