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Report

Novel Form of Long-Term Synaptic Depression in Rat Hippocampus Induced By Activation of 1 Adrenergic Receptors

¹Department of Neurobiology and the Civitan International Research Center and ²Department of Physiology and Biophysics, University of Alabama, Birmingham, Alabama 35294

Submitted 30 April 2003; accepted in final form 20 October 2003

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
Neurons located in the locus coeruleus project to hippocampus and provide noradrenergic innervation necessary for hippocampal-dependent learning and memory. The mechanisms underlying the function of norepinephrine (NE) in memory processing are unknown but likely reside in the ability of NE to modulate the efficacy of glutamate synaptic transmission via activation of G-protein-coupled adrenergic receptors. Here we show that application of NE to rat hippocampal slices in vitro induces a long-term depression (LTD) of synaptic transmission at excitatory CA3–CA1 synapses that persists for 40 min after agonist washout. This LTD, which we refer to as NE LTD, is mediated by activation of 1 adrenergic receptors because the 1 agonist methoxamine can induce LTD at the same magnitude as that induced with the nonselective adrenergic agonist NE. Furthermore, NE LTD induced by either NE or methoxamine is blocked with the 1 receptor antagonist, prazosin, but is unaffected by antagonists of 2 and receptors. This plasticity persists in the presence of the GABA_A receptor antagonist bicuculline, indicating that adrenergic modulation of GABA_A receptor-mediated transmission does not underlie NE LTD. Induction of NE LTD requires presynaptic activity during agonist application and postsynaptic activation of N-methyl-D-aspartate receptors, fulfilling Hebbian criteria of coincident pre- and postsynaptic activity. The expression of NE LTD is likely to be postsynaptic because paired-pulse facilitation ratios during NE LTD expression are not different from baseline, similar to LTD induced by low-frequency stimulation. Thus we report the identification and characterization of a novel Hebbian form of LTD in hippocampus that is induced after activation of 1 adrenergic receptors. This plasticity may be a mechanism by which the adrenergic system participates in normal cognitive function.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
Activity-dependent modifications of synaptic efficacy are collectively referred to as synaptic plasticity (Bliss and Collingridge 1993). Synaptic plasticity at hippocampal glutamate synapses is considered to be a cellular mechanism underlying learning and memory, and it can be expressed as a long-term increase (potentiation; LTP) or decrease (depression; LTD) in the efficacy of transmission. Especially relevant to memory processes are those plasticities dependent on postsynaptic Ca²⁺ entry through N-methyl-D-aspartate receptors (NMDARs) (Malenka 1999). In fact, NMDAR knockout mice lack NMDAR-dependent LTP and perform poorly on spatial-memory tasks (Tonegawa et al. 1996; Tsien et al. 1996). Although there has been much focus on LTP and its relation to learning and memory, a growing literature suggests that LTD is also critical to cognitive function (Braunewell and Manahan-Vaughan 2001; Manahan-Vaughan and Braunewell 1999; Nakao et al. 2002).

Imbalances in brain norepinephrine (NE) are implicated in cognitive deficits in several conditions, including schizophrenia, Alzheimer's disease, and Parkinson's disease (Friedman et al. 1999; Sirvio and MacDonald 1999). NE, which is released from fibers that originate in the locus coeruleus, modulates synaptic function via activation of G-protein-coupled adrenergic receptors, including 1, 2, and receptors. Interactions between the adrenergic system and synaptic plasticity are well documented, and these interactions may provide a mechanism through which the adrenergic system participates in memory processing (Bramham et al. 1997; Brocher et al. 1992; Hopkins and Johnston 1984; Huang and Kandel 1996; Izumi and Zorumski 1999; Katsuki et al. 1997; Pelletier et al. 1994; Thomas et al. 1996). Several reports have shown a facilitation of tetanus-induced LTP induction by NE through activation of adrenergic receptors (Hopkins and Johnston 1988; Huang and Kandel 1996; Lin et al. 2003; Thomas et al. 1996) with fewer studies examining a modulatory effect of NE on LTD induced by low-frequency stimulation (LFS) (Dahl and Sarvey 1989; Katsuki et al. 1997; Kirkwood et al. 1999). After activation of 1 adrenergic receptors by NE, a LTD of glutamate transmission has been observed previously in slices of visual cortex but not hippocampus (Kirkwood et al. 1999). This LTD is induced de novo during stimulation of basal transmission (0.1 Hz) without requiring a change in stimulation frequency or pattern that is usually required to induce LTD (e.g., LFS at 1 Hz for 15 min).

We now report that activation of 1 adrenergic receptors does indeed induce LTD at hippocampal CA3–CA1 synapses. This LTD, which we term NE LTD, possesses characteristics of a Hebbian form of synaptic plasticity (Hebb 1949) in that it requires coincident presynaptic activity and postsynaptic NMDAR activation. The finding that NE can induce LTD of glutamate transmission in hippocampus, as well as in visual cortex, suggests that this NE-dependent form of synaptic modulation is a general mechanism by which the adrenergic system manipulates synaptic efficacy. A documented role of 1 adrenergic receptors in memory processes (Sirvio and MacDonald 1999; Spreng et al. 2001) suggests the possibility that NE LTD may be a mechanism by which the adrenergic system contributes to normal hippocampal-dependent cognitive function.

	METHODS

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Slice preparation and electrophysiology

All experiments in this manuscript were conducted with an approved protocol from the University of Alabama at Birmingham Institutional Animal Care and Use Committee in compliance with National Institutes of Health guidelines. Hippocampal slices (400 µm) were prepared from 3- to 4-wk-old Sprague-Dawley rats using standard methods. Rats were anesthetized with halothane and decapitated, and the brain was removed and placed in ice-cold "high sucrose" artificial cerebrospinal fluid [ACSF containing (mM) 85 NaCl, 2.5 KCl, 4 MgSO₄, 0.5 CaCl₂, 1.25 NaH₂PO₄, 25 NaHCO₃, 25 glucose, 75 sucrose, 2 kynurenic acid, and 0.5 ascorbate]. The low-Na⁺ and -Ca²⁺ and high-sucrose content of this solution enhances neuronal survival during the slicing procedure. Coronal slices from the dorsal hippocampus were cut using a vibratome (Vibratome, St. Louis, MO). After a 30-min postslice incubation in high-sucrose ACSF, slices were transferred to a standard ACSF containing (mM) 119 NaCl, 2.5 KCl, 2.5 CaCl₂, 1.3 MgSO₄, 1 NaH₂PO₄, 26 NaHCO₃, and 10 glucose, saturated with 95% O₂-5% CO₂ (pH 7.4) and 2 mM kynurenic acid for an additional 30 min. For recordings, the slices were transferred to a submersion recording chamber and were continuously perfused at 3–4 ml/min with standard ACSF (described in the preceding text) without kynurenic acid warmed to 28–30°C.

CA1 extracellular dendritic field potentials were recorded (Axo-clamp 2B, Axon Instruments, CA) using standard methods (McMahon and Kauer 1997). A stainless steel bipolar stimulating electrode (FHC, Bowdoinham, ME) was placed in stratum(s.) radiatum to stimulate the Schaffer collaterals and a glass microelectrode filled with 2M NaCl was placed in CA1 s. radiatum to record extracellular dendritic field potentials (fEPSPs). Stimulus frequency was 0.1 Hz (100-µs duration), and the stimulus intensity was adjusted to yield a field EPSP of 0.8–1.0 mV in amplitude. The protocol for induction of NE-mediated LTD was adapted from Kirkwood et al. (Kirkwood et al. 1999). After acquisition of a stable baseline of fEPSPs for 20 min, agonists were bath applied to induce NE LTD. Antagonists were bath applied for 10 min prior to agonists. In experiments with the GABA_A receptor antagonist bicuculline, area CA3 was removed from the slice to prevent epileptic bursting. All drugs were prepared as stock solutions and frozen in aliquots until used in experiments. Immediately before recording, drugs were diluted to appropriate concentrations in the perfusate. All drugs were obtained from Sigma (St. Louis, MO).

Experiments testing activity dependence of NE LTD were performed by stimulating two independent pathways within the same slice with area CA3 removed to prevent potential oscillatory activity induced by adrenergic agonists. Pathway independence was assessed by testing for lack of paired-pulse facilitation between the two pathways (interpulse interval, 50 ms). During methoxamine application and for 3 min after (to ensure methoxamine was completely washed out of the chamber), stimulation to one pathway was ceased.

Data analysis

Data were filtered at 3 kHz, digitized at 10 kHz, and stored on a computer using Labview data-acquisition software (a gift from Richard Mooney, Duke University). The initial slope of the fEPSP was measured and plotted versus time, each point representing the average of five raw data points. Statistical significance between groups was carried out with Student's t-test. Significance was determined by P < 0.05. Data are presented as means ± SE. Only experiments with less than a 5% change in the original baseline were included in the analysis. All depression was measured at 30 min after washout of the agonist.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
Activation of 1 adrenergic receptors induces LTD in rat hippocampus

At CA3–CA1 glutamate synapses in rat hippocampal slices, we have found that application of NE (40 µM) reliably induces a LTD of synaptic transmission in extracellular dendritic field potential recordings that persists after agonist washout and continues for the duration of the experiment (Fig. 1, A and B; 82 ± 3% of baseline fEPSP slope, n = 6, P < 0.05). This LTD, which we refer to as norepinephrine LTD (NE LTD), is likely to be similar to an 1 adrenergic receptor-dependent form of LTD at glutamate synapses in slices of visual cortex (Kirkwood et al. 1999). Interestingly, this form of LTD was previously reported to be absent at hippocampal synapses (Kirkwood et al. 1999).

View larger version (28K): [in this window] [in a new window]   FIG. 1. Activation of 1 adrenergic receptors induces long-term depression (LTD) at hippocampal CA3–CA1 synapses. A: representative traces (average of 20 events) demonstrating the depression of the baseline dendritic field excitatory postsynaptic potential (fEPSP; before) during norepinephrine (NE) application (40 µM; during) and 30 min after washout (after). The sequence of the traces of the second event is the same as the 1st event. B: summary of 7 experiments showing that a 10-min application of NE induces a LTD of transmission (NE LTD) at CA3–CA1 synapses that persists after agonist washout. C: summary of 7 experiments showing that methoxamine (40 µM), an 1 adrenergic receptor agonist, induces LTD of the same magnitude as NE. D: summary of 4 experiments demonstrating that NE LTD (induced by 40 µM methoxamine) is unaffected by blockade of GABAA receptor-mediated inhibition with bicuculline (10 µM).

Because there is no change in the paired-pulse facilitation (PPF) ratio during expression of LTD induced by LFS (LFSLTD; 1 Hz 15-min duration), which is believed to have a postsynaptic expression mechanism (Luscher et al. 1999; Santschi and Stanton 2003), we were interested to determine if the PPF ratio is unaltered during expression of NE LTD as a preliminary indicator that expression of this form of LTD also might be postsynaptic. The PPF ratio (determined by dividing the slope of the 2nd fEPSP by that of the 1st when pairs of stimuli are given at interstimulus intervals usually ranging from 30 to 80 ms) varies inversely with release probability (Dobrunz and Stevens 1997). Therefore a lack of change in this ratio most often indicates a lack of change in the probability of release and may indicate that the site of change in synaptic efficacy is postsynaptic (but see Santschi and Stanton 2003). We found that the PPF ratio does not change during NE LTD expression, like during LFS-LTD, regardless of whether the plasticity was induced with methoxamine or NE (PPF ratio of 1.64 ± 0.04 during baseline and 1.66 ± 0.05 during NE LTD expression when induced with methoxamine n = 6, P > 0.2; PPF ratio of 1.54 ± 0.04 during baseline and 1.60 ± 0.04 during NE LTD expression when induced with NE, n = 6, P > 0.2, data not shown). Further analysis shows that the PPF ratio does not change during application of methoxamine but does significantly change during NE application (PPF ratio of 1.68 ± 0.05 during methoxamine application compared with 1.64 ± 0.04 during baseline, n = 6, P > 0.2; PPF ratio of 1.65 ± 0.04 during the NE application compared with 1.54 ± 0.04 during baseline, n = 6, P < 0.02, data not shown). This finding suggests that the nonselective adrenergic receptor agonist NE is activating a mechanism to cause a transient synaptic depression that the selective 1 adrenergic agonist does not and therefore may explain the significantly larger depression observed during NE application compared with methoxamine (Fig. 1, B and C, 66 ± 3% of baseline fEPSP slope during NE application, n = 6 and 85 ± 4% of baseline fEPSP slope during methoxamine application, n = 7, P < 0.01). In fact, previous reports have documented a short-term synaptic depression during adrenergic agonist application that is mediated by presynaptic adrenergic receptors (Boehm 1999; Scanziani et al. 1993). Because the magnitude of NE LTD is the same between the two agonists, this additional mechanism activated by NE must be unrelated to that necessary for induction of the long-term plasticity. Furthermore, because the PPF ratio does not change at any point during the experiment with methoxamine, the depression during methoxamine application is likely to be a result of the onset of NE LTD rather than the activation of presynaptic receptors.

We next tested whether changes in GABA_AR-mediated transmission may contribute to NE LTD because activation of 1 receptors increases the activity of inhibitory interneurons (Bergles et al. 1996; Madison and Nicoll 1988). We found that the magnitude of NE LTD induced by methoxamine in the presence of the GABA_A receptor antagonist bicuculline (10 µM) is not different from control (Fig. 1D; 82 ± 4% of baseline fEPSP slope in bicuculline n = 4; 82 ± 3% of baseline fEPSP slope in control, n = 4, P > 0.4), demonstrating that this plasticity is not a result of NE-induced changes in synaptic inhibition.

Other adrenergic receptor subtypes do not participate in NE LTD

Our finding that the 1 agonist methoxamine induces NE LTD at the same magnitude as NE provides strong evidence that the plasticity is mediated by 1 receptors. However, to provide additional support for a role of 1 receptors in NE LTD and to determine if activation of other receptor subtypes is involved, we tested whether antagonists of 1, 2, and receptors could prevent induction of NE LTD. When we used the 1 antagonist prazosin (10 µM), NE LTD induced by either methoxamine or NE was completely prevented (Fig. 2, A and B, 93 ± 2% of baseline fEPSP slope with methoxamine in prazosin, n = 6, P > 0.2; 95 ± 3% of baseline fEPSP slope with NE in prazosin, n = 6, P > 0.2), thus providing further evidence for a role of 1 receptors in NE LTD. Moreover, no methoxamine-induced depression of any kind was observed in the presence of prazosin, but NE was still able to elicit the transient depression in the presence of prazosin that was not different from control (Fig. 2B, 70 ± 15% of baseline fEPSP slope during NE application in prazosin, n = 6; 66 ± 3% of baseline fEPSP slope during NE alone, n = 6, P > 0.22). The lack of an effect of prazosin on the NE-induced transient depression supports the idea that this effect of NE is not mediated by 1 receptors and that the transient depression and the LTD are mediated by two separate mechanisms. In testing a potential involvement of other adrenergic receptors, we found that the magnitude of the NE LTD is completely unaffected by the 2 antagonist yohimbine (3 µM, Fig. 2C; 83 ± 5% of baseline fEPSP slope in yohimbine, n = 6; 82 ± 3% of baseline fEPSP slope without yohimbine, n = 6, P > 0.9) or the receptor antagonist propranolol (10 µM, Fig. 2D; 80 ± 3% of baseline fEPSP slope in propranolol, n = 5; 82 ± 3% of baseline fEPSP slope without propranolol n = 6, P > 0.6), indicating that adrenergic receptor subtypes other than 1 receptors are not likely to be involved in NE LTD. Surprisingly, neither the 2 or antagonist, when applied alone, had any affect on the magnitude of the transient depression, although the 2 antagonist prevented the increase in the PPF ratio during NE application (PPF ratio of 1.65 ± 0.06 during baseline and 1.86 ± 0.11 during NE application in yohimbine, n = 6, P > 0.06, data not shown), suggesting the possibility that NE is activating presynaptic 2 receptors. However, when we simultaneously blocked 2 and receptors, we observed a significantly reduced transient depression during NE application (Fig. 2E; 66 ± 3% of baseline fEPSP slope during NE alone, n = 6 and 79 ± 4% of baseline fEPSP slope during NE with yohimbine plus propranolol, n = 5, P < 0.01). Simultaneous blockade of and receptors prevented the increase in the PPF ratio during NE application (PPF ratio of 1.66 ± 0.06 during baseline and 1.73 ± 0.08 during NE application, n = 5, P 0.05) but had no affect on the magnitude of the LTD (82 ± 3% of baseline fEPSP slope with NE alone and 79 ± 3% of baseline fEPSP slope with NE in yohimbine plus propranolol, P > 0.05). In fact, the effect of NE on transmission during simultaneous blockade of 2 and receptors completely mimics that observed during 1 receptor activation with methoxamine (85 ± 3% of baseline fEPSP slope during methoxamine and 79 ± 4% of baseline fEPSP slope during NE in yohimbine and propranolol, P > 0.05).

View larger version (35K): [in this window] [in a new window]   FIG. 2. An adrenergic 1 but not 2 or receptor antagonist prevents induction of NE LTD. A: prazosin (10 µM), an 1 adrenergic receptor antagonist, prevents induction of NE LTD by the 1 agonist, methoxamine (40 µM; n = 6). B: prazosin (10 µM) also prevents induction of NE LTD by the nonselective adrenergic receptor agonist, NE (40 µM), but the transient depression during the agonist application remains (n = 6). C: application of NE (40 µM) in the presence of yohimbine (3 µM), an 2 adrenergic receptor antagonist, does not prevent NE LTD (n = 6). D: application of NE in the presence of propranolol (10 µM), a adrenergic receptor antagonist, does not prevent NE LTD (n = 6). E: co-application of yohimbine (3 µM) and propranolol (10 µM) reduces the magnitude of the transient depression elicited by NE (40 µM) but has no effect on NE LTD (n = 5). F: blockade of 1 receptors with prazosin (10 µM) does not prevent induction of LTD induced by low-frequency stimulation (1 Hz, 15 min).

NE LTD has Hebbian characteristics

Forms of synaptic plasticity that satisfy the criteria defined by Hebb (1949) are thought to be especially relevant to learning and memory (Malenka 1999). We next tested whether NE LTD requires coincident pre- and postsynaptic activity. We found that NE LTD is dependent on presynaptic activity and is homosynaptic because when we stimulate two independent pathways within the same slice, NE LTD is expressed only in the pathway that is active during methoxamine application (Fig. 3, A and B; unstimulated path: 95 ± 5% of baseline fEPSP slope, P > 0.4, stimulated path: 80 ± 3% of baseline fEPSP slope, n = 6, P < 0.01). Furthermore, we have found that NE LTD requires activation of postsynaptic NMDARs, as it is blocked by 100 µM D,L-2-amino-5-phosphonovaleric acid, an NMDAR antagonist (Fig. 3, C and D; 93 ± 4% of baseline fEPSP slope, n = 6, P > 0.05). Normal NE LTD was expressed in interleaved control slices (n = 4, 83 ± 3% of baseline fEPSP slope, data not shown).

View larger version (29K): [in this window] [in a new window]   FIG. 3. NE LTD possesses criteria of a Hebbian form of synaptic plasticity. A, 1 and 2: representative traces (average of 20 events) demonstrating that NE LTD is induced in the pathway that receives presynaptic stimulation during methoxamine (40 µM) application (A1) but is not induced in the pathway that receives no presynaptic stimulation during methoxamine application (A2). Scale bars: 10 ms, 0.5 mV. A representative single example (B1) and summary of 6 experiments (B2) demonstrating that NE LTD (induced with 40 µM methoxamine) is homosynaptic and requires presynaptic activity. When stimulation to 1 pathway is ceased during methoxamine application in slices with CA3 cell bodies removed, LTD is not expressed in that pathway () but is expressed in the active pathway (). A representative single example (C1) and summary of 7 experiments (C2) demonstrating that NE LTD (induced with 40 µM methoxamine) is NMDAR dependent as it is blocked in the presence of the NMDA receptor antagonist, D,L-2-amino-5-phosphonovaleric acid (100 µM).

	DISCUSSION

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Despite the fact that during the past two decades there have been numerous reports examining modulation of hippocampal excitability by the adrenergic system, a long-lasting depression of transmission at CA3–CA1 synapses mediated by this system surprisingly has not been described previously. In elegant early studies, Dunwiddie and colleagues (Mynlieff and Dunwiddie 1988) likely observed the 1 adrenergic receptor-dependent LTD that we describe here because they found that activation of 1 receptors elicits a long-lasting depression of the CA1 population spike amplitude recorded in hippocampal slices that persisted after agonist application. These investigators attributed the lack of recovery of the population spike amplitude to poor washout of the agonist from the slice rather than to a long-term change in synaptic efficacy. However, the fact that the long-lasting depression we observe is prevented by blocking NMDA receptors and is dependent on presynaptic activity demonstrates that it is not due to incomplete agonist washout. In another study, Thompson and coworkers (Scanziani et al. 1993) have shown in area CA3 of cultured hippocampal slices that activation of 1 receptors depresses transmission at both mossy fiber synapses and synapses made by recurrent Schaffer collaterals, although the depression recovered to baseline after agonist washout. In their experiments, NMDARs were blocked by the selective antagonist AP5, which, based on our results, could have prevented induction of LTD in their system. Although NMDAR blockade prevents induction of NE LTD, as we show in Fig. 3C and D, the synaptic depression during agonist application (transient depression) is unaffected and appears similar to the depression observed by Scanziani et al. These investigators suggest that the mechanism underlying the depression is a result of activation of presynaptic 1 receptors, although they did not observe a change in either miniature excitatory postsynaptic current amplitude or frequency. However, based on our analysis that the PPF ratio does not change at any point after 1 activation, we propose that the depression observed during 1 agonist application is the result of a postsynaptic depression that can become long-lasting with concurrent NMDAR activation. Thus although it appears clear that 1 receptors are required for induction of NE LTD, the identity of the adrenergic receptor subtype responsible for the transient depression is less clear. We show that blockade of 2 or receptors alone has no effect on the magnitude of the NE LTD or the transient depression, although the 2 antagonist prevented the increase in the PPF ratio that occurs during NE application. Surprisingly however, we found that simultaneous blockade of 2 and receptors reduces the depression during agonist application to the level induced by selective 1 receptor activation without altering the magnitude of the LTD. This finding demonstrates that when 2 and receptors are unavailable, the nonselective adrenergic agonist NE is able to completely mimic the effects of methoxamine, the selective 1 agonist. Furthermore, this finding implies cross-talk between 2 and receptors so that blockade of one does not prevent the short-term modulation by NE on synaptic transmission. Future studies are required to fully understand the nature of the interactions between these two classes of receptors and their combined ability to modulate transmission at these synapses.

The specific biochemical mechanism underlying NE LTD is presently unexplored, but likely involves an increase in intracellular Ca²⁺ as do other forms of synaptic plasticity (Chittajallu et al. 1998). The role of intracellular Ca²⁺ in this plasticity is implicit due to the NMDAR dependence of NE LTD induction. However, the involvement of NMDARs in this LTD is surprising because under basal stimulating conditions, where NE LTD is induced, NMDARs are normally inactive (Mayer et al. 1984). Interestingly, 1 adrenergic receptor activation can increase the amplitude of NMDAR-mediated responses (Segal et al. 1991), potentially allowing NMDARs, in the presence of NE, to be active during basal transmission and participate in the induction of NE LTD. In addition to increasing intracellular Ca²⁺ through modulation of NMDARs, activation of 1 adrenergic receptors can increase intracellular Ca²⁺ as a result of G_q-coupled phospholipase C activation and the production of IP₃ (Summers and McMartin 1993). IP₃ increases the intracellular Ca²⁺ concentration through activation of IP₃ receptors located on the endoplasmic reticulum, an intracellular Ca²⁺ store. Thus 1 adrenergic receptor-mediated plasticity in hippocampus may result from a combination of IP₃- and NMDAR-mediated Ca²⁺ transients.

Evidence linking LTD to learning and memory has lagged behind reports associating LTP with cognitive processes. However, LTD has been observed in the CA1 hippocampal region in vivo (Heynen et al. 1996; Thiels et al. 1996) and like LTP, is becoming recognized as a necessary cellular mechanism underlying learning and memory. This idea is supported by studies demonstrating that bidirectional plasticity is required for normal memory acquisition and consolidation (Braunewell and Manahan-Vaughan 2001; Manahan-Vaughan and Braunewell 1999; Migaud et al. 1998; Zeng et al. 2001). Facilitation of LTD induction during learning in a novel environment provides direct evidence demonstrating an active role for LTD in hippocampal-dependent memory processing (Manahan-Vaughan and Braunewell 1999). In addition, the loss of LTD at CA3–CA1 synapses after fibria-fornix lesions and in knockout animals that lack calcineurin or PSD-95 correlates with poor spatial memory (Migaud et al. 1998; Nakao et al. 2002; Zeng et al. 2001).

1 adrenergic receptors are implicated in spatial memory, as 1 adrenergic receptor agonists enhance and antagonists impair memory formation (Pussinen et al. 1997; Puumala et al. 1998; Riekkinen et al. 1997). Moreover, 1_b adrenergic receptor knockout mice are unable to learn a water-maze task, indicating spatial memory deficits (Spreng et al. 2001). It has been hypothesized that cognitive deficits associated with human aging or Alzheimer's disease are due in part to decreased number and/or function of 1 receptors throughout the brain (Burnett and Zahniser 1989; Burnett et al. 1990; Knauber and Muller 2000). Given the role of 1 adrenergic receptors in memory and LTD, the potential exists that the NE LTD we describe in this study may participate in hippocampal-dependent memory.

	ACKNOWLEDGMENTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
We thank C. Starr for secretarial assistance.

GRANTS

This study was supported by National Institutes of Health Grants AG-16582 Pilot Project to L. L. McMahon and L. E. Dobrunz and NS-45469 to C. L. Scheiderer.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Address for reprint requests and other correspondence: L. L. McMahon, The University of Alabama, 1918 University Blvd., MCLM 964, Birmingham, AL 35294-0005 USA (E-mail: mcmahon{at}physiology.uab.edu).

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
Bergles DE, Doze VA, Madison DV, and Smith SJ. Excitatory actions of norepinephrine on multiple classes of hippocampal CA1 interneurons. J Neurosci 16: 572-585, 1996.[Abstract/Free Full Text]

Bliss TV and Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361: 31-39, 1993.[CrossRef][Medline]

Boehm S. Presynaptic alpha2-adrenoceptors control excitatory, but not inhibitory, transmission at rat hippocampal synapses. J Physiol 519: 439-449, 1999.[Abstract/Free Full Text]

Bramham CR, Bacher-Svendsen K, and Sarvey JM. LTP in the lateral perforant path is beta-adrenergic receptor-dependent. Neuroreport 8: 719-724, 1997.[Web of Science][Medline]

Braunewell KH and Manahan-Vaughan D. Long-term depression: a cellular basis for learning? Rev Neurosci 12: 121-140, 2001.[Web of Science][Medline]

Brocher S, Artola A, and Singer W. Agonists of cholinergic and noradrenergic receptors facilitate synergistically the induction of long-term potentiation in slices of rat visual cortex. Brain Res 573: 27-36, 1992.[CrossRef][Web of Science][Medline]

Burnett DM, Bowyer JF, Masserano JM, and Zahniser NR. Effect of aging on alpha-1 adrenergic stimulation of phosphoinositide hydrolysis in various regions of rat brain. J Pharmacol Exp Ther 255: 1265-1270, 1990.[Abstract/Free Full Text]

Burnett DM and Zahniser NR. Region-specific loss of alpha 1-adrenergic receptors in rat brain with aging: a quantitative autoradiographic study. Synapse 4: 143-155, 1989.[CrossRef][Web of Science][Medline]

Chittajallu R, Alford S, and Collingridge GL. Ca²⁺ and synaptic plasticity. Cell Calcium 24: 377-385, 1998.[CrossRef][Web of Science][Medline]

Dahl D and Sarvey JM. Norepinephrine induces pathway-specific long-lasting potentiation and depression in the hippocampal dentate gyrus. Proc Natl Acad Sci USA 86: 4776-4780, 1989.[Abstract/Free Full Text]

Dobrunz LE and Stevens CF. Heterogeneity of release probability, facilitation, and depletion at central synapses. Neuron 18: 995-1008, 1997.[CrossRef][Web of Science][Medline]

Friedman JI, Adler DN, and Davis KL. The role of norepinephrine in the pathophysiology of cognitive disorders: potential applications to the treatment of cognitive dysfunction in schizophrenia and Alzheimer's disease. Biol Psychiatry 46: 1243-1252, 1999.[CrossRef][Web of Science][Medline]

Hebb D. The Organization of Behavior. New York: Wiley, 1949.

Heynen AJ, Abraham WC, and Bear MF. Bidirectional modification of CA1 synapses in the adult hippocampus in vivo. Nature 381: 163-166, 1996.[CrossRef][Medline]

Hopkins WF and Johnston D. Frequency-dependent noradrenergic modulation of long-term potentiation in the hippocampus. Science 226: 350-352, 1984.[Abstract/Free Full Text]

Hopkins WF and Johnston D. Noradrenergic enhancement of long-term potentiation at mossy fiber synapses in the hippocampus. J Neurophysiol 59: 667-687, 1988.[Abstract/Free Full Text]

Huang YY and Kandel ER. Modulation of both the early and the late phase of mossy fiber LTP by the activation of beta-adrenergic receptors. Neuron 16: 611-617, 1996.[CrossRef][Web of Science][Medline]

Izumi Y and Zorumski CF. Norepinephrine promotes long-term potentiation in the adult rat hippocampus in vitro. Synapse 31: 196-202, 1999.[CrossRef][Web of Science][Medline]

Katsuki H, Izumi Y, and Zorumski CF. Noradrenergic regulation of synaptic plasticity in the hippocampal CA1 region. J Neurophysiol 77: 3013-3020, 1997.[Abstract/Free Full Text]

Kirkwood A, Rozas C, Kirkwood J, Perez F, and Bear MF. Modulation of long-term synaptic depression in visual cortex by acetylcholine and norepinephrine. J Neurosci 19: 1599-1609, 1999.[Abstract/Free Full Text]

Knauber J and Muller WE. Subchronic treatment with prazosin improves passive avoidance learning in aged mice: possible relationships to alpha1-receptor up-regulation. J Neural Transm 107: 1413-1426, 2000.[CrossRef][Web of Science][Medline]

Lin YW, Min MY, Chiu TH, and Yang HW. Enhancement of associative long-term potentiation by activation of beta-adrenergic receptors at CA1 synapses in rat hippocampal slices. J Neurosci 23: 4173-4181, 2003.[Abstract/Free Full Text]

Luscher C, Xia H, Beattie EC, Carroll RC, von Zastrow M, Malenka RC, and Nicoll RA. Role of AMPA receptor cycling in synaptic transmission and plasticity. Neuron 24: 649-658, 1999.[CrossRef][Web of Science][Medline]

Madison DV and Nicoll RA. Norepinephrine decreases synaptic inhibition in the rat hippocampus. Brain Res 442: 131-138, 1988.[CrossRef][Web of Science][Medline]

Malenka RC. Long-term potentiation—a decade of progress? Science 285: 1870-1875, 1999.[Abstract/Free Full Text]

Manahan-Vaughan D and Braunewell KH. Novelty acquisition is associated with induction of hippocampal long-term depression. Proc Natl Acad Sci USA 96: 8739-8744, 1999.[Abstract/Free Full Text]

Mayer ML, Westbrook GL, and Guthrie PB. Voltage-dependent block by Mg²⁺ of NMDA responses in spinal cord neurones. Nature 309: 261-263, 1984.[CrossRef][Medline]

McMahon LL and Kauer JA. Hippocampal interneurons express a novel form of synaptic plasticity. Neuron 18: 295-305, 1997.[CrossRef][Web of Science][Medline]

Migaud M, Charlesworth P, Dempster M, Webster LC, Watabe AM, Makhinson M, He Y, Ramsay MF, Morris RG, Morrison JH, O'Dell TJ, and Grant SG. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 396: 433-439, 1998.[CrossRef][Medline]

Mulkey RM and Malenka RC. Mechanisms underlying induction of homo-synaptic long-term depression in area CA1 of the hippocampus. Neuron 9: 967-975, 1992.[CrossRef][Web of Science][Medline]

Mynlieff M and Dunwiddie TV. Noradrenergic depression of synaptic responses in hippocampus of rat: evidence for mediation by alpha 1-receptors. Neuropharmacology 27: 391-398, 1988.[CrossRef][Web of Science][Medline]

Nakao K, Ikegaya Y, Yamada MK, Nishiyama N, and Matsuki N. Hippocampal long-term depression as an index of spatial working memory. Eur J Neurosci 16: 970-974, 2002.[CrossRef][Web of Science][Medline]

Pelletier MR, Kirkby RD, Jones SJ, and Corcoran ME. Pathway specificity of noradrenergic plasticity in the dentate gyrus. Hippocampus 4: 181-188, 1994.[CrossRef][Web of Science][Medline]

Pussinen R, Nieminen S, Koivisto E, Haapalinna A, Riekkinen P Sr, and Sirvio J. Enhancement of intermediate-term memory by an alpha-1 agonist or a partial agonist at the glycine site of the NMDA receptor. Neurobiol Learn Mem 67: 69-74, 1997.[CrossRef][Web of Science][Medline]

Puumala T, Greijus S, Narinen K, Haapalinna A, Riekkinen P Sr, and Sirvio J. Stimulation of alpha-1 adrenergic receptors facilitates spatial learning in rats. Eur Neuropsychopharmacol 8: 17-26, 1998.[CrossRef][Web of Science][Medline]

Riekkinen M, Kemppainen S, and Riekkinen P Jr. Effects of stimulation of alpha 1-adrenergic and NMDA/glycine-B receptors on learning defects in aged rats. Psychopharmacology 131: 49-56, 1997.[CrossRef][Medline]

Santschi LA and Stanton PK. A paired-pulse facilitation analysis of long-term synaptic depression at excitatory synapses in rat hippocampal CA1 and CA3 regions. Brain Res 962: 78-91, 2003.[CrossRef][Web of Science][Medline]

Scanziani M, Gahwiler BH, and Thompson SM. Presynaptic inhibition of excitatory synaptic transmission mediated by alpha adrenergic receptors in area CA3 of the rat hippocampus in vitro. J Neurosci 13: 5393-5401, 1993.[Abstract]

Segal M, Markram H, and Richter-Levin G. Actions of norepinephrine in the rat hippocampus. Prog Brain Res 88: 323-330, 1991.[Web of Science][Medline]

Sirvio J and MacDonald E. Central alpha1-adrenoceptors: their role in the modulation of attention and memory formation. Pharmacol Ther 83: 49-65, 1999.[CrossRef][Web of Science][Medline]

Spreng M, Cotecchia S, and Schenk F. A behavioral study of alpha-1b adrenergic receptor knockout mice: increased reaction to novelty and selectively reduced learning capacities. Neurobiol Learn Mem 75: 214-229, 2001.[CrossRef][Web of Science][Medline]

Summers RJ and McMartin LR. Adrenoceptors and their second messenger systems. J Neurochem 60: 10-23, 1993.[Web of Science][Medline]

Thiels E, Xie X, Yeckel MF, Barrionuevo G, and Berger TW. NMDA receptor-dependent LTD in different subfields of hippocampus in vivo and in vitro. Hippocampus 6: 43-51, 1996.[CrossRef][Web of Science][Medline]

Thomas MJ, Moody TD, Makhinson M, and O'Dell TJ. Activity-dependent beta-adrenergic modulation of low-frequency stimulation induced LTP in the hippocampal CA1 region. Neuron 17: 475-482, 1996.[CrossRef][Web of Science][Medline]

Tonegawa S, Tsien JZ, McHugh TJ, Huerta P, Blum KI, and Wilson MA. Hippocampal CA1-region-restricted knockout of NMDAR1 gene disrupts synaptic plasticity, place fields, and spatial learning. Cold Spring Harb Symp Quant Biol 61: 225-238, 1996.[Abstract/Free Full Text]

Tsien JZ, Huerta PT, and Tonegawa S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87: 1327-1338, 1996.[CrossRef][Web of Science][Medline]

Zeng H, Chattarji S, Barbarosie M, Rondi-Reig L, Philpot BD, Miyakawa T, Bear MF, and Tonegawa S. Forebrain-specific calcineurin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory. Cell 107: 617-629, 2001.[CrossRef][Web of Science][Medline]

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