"Silent" metaplasticity of the late phase of long-term potentiation requires protein phosphatases

The late phase of long-term potentiation (L-LTP) is correlated with some types of long-term memory, but the mechanisms by which L-LTP is modulated by prior synaptic activity are undefined. Activation of protein phosphatases by low-frequency stimulation (LFS) given before induction of L-LTP may significantly modify L-LTP. Using cellular electrophysiological recording methods in mouse hippocampal slices, we show that LFS given before induction of L-LTP inhibited L-LTP in an activity-dependent manner without affecting either basal synaptic strength or the early phase of LTP (E-LTP). This anterograde inhibitory effect of LFS was persistent, required N-methyl-D-aspartate (NMDA) receptor activation, and was blocked by inhibitors of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A). These data indicate that certain patterns of LFS can activate PP1 and/or PP2A, and that long-lasting activation of these phosphatases by prior LFS can suppress the subsequent expression of L-LTP without affecting E-LTP. Because this inhibition of L-LTP is caused by prior synaptic activity that, alone, produced no net effect on synaptic efficacy, we suggest that this is a “silent” form of metaplasticity that may influence long-term information storage by modulating the capacity of synapses to express L-LTP after repeated bouts of activity.     

Age-related enhancement of a protein synthesis-dependent late phase of LTP induced by low frequency paired-pulse stimulation in hippocampus

Protein synthesis-dependent late phase of LTP (L-LTP) is typically induced by repeated high-frequency stimulation (HFS). This form of L-LTP is reduced in the aged animal and is positively correlated with age-related memory loss. Here we report a novel form of protein synthesis-dependent late phase of LTP in the CA1 region of hippocampus induced by a brief 1-Hz paired-pulse stimulation (PP-1 Hz, 1 min). In contrast to L-LTP induced by HFS, the late phase of PP-1 Hz LTP does not exist in young adult animals. Rather, it emerges and becomes enhanced in an age-related way. Thus, in 1.5- to 2-mo-old mice, a brief PP-1 Hz stimulation induces only a short lasting LTP, decaying to baseline in about 90 min. By contrast, PP-1 Hz stimulation induces an enduring and protein synthesis dependent LTP in 12- to 18-mo-old mice. The PP-1 Hz-induced L-LTP is dependent on NMDA receptor activation, requires voltage-dependent calcium channels, and is modulated by dopamine D1/D5 receptors. Because memory ability declines with aging, the age-related enhancement of L-LTP induced by PP-1 Hz stimulation indicates that this form of L-LTP appears to be inversely correlated with memory ability.     

Chronic nicotine exposure induces a long-lasting and pathway-specific facilitation of LTP in the amygdala

Nicotine, in the form of tobacco, is the most commonly used drug of abuse. In addition to its rewarding properties, nicotine also affects many cognitive and emotional processes that involve several brain regions, including hippocampus and amygdala. Long-term changes in synaptic strength in these brain regions after drug exposure may be importantly correlated with behavioral changes induced by nicotine. Here, we study the effect of chronic oral administration of nicotine on the long-term synaptic potentiation in the amygdala, a key structure for emotional memory. We find that oral administration of nicotine for 7 d produces a significant enhancement of LTP in the amygdala. This facilitation is pathway specific: Nicotine selectively facilitates LTP in the cortical-lateral amygdala pathway, but not the thalamic-lateral and the lateral-basolateral synaptic pathway. The synaptic facilitation induced by a 7-d exposure to nicotine is long-lasting, it persists for 72 h after cessation of nicotine but decays 8 d after its cessation. In contrast, a shorter exposure of nicotine (24 h) induces only a short-lasting facilitation of synaptic plasticity that dissipates 24 and 72 h after cessation of nicotine. The facilitation of LTP in the amygdala after exposure to nicotine is mediated by removal of GABAergic inhibition, is dependent on the activation NMDA receptors, and can be prevented by blocking either α7 or β2 nACh receptors. Our results indicate that chronic exposure to nicotine can promote the induction of long-lasting modifications of synapses in a specific pathway in the amygdala.These changes in synaptic plasticity may contribute to the complex neural adaptations and behaviors caused by nicotine.     

Kindling-induced changes in plasticity of the rat amygdala and hippocampus

Temporal lobe epilepsy (TLE) is often accompanied by interictal behavioral abnormalities, such as fear and memory impairment. To identify possible underlying substrates, we analyzed long-term synaptic plasticity in two relevant brain regions, the lateral amygdala (LA) and the CA1 region of the hippocampus, in the kindling model of epilepsy. Wistar rats were kindled through daily administration of brief electrical stimulations to the left basolateral nucleus of the amygdala. Field potential recordings were performed in slices obtained from kindled rats 48 h after the last induced seizure, and in slices from sham-implanted and nonimplanted controls. Kindling resulted in a significant impairment of long-term potentiation (LTP) in both the LA and the CA1, the magnitude of which was dependent on the number of prior stage V seizures. Saturation of CA1-LTP, assessed through repeated spaced delivery of high-frequency stimulation, occurred at lower levels in kindled compared to sham-implanted animals, consistent with the hypothesis of reduced capacity of further synaptic strengthening. Furthermore, theta pulse stimulation elicited long-term depression in the amygdala in nonimplanted and sham-implanted controls, whereas the same stimulation protocol stimulation caused LTP in kindled rats. In conclusion, kindling differentially affects the magnitude, saturation, and polarity of LTP in the CA1 and LA, respectively, most likely indicating an activity-dependent mechanism in the context of synaptic metaplasticity.     

Involvement of IP3 receptors in LTP and LTD induction in guinea pig hippocampal CA1 neurons

The role of inositol 1, 4, 5-trisphosphate receptors (IP3Rs) in long-term potentiation (LTP) and long-term depression (LTD) was studied in CA1 neurons in guinea pig hippocampal slices. In standard solution, short tetanic stimulation consisting of 15 pulses at 100 Hz induced LTP, while three short trains of low-frequency stimulation (LFS; 200 pulses at 1 Hz) at 18-min intervals or one long train of LFS (1000 pulses at 1 Hz) induced stable LTD in both the slope of the field EPSP (S-EPSP) and the amplitude of the population spike (A-PS). Bath application of 2-aminoethoxydiphenyl borate (2-APB), an IP3R antagonist, or of alpha-methyl-4-carboxyphenylglycine (MCPG), a wide-spectrum metabotropic glutamate receptor antagonist, during weak tetanic stimulation significantly increased the magnitude of the LTP in both the S-EPSP and A-PS. Three short trains of LFS or one long train of LFS delivered in the presence of 2-APB or MCPG did not induce LTD, but elicited LTP. Based on these results, we conclude that, in hippocampal CA1 neurons, IP3Rs play an important role in synaptic plasticity by attenuating LTP and facilitating LTD.     

Metaplastic effect of apamin on LTP and paired-pulse facilitation

In area CA1 of hippocampal slices, a single 1-sec train of 100-Hz stimulation generally triggers a short-lasting long-term potentiation (S-LTP) of 1–2 h. Here, we found that when such a train was applied 45 min after application of the small conductance Ca²⁺-activated K⁺ (SK) channel blocker apamin, it induced a long-lasting LTP (L-LTP) of several hours, instead of an S-LTP. Apamin-induced SK channel blockage is known to resist washing. Nevertheless, the aforementioned effect is not a mere delayed effect; it is metaplastic. Indeed, when a single train was delivered to the Schaffer’s collaterals during apamin application, it induced an S-LTP, like in the control situation. At the moment of this LTP induction (15th min of apamin application), the SK channel blockage was nevertheless complete. Indeed, at that time, under the influence of apamin, the amplitude of the series of field excitatory postsynaptic potentials (fEPSPs) triggered by a stimulation train was increased. We found that the metaplastic effect of apamin on LTP was crucially dependent on the NO-synthase pathway, whereas the efficacy of the NMDA receptors was not modified at the time of its occurrence. We also found that apamin produced an increase in paired-pulse facilitation not during, but after, the application of the drug. Finally, we found that the induction of each of these two metaplastic phenomena was mediated by NMDA receptors. A speculative unitary hypothesis to explain these phenomena is proposed.     

Differential effects of predator stress and the antidepressant tianeptine on physiological plasticity in the hippocampus and basolateral amygdala

Stress can profoundly affect memory and alter the functioning of the hippocampus and amygdala. Studies have also shown that the antidepressant tianeptine can block the effects of stress on hippocampal and amygdala morphology and synaptic plasticity. We examined the effects of acute predator stress and tianeptine on long-term potentiation (LTP; induced by 100 pulses in 1 s) and primed burst potentiation (PB; a low threshold form of LTP induced by only five physiologically patterned pulses) in CA1 and in the basolateral nucleus (BLA) of the amygdala in anesthetized rats. Predator stress blocked the induction of PB potentiation in CA1 and enhanced LTP in BLA. Tianeptine blocked the stress-induced suppression of PB potentiation in CA1 without affecting the stress-induced enhancement of LTP in BLA. In addition, tianeptine administered under non-stress conditions enhanced PB potentiation in the hippocampus and LTP in the amygdala. These findings support the hypothesis that acute stress impairs hippocampal functioning and enhances amygdaloid functioning. The work also provides insight into the actions of tianeptine with the finding that it enhanced electrophysiological measures of plasticity in the hippocampus and amygdala under stress, as well as non-stress, conditions.     

Angiotensin-(1-7)-induced plasticity changes in the lateral amygdala are mediated by COX-2 and NO

It is known from studies outside the brain that upon binding to its receptor, angiotensin-(1-7) elicits the release of prostanoids and nitric oxide (NO). Cyclooxygenase (COX) is a key enzyme that converts arachidonic acid to prostaglandins. Since there are no data available so far on the role of COX-2 in the amygdala, in a first step we demonstrated that the selective COX-2 inhibitor NS-398 significantly reduced the probability of long-term potentiation (LTP) induction in the lateral nucleus of the amygdala. Similarly, in COX-2^−/− mice, LTP induced by external capsule (EC) stimulation was impaired. Second, we evaluated the action of angiotensin-(1-7) in the amygdala. In wild-type mice, angiotensin-(1-7) increased LTP. This LTP-enhancing effect of Ang-(1-7) was not observed in COX-2^+/− mice. However, in COX-2^−/− mice, Ang-(1-7) caused an enhancement of LTP similar to that in wild-type mice. The NO synthetase inhibitor L-NAME blocked this angiotensin-(1-7)-induced increase in LTP in COX-2^−/− mice. Low-frequency stimulation of external capsule fibers did not cause long-term depression (LTD) in drug-free and angiotensin-(1-7)-treated brain slices in wild-type mice. In contrast, in COX-2^−/− mice, angiotensin-(1-7) caused stable LTD. Increasing NO concentration by the NO-donor SNAP also caused LTD in wild-type mice. Our study shows for the first time that LTP in the amygdala is dependent on COX-2 activity. Moreover, COX-2 is involved in the mediation of angiotensin-(1-7) effects on LTP. Finally, it is recognized that there is a molecular cross-talk between COX-2 and NO that may regulate synaptic plasticity.     

Cholinergic afferents to the locus coeruleus and noradrenergic afferents to the medial septum mediate LTP-reinforcement in the dentate gyrus by stimulation of the amygdala

Transient long-term potentiation (E-LTP) can be transformed into a long-lasting LTP (L-LTP) in the dentate gyrus (DG) by behavioral stimuli with high motivational content. Previous research from our group has identified several brain structures, such as the basolateral amygdala (BLA), the locus coeruleus (LC), the medial septum (MS) and transmitters as noradrenaline (NA) and acetylcholine (ACh) that are involved in these processes. Here we have investigated the functional interplay among brain structures and systems which result in the conversion of a E-LTP into a L-LTP (reinforcement) by stimulation of the BLA (BLA-R). We used topical application of specific drugs into DG, and other targets, while following the time course of LTP induced by stimulation of the perforant pathway (PP) to study their specific contribution to BLA-R. One injection cannula, a recording electrode in the DG and stimulating electrodes in the PP and the BLA were stereotactically implanted one week before electrophysiological experiments. Topical application of atropine or propranolol into the DG blocked BLA-R in both cases, but the effect of propranolol occurred earlier, suggesting a role of NA within the DG during an intermediate stage of LTP maintenance. The injection of lidocaine into the LC abolished BLA-R indicating that the LC is part of the functional neural reinforcing system. The effect on the LC is mediated by cholinergic afferents because application of atropine into the LC produced the same effect. Injection of lidocaine inactivating the MS also abolished BLA-R. This effect was mediated by noradrenergic afferents (probably from the LC) because the application of propranolol into the MS prevented BLA-R. These findings suggest a functional loop for BLA-R involving cholinergic afferents to the LC, a noradrenergic projection from the LC to the DG and the MS, and finally, the cholinergic projection from the MS to the DG.     

Input-specific long-term potentiation in the rat lateral amygdala of horizontal slices

Long-term potentiation (LTP) at input synapses to the lateral nucleus of the amygdala (LA) is a candidate mechanism for memory storage during fear learning. Cellular mechanisms of LTP have been nearly exclusively investigated in coronal brain slices. In our experiments, we used a horizontal brain slice preparation of rats that preserved most of the connections to cortical areas and the hippocampus. The stimulation electrodes were located either within the external capsule (EC) or the LA. The aim of the present study was to investigate the mechanisms of LTP induced either by weak theta burst stimulation (TBS) or strong high frequency stimulation (HFS) using the two different stimulation sites. Whereas both TBS and HFS of afferences running through the LA induced stable LTP, TBS failed to induce LTP of EC-inputs to the LA. The present findings also show that LTP in the LA exhibits vulnerability at different time windows after induction. The time window was dependent on the kind of stimulated afferences. Later LTP becomes resistant to disruption by low frequency stimulation. We could show that both used inputs depended on NMDA receptors for LTP-induction. LTP induced by stimulation of fibers within the LA was not altered by nifedipine (10 microM). In contrast, EC-induced LTP was dependent on L-type voltage-gated calcium channels (VGCC). Finally, we found a higher magnitude of LTP in females using TBS, whereas HFS did not cause gender-specific differences. Our study supports the conclusion that the form of LA-LTP depend on which afferences are activated and what pattern of stimulation is used to induce LTP.     

Synaptic plasticity in hippocampal CA1 neurons of mice lacking type 1 inositol-1,4,5-trisphosphate receptors

In hippocampal CA1 neurons of wild-type mice, delivery of a standard tetanus (100 pulses at 100 Hz) or a train of low-frequency stimuli (LFS; 1000 pulses at 1 Hz) to a naive input pathway induces, respectively, long-term potentiation (LTP) or long-term depression (LTD) of responses, and delivery of LFS 60 min after tetanus results in reversal of LTP (depotentiation, DP), while LFS applied 60 min before tetanus suppresses LTP induction (LTP suppression). To evaluate the role of the type 1 inositol-1,4,5-trisphosphate receptor (IP3R1) in hippocampal synaptic plasticity, we studied LTP, LTD, DP, and LTP suppression of the field excitatory postsynaptic potentials (EPSPs) in the CA1 neurons of mice lacking the IP3R1. No differences were seen between mutant and wild-type mice in terms of the mean magnitude of the LTP or LTD induced by a standard tetanus or LFS. However, the mean magnitude of the LTP induced by a short tetanus (10 pulses at 100 Hz) was significantly greater in mutant mice than in wild-type mice. In addition, DP or LTP suppression was attenuated in the mutant mice, the mean magnitude of the responses after delivery of LFS or tetanus being significantly greater than in wild-type mice. These results suggest that, in hippocampal CA1 neurons, the IP3R1 is involved in LTP, DP, and LTP suppression but is not essential for LTD. The facilitation of LTP induction and attenuation of DP and LTP suppression seen in mice lacking the IP3R1 indicates that this receptor plays an important role in blocking synaptic potentiation in hippocampal CA1 neurons.     

A nitric oxide-independent and beta-adrenergic receptor-sensitive form of metaplasticity limits theta-frequency stimulation-induced LTP in the hippocampal CA1 region

The induction of long-term potentiation (LTP) and long-term depression (LTD) at excitatory synapses in the hippocampus can be strongly modulated by patterns of synaptic stimulation that otherwise have no direct effect on synaptic strength. Likewise, patterns of synaptic stimulation that induce LTP or LTD not only modify synaptic strength but can also induce lasting changes that regulate how synapses will respond to subsequent trains of stimulation. Collectively known as metaplasticity, these activity-dependent processes that regulate LTP and LTD induction allow the recent history of synaptic activity to influence the induction of activity-dependent changes in synaptic strength and may thus have an important role in information storage during memory formation. To explore the cellular and molecular mechanisms underlying metaplasticity, we investigated the role of metaplasticity in the induction of LTP by υ-frequency (5-Hz) synaptic stimulation in the hippocampal CA1 region. Our results show that brief trains of υ-frequency stimulation not only induce LTP but also activate a process that inhibits the induction of additional LTP at potentiated synapses. Unlike other forms of metaplasticity, the inhibition of LTP induction at potentiated synapses does not appear to arise from activity-dependent changes in NMDA receptor function, does not require nitric oxide signaling, and is strongly modulated by β-adrenergic receptor activation. Together with previous findings, our results indicate that mechanistically distinct forms of metaplasticity regulate LTP induction and suggest that one way modulatory transmitters may act to regulate synaptic plasticity is by modulating metaplasticity.     

Long-term potentiation in the dentate gyrus in freely moving rats is reinforced by intraventricular application of norepinephrine, but not oxotremorine

Growing evidence suggests that processes of synaptic plasticity, such as long-term potentiation (LTP) occurring in one synaptic population, can be modulated by consolidating afferents from other brain structures. We have previously shown that an early-LTP lasting less than 4 h (E-LTP) in the dentate gyrus can be prolonged by stimulating the basolateral amygdala, the septum or the locus coeruleus within a specific time window. Pharmacological experiments have suggested that noradregeneric (NE) and/or cholinergic systems might be involved in these effects. We have therefore investigated whether the direct intraventricular application of agonists for NE- or muscarinic receptors is able to modulate synaptic plasticity. E-LTP was induced at the dentate gyrus of freely moving rats using a mild tetanization protocol that induces only an E-LTP. NE or oxotremorine (OXO) were applied icv 10 min after the tetanus. Results show that low doses of NE (1.5 and 5 nM) effectively prolong LTP. A higher dose (50 nM) was not effective. None of the OXO doses employed (5, 25, and 50 nM) showed similar effects. These results stress the importance of transmitter-specific modulatory influences on the time course of synaptic plasticity, in particular NE whose application mimics the reinforcing effect of directly stimulating limbic structures on LTP.     

Differential Effect of TEA on Long-Term Synaptic Modification in Hippocampal CA1 and Dentate Gyrus in vitro

The effectiveness of tetraethylammonium (TEA) and high-frequency stimulation (HFS) in inducing long-term synaptic modification is compared in CA1 and dentate gyrus (DG) in vitro. High-frequency stimulation induces long-term potentiation (LTP) at synapses of both perforant path-DG granule cell and Schaffer collateral-CA1 pyramidal cell pathways. By contrast, TEA (25 mM) induces long-term depression in DG while inducing LTP in CA1. The mechanisms underlying the differential effect of TEA in CA1 and DG were investigated. It was observed that T-type voltage-dependent calcium channel (VDCC) blocker, Ni²⁺ (50 μM), partially blocked TEA-induced LTP in CA1. A complete blockade of the TEA-induced LTP occurred when Ni²⁺ was applied together with the NMDA receptor antagonist, D-APV. The L-type VDCC blocker, nifidipine (20 μM), had no effect on CA1 TEA-induced LTP. In DG of the same slice, TEA actually induced long-term depression (LTD) instead of LTP, an effect that was blocked by D-APV. Neither T-type nor L-type VDCC blockade could prevent this LTD. When the calcium concentration in the perfusion medium was increased, TEA induced a weak LTP in DG that was blocked by Ni²⁺. During exposure to TEA, the magnitude of field EPSPs was increased in both CA1 and DG, but the increase was substantially greater in CA1. Tetraethylammonium application also was associated with a large, late EPSP component in CA1 that persisted even after severing the connections between CA3 and CA1. All of the TEA effects in CA1, however, were dramatically reduced by Ni²⁺. The results of this study indicate that TEA indirectly acts via both T-type VDCCs and NMDA receptors in CA1 and, as a consequence, induces LTP. By contrast, TEA indirectly acts via only NMDA receptors in DG and results in LTD. The results raise the possibility of a major synaptic difference in the density and/or distribution of T-type VDCCs and NMDA receptors in CA1 and DG of the rat hippocampus.     

Impairment of spatial learning and hippocampal synaptic potentiation in c-kit mutant rats

The c-kit receptor tyrosine kinase encoded by the white-spotting (W) gene is highly expressed in rat hippocampal CA1–CA4 regions. We found an impaired spatial learning and memory in homozygous c-kit (Ws/Ws) mutant rats that have a 12-base deletion in the tyrosine kinase domain of the c-kit gene and a very low kinase activity. Electrophysiological studies in hippocampal slices revealed that the long-term potentiation (LTP) induced by the tetanic stimulation (100 Hz, 1 sec) in the mossy fiber (MF)–CA3 pathway, but not in the Schaffer collaterals/commissural–CA1 pathway, was significantly reduced in c-kit mutants compared with wild-type (+/+) rats. The paired-pulse facilitation (PPF) was measured before the tetanus and after the establishment of the LTP in each slice. The initial PPF in the MF–CA3 pathway positively correlated with the amplitude of the LTP in the wild-type rats but not in the c-kit mutant rats. Furthermore, they failed to show the normal characteristics observed in the MF–CA3 pathway of +/+ rats; that is, the negative correlation between the initial PPF and the changes in PPF measured after the LTP. These findings suggest an involvement of SCF/c-kit signaling in hippocampal synaptic potentiation and spatial learning and memory.     

Phosphorylation of ERK/MAP kinase is required for long-term potentiation in anatomically restricted regions of the lateral amygdala in vivo

We have previously shown that the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/ MAPK) is transiently activated in anatomically restricted regions of the lateral amygdala (LA) following Pavlovian fear conditioning and that blockade of ERK/MAPK activation in the LA impairs both fear memory consolidation and long-term potentiation (LTP) in the amygdala, in vitro. The present experiments evaluated the role of the ERK/MAPK signaling cascade in LTP at thalamo-LA input synapses, in vivo. We first show that ERK/MAPK is transiently activated/phosphorylated in the LA at 5 min, but not 15 or 60 min, after high-frequency, but not low-frequency, stimulation of the auditory thalamus. ERK activation induced by LTP-inducing stimulation was anatomically restricted to the same regions of the LA previously shown to exhibit ERK regulation following fear conditioning. We next show that intra-LA infusion of U0126, an inhibitor of ERK/MAPK activation, impairs LTP at thalamo-LA input synapses. Collectively, results demonstrate that ERK/MAPK activation is necessary for synaptic plasticity in anatomically defined regions of the LA, in vivo.     

Synaptic plasticity in the lateral amygdala: a cellular hypothesis of fear conditioning

Fear conditioning is a form of associative learning in which subjects come to express defense responses to a neutral conditioned stimulus (CS) that is paired with an aversive unconditioned stimulus (US). Considerable evidence suggests that critical neural changes mediating the CS-US association occur in the lateral nucleus of the amygdala (LA). Further, recent studies show that associative long-term potentiation (LTP) occurs in pathways that transmit the CS to LA, and that drugs that interfere with this LTP also disrupt behavioral fear conditioning when infused into the LA, suggesting that associative LTP in LA might be a mechanism for storing memories of the CS-US association. Here, we develop a detailed cellular hypothesis to explain how neural responses to the CS and US in LA could induce LTP-like changes that store memories during fear conditioning. Specifically, we propose that the CS evokes EPSPs at sensory input synapses onto LA pyramidal neurons, and that the US strongly depolarizes these same LA neurons. This depolarization, in turn, causes calcium influx through NMDA receptors (NMDARs) and also causes the LA neuron to fire action potentials. The action potentials then back-propagate into the dendrites, where they collide with CS-evoked EPSPs, resulting in calcium entry through voltage-gated calcium channels (VGCCs). Although calcium entry through NMDARs is sufficient to induce synaptic changes that support short-term fear memory, calcium entry through both NMDARs and VGCCs is required to initiate the molecular processes that consolidate synaptic changes into a long-term memory.     

Corticosterone time-dependently modulates beta-adrenergic effects on long-term potentiation in the hippocampal dentate gyrus

Previous experiments in the hippocampal CA1 area have shown that corticosterone can facilitate long-term potentiation (LTP) in a rapid non-genomic fashion, while the same hormone suppresses LTP that is induced several hours after hormone application. Here, we elaborated on this finding by examining whether corticosterone exerts opposite effects on LTP depending on the timing of hormone application in the dentate gyrus as well. Moreover, we tested rapid and delayed actions by corticosterone on β-adrenergic-dependent changes in LTP. Unlike the CA1 region, our in vitro field potential recordings show that rapid effects of corticosterone do not influence LTP induced by mild tetanization in the hippocampal dentate gyrus, unless GABA_A receptors are blocked. In contrast, the β-adrenergic agonist isoproterenol does initiate a slow-onset, limited amount of potentiation. When corticosterone was applied concurrently with isoproterenol, a further enhancement of synaptic strength was identified, especially during the early stage of potentiation. Yet, treatment with corticosterone several hours in advance of isoproterenol fully prevented any effect of isoproterenol on LTP. This emphasizes that corticosterone can regulate β-adrenergic modulation of synaptic plasticity in opposite directions, depending on the timing of hormone application.