Pharmacological antagonism of metabotropic glutamate receptor 1 regulates long-term potentiation and spatial reference memory in the dentate gyrus of freely moving rats via N-methyl-D-aspartate and metabotropic glutamate receptor-dependent mechanisms

Group I metabotropic glutamate receptors (mGluRs) are critically required for multiple forms of hippocampal synaptic plasticity in vivo. The role of the receptor subtype mGluR1 in long-term potentiation (LTP) and learning is unclear. We examined the contribution of mGluR1 to hippocampal LTP and spatial learning using the selective antagonist (S)-(+)-alpha-amino-4carboxy-2-methylbenzene-acetic acid (LY367385). Male Wistar rats were chronically implanted with recording and stimulating electrodes to enable measurement of evoked potentials from medial perforant path-dentate gyrus granule cell synapses. An injection cannula was inserted into the ipsilateral cerebral ventricle to enable drug application. Experiments were begun 10 days after the implantation procedure. We induced a robust LTP which lasted over 25 h with a 200-Hz tetanization. Injections of LY367385 at all concentrations under investigation (4-32 nmol in a 5-microL injection volume) did not affect basal synaptic transmission. In contrast, we observed a dose-dependent impairment of LTP expression: LY367385 (4 nmol) had no effect on LTP induction, whereas 8 and 16 nmol LY367385 reduced both LTP induction and expression, suggestive of an interaction with N-methyl-d-aspartate receptors. We assessed the effects of daily LY367385 application (8 nmol) on performance in an eight-arm radial maze. LY367385-treated rats showed deficits in reference but not working memory performance compared with vehicle-treated controls. Rearing, grooming and locomotor activity were unaffected by LY367385. These data suggest an important role for mGluR1 in LTP and learning and highlight the specific significance of this mGluR subtype for reference memory.     

Metabotropic glutamate receptor 1 (mGluR1) and 5 (mGluR5) regulate late phases of LTP and LTD in the hippocampal CA1 region in vitro

The group I metabotropic glutamate receptors, mGluR1 and mGluR5, exhibit differences in their regulation of synaptic plasticity, suggesting that these receptors may subserve separate functional roles in information storage. In addition, although effects in vivo are consistently described, conflicting reports of the involvement of mGluRs in hippocampal synaptic plasticity in vitro exist. We therefore addressed the involvement of mGluR1 and mGluR5 in long-term potentiation (LTP) and long-term depression (LTD) in the hippocampal CA1 region of adult male rats in vitro . The mGluR1 antagonist (S)-(+)-α-amino-4-carboxy-2-methylbenzene-acetic acid (LY367385) impaired both induction and late phases of both LTP and LTD, when applied before high-frequency tetanization (HFT; 100 Hz) or low-frequency stimulation (LFS; 1 Hz), respectively. Application after either HFT or LFS had no effect. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), when given before HFT, inhibited both the induction and late phases of LTP. When given after HFT, late LTP was inhibited. MPEP, given prior to LFS, impaired LTD induction, although stable LTD was still expressed. Application after LFS significantly impaired late phases of LTD. Activation of protein synthesis may comprise a key mechanism underlying the group I mGluR contribution to synaptic plasticity. The mGluR5 agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG) converted short-term depression into LTD. Effects were prevented by application of the protein synthesis inhibitor anisomycin, suggesting that protein synthesis is triggered by group I mGluR activation to enable persistency of synaptic plasticity. Taken together, these data support the notion that both mGluR1 and mGluR5 are critically involved in bidirectional synaptic plasticity in the CA1 region and may enable functional differences in information encoding through LTP and LTD.     

Hippocampal long‐term potentiation that is elicited by perforant path stimulation or that occurs in conjunction with spatial learning is tightly controlled by beta‐adrenoreceptors and the locus coeruleus

The noradrenergic system, driven by locus coeruleus (LC) activation, plays a key role in the regulating and directing of changes in hippocampal synaptic efficacy. The LC releases noradrenaline in response to novel experience and LC activation leads to an enhancement of hippocampus‐based learning, and facilitates synaptic plasticity in the form of long‐term depression (LTD) and long‐term potentiation (LTP) that occur in association with spatial learning. The predominant receptor for mediating these effects is the β‐adrenoreceptor. Interestingly, the dependency of synaptic plasticity on this receptor is different in the hippocampal subfields whereby in the CA1 in vivo, LTP, but not LTD requires β‐adrenoreceptor activation, whereas in the mossy fiber synapse LTP and LTD do not depend on this receptor. By contrast, synaptic plasticity that is facilitated by spatial learning is highly dependent on β‐adrenoreceptor activation in both hippocampal subfields. Here, we explored whether LTP induced by perforant‐path (pp) stimulation in vivo or that is facilitated by spatial learning depends on β‐adrenoreceptors. We found that under both LTP conditions, antagonising the receptors disabled the persistence of LTP. β‐adrenoreceptor‐antagonism also prevented spatial learning. Strikingly, activation of the LC before high‐frequency stimulation (HFS) of the pp prevented short‐term potentiation but not LTP, and LC stimulation after pp‐HFS‐induced depotentiation of LTP. This depotentiation was prevented by β‐adrenoreceptor‐antagonism. These data suggest that β‐adrenoreceptor‐activation, resulting from noradrenaline release from the LC during enhanced arousal and learning, comprises a mechanism whereby the duration and degree of LTP is regulated and fine tuned. This may serve to optimize the creation of a spatial memory engram by means of LTP and LTD. This process can be expected to support the special role of the dentate gyrus as a crucial subregional locus for detecting and processing novelty within the hippocampus. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Modulation by group 1 metabotropic glutamate receptors of depotentiation in the dentate gyrus of freely moving rats

In the hippocampus, synaptic depression of potentiated synapses in the form of depotentiation, or of naive synapses in the form of long-term depression (LTD) is mediated by distinct molecular mechanisms. Activation of group 1 metabotropic glutamate receptors (mGluRs) is critically required for both hippocampal long-term potentiation (LTP) and LTD in vivo, but their involvement in depotentiation is unclear. In this study, we investigated whether this class of mGluRs contributes to depotentiation in freely moving rats. Male adult Wistar rats underwent chronic implantation of stimulating and recording electrodes in the perforant path and dentate gyrus granule cell layer, respectively, as well as an injection cannula in the ipsilateral cerebral ventricle. Robust LTP which endured for over 24 h, was induced by high frequency tetanization (HFT, 200 Hz). Depotentiation was induced with LFS (5 Hz, 600 pulses) given 5 min after the LTP-inducing tetanus was applied. The selective group 1 mGluR antagonists, (S)-4-carboxyphenylglycine and (R,S)-1-aminoindan-1,5-dicarboxylic acid significantly inhibited both depotentiation and LTP. Activation of group I mGluRs leads to changes in postsynaptic intracellular calcium levels. These findings suggest that activation of group I mGluRs mediate thresholds for depotentiation and for persistent LTP. Effects may be linked to the intensity and duration of the calcium signal elicited by LFS and HFT.     

Metabotropic glutamate receptors contribute to neocortical synaptic plasticity in vivo

Metabotropic glutamate receptors (mGluRs) have been shown to be important for hippocampus-dependent memory, as well as activity-dependent synaptic plasticity in the hippocampus. In this study, we examined the role of mGluRs in the induction of two forms of activity-dependent synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), in the neocortex of awake, freely-moving rats. The mGluR antagonist AIDA was administered during the induction of LTP or LTD in the motor cortex. There was a 50% reduction of LTP induced in the early component of the evoked response, but there was no effect on the late component and no effect on the induction of LTD. Thus, mGluRs contribute to at least one form of activity dependent synaptic plasticity in the neocortex.     

Group I metabotropic glutamate receptors enable two distinct forms of long-term depression in the rat dentate gyrus in vivo

The existence of long-term depression (LTD) in the dentate gyrus of freely moving rats, as well as the contribution of different types of metabotropic glutamate receptors (mGluRs) to this form of plasticity, has been the subject of much debate. Here, we describe two distinct forms of mGluR-dependent hippocampal LTD in the dentate gyrus of freely moving adult rats. LTD, induced by low-frequency stimulation (LFS) of the medial perforant path (LFS-LTD), was prevented by antagonism of the phospholipase C-coupled receptors, mGluR1 but not mGluR5. Chemical LTD, induced by intracerebral application of the group I mGluR agonist (R,S)-3,5-dihydroxyphenylglycine, was blocked by antagonism of both mGluR5 and mGluR1. Selective activation of mGluR5, using (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG), also led to chemical LTD. To test whether LFS-LTD and chemical LTD share common induction mechanisms, we applied LFS following the induction of chemical LTD by CHPG (CHPG-LTD). Surprisingly, LFS impaired CHPG-LTD. Further analysis revealed that induction of CHPG-LTD led to altered calcium dynamics sufficient for its reversal by LFS. We found that LTD induced by (R,S)-3,5-dihydroxyphenylglycine, but not by CHPG, is impaired by N-methyl-d-aspartate receptor antagonism. Both forms of chemical LTD strongly require calcium influx through L-type voltage-gated calcium channels. This contrasts with previous findings that LFS-LTD in the dentate gyrus is both N-methyl-d-aspartate receptor and voltage-gated calcium channel independent. LFS-LTD and LTD induced by group I mGluR agonists thus appear to comprise distinct forms of LTD that require the activation of specific group I mGluRs and recruit calcium from different sources.     

The requirement of BDNF for hippocampal synaptic plasticity is experience‐dependent

Brain‐derived neurotrophic factor (BDNF) supports neuronal survival, growth, and differentiation and has been implicated in forms of hippocampus‐dependent learning. In vitro, a specific role in hippocampal synaptic plasticity has been described, although not all experience‐dependent forms of synaptic plasticity critically depend on BDNF. Synaptic plasticity is likely to enable long‐term synaptic information storage and memory, and the induction of persistent (>24 h) forms, such as long‐term potentiation (LTP) and long‐term depression (LTD) is tightly associated with learning specific aspects of a spatial representation. Whether BDNF is required for persistent (>24 h) forms of LTP and LTD, and how it contributes to synaptic plasticity in the freely behaving rodent has never been explored. We examined LTP, LTD, and related forms of learning in the CA1 region of freely dependent mice that have a partial knockdown of BDNF (BDNF^+/?). We show that whereas early‐LTD (<90min) requires BDNF, short‐term depression (<45 min) does not. Furthermore, BDNF is required for LTP that is induced by mild, but not strong short afferent stimulation protocols. Object‐place learning triggers LTD in the CA1 region of mice. We observed that object‐place memory was impaired and the object‐place exploration failed to induce LTD in BDNF^+/? mice. Furthermore, spatial reference memory, that is believed to be enabled by LTP, was also impaired. Taken together, these data indicate that BDNF is required for specific, but not all, forms of hippocampal‐dependent information storage and memory. Thus, very robust forms of synaptic plasticity may circumvent the need for BDNF, rather it may play a specific role in the optimization of weaker forms of plasticity. The finding that both learning‐facilitated LTD and spatial reference memory are both impaired in BDNF^+/? mice, suggests moreover, that it is critically required for the physiological encoding of hippocampus‐dependent memory. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Prenatal stress modifies hippocampal synaptic plasticity and spatial learning in young rat offspring

Clinical studies demonstrate that prenatal stress causes cognitive deficits and increases vulnerability to affective disorders in children and adolescents. The underlying mechanisms are not yet fully understood. Here, we reported that prenatal stress (10 unpredictable, 1 s, 0.8 mA foot shocks per day during gestational days 13-19) impaired long-term potentiation (LTP) but facilitated long-term depression (LTD) in hippocampal CA1 region in slices of the prenatal stressed offspring (5 weeks old). Cross-fostering neonate offspring by the prenatal stressed or control mothers did not change the effects of prenatal stress on the hippocampal LTP and LTD. Furthermore, prenatal stress enhanced the effects of acute stress on the hippocampal LTP and LTD and impaired spatial learning and memory in the Morris water maze in the young rat offspring. Therefore, prenatal stress alters synaptic plasticity and enhances the effects of acute stress on synaptic plasticity in the hippocampus, which may be the mechanism for the impaired spatial learning and memory in young rat offspring.     

β-Estradiol unmasks metabotropic receptor-mediated metaplasticity of NMDA receptor transmission in the female rat dentate gyrus

Loss of estrogen in women following menopause is associated with increased risk for cognitive decline, dementia and depression, all of which can be prevented by estradiol replacement. The dentate gyrus plays an important role in cognition, learning and memory. The gatekeeping function of the dentate gyrus to filter incoming activity into the hippocampus is modulated by estradiol in a frequency-dependent manner and involves activation of metabotropic glutamate receptors (mGluR). In the present study, we investigated whether estradiol (EB) modulates the metaplastic effect of inducing synaptic long-term potentiation (LTP) on subsequent propensity for expression of LTP in the dentate gyrus. At medial perforant path-dentate granule cell synapses in hippocampal slices of ovariectomized female rats, EB replacement was critical for an initial induction of LTP to enhance the magnitude of subsequent LTP elicited by a second high-frequency stimulation, metaplasticity, which was not present in slices from oil-treated control animals. EB enhanced expression of group I mGluRs, and the metaplastic effect of EB on LTP required activation of group I mGluRs that led to Src-family tyrosine kinase-mediated phosphorylation of NR2B subunits of N-methyl-d-aspartate receptors (NMDAR) that enhanced the magnitude of NMDAR-dependent LTP. Our data show that EB effects on LTP in the hippocampal dentate gyrus require activation of group I mGluRs, which in turn leads to functional metaplastic regulation of NR2B subunit-containing NMDARs, as opposed to direct effects of EB on NMDARs.     

Differential effects of the group II mGluR agonist, DCG-IV, on depolarization-induced suppression of inhibition in hippocampal CA1 and CA3 neurons

We investigated the role of metabotropic glutamate receptors in the mediation of depolarization-induced suppression of inhibition (DSI), using whole-cell electrophysiological techniques in rat hippocampal slice preparation. In a previous work, we showed that a retrograde signal travels from CA1 pyramidal cells to GABA interneurons and prevents them from releasing GABA for tens of seconds at 30 degrees C. The resulting suppression of inhibition is DSI. The retrograde signal appeared to be glutamate, or a glutamate analog, which acted on group I metabotropic receptors on the interneurons. It is not known if DSI occurs in hippocampal subregions besides CA1. If DSI does occur in other regions, it will be important to know if the role of metabotropic glutamate receptors (mGluRs) in mediating DSI is the same everywhere. The distribution of mGluR subtypes varies among hippocampal subregions. In the CA3 region, unlike CA1, group II mGluRs are prevalent. It was possible, therefore, that in CA3, the group II mGluRs would mediate DSI. We have begun to investigate these issues. We now report that: 1) DSI does occur in CA3. 2) Carbachol induces IPSC activity that can be recorded in CA1 and CA3a. This carbachol-induced activity can be reduced by the selective group II mGluR agonist, DCG-IV, and by DSI. 3) Evoked IPSCs in CA3a, but not in CA1, can be reduced by DCG-IV; hence the interneurons activated by carbachol may reside in CA3a. 4) Despite the group II mGluR agonist sensitivity of CA3a interneurons, DSI in this region is not affected by a group II mGluR antagonist, CPPG, and therefore does not appear to be mediated by group II mGluRs.     

Bidirectional synaptic plasticity induced by conditioned stimulations with different number of pulse at hippocampal CA1 synapses: roles of N-methyl-D-aspartate and metabotropic glutamate receptors

In the mammalian brain, the hippocampus has been established as a principle structure for learning and memory processes, which involve synaptic plasticity. Although a relationship between synaptic plasticity and stimulation frequency has been reported in numerous studies, little is known about the importance of pulse number on synaptic plasticity. Here we investigated whether the pulse number can modulate bidirectional plasticity in hippocampal CA1 areas. When a CA1 area was induced by a paired-pulse (PP) with a 10-ms interval, the strength of the synapse was altered to form a long-term depression (LTD), with a 68 ± 4% decrease in expression. The PP-induced LTD (PP-LTD) was blocked by the metabotropic glutamate receptors subtype 5 (mGluR5) antagonist MPEP, suggesting that the PP-LTD relied on the activation of GluR5. In addition, this modulation of LTD was protein kinase C (PKC)- and Group II mGluR-independent. However, when increasing the pulse number to 4 and 6, potentiated synaptic strength was observed, which was N-methyl-D-aspartate receptor (NMDAR)-dependent but mGluR5-independent. Surprisingly, when blocking mGluR, the synaptic efficacy induced by triple-pulse stimulation was altered to form a long-term potentiation (LTP) with a 142 ± 7% enhancement, and was further blocked by NMDA antagonist APV. Following treatment with APV and PKC blocker chelerythrine, the LTP expression induced by 4- and 6-pulse stimulation was switched to LTD. We suggest that CA1 synaptic plasticity is regulated by the result of competition between NMDA and mGluR5 receptors. We suggest that the pulse number can bidirectionally modulate synaptic plasticity through the activation of NMDA and mGluR5 in hippocampal CA1 areas.     

Group I metabotropic glutamate receptors regulate the frequency-response function of hippocampal CA1 synapses for the induction of LTP and LTD

Synaptically released glutamate binds to ionotropic or metabotropic glutamate receptors. Metabotropic glutamate receptors (mGluRs) are G‐protein‐coupled receptors and can be divided into three subclasses (Group I–III) depending on their pharmacology and coupling to signal transduction cascades. Group I mGluRs are coupled to phospholipase C and are implicated in several important physiological processes, including activity‐dependent synaptic plasticity, but their exact role in synaptic plasticity remains unclear. Synaptic plasticity can manifest itself as an increase or decrease of synaptic efficacy, referred to as long‐term potentiation (LTP) and long‐term depression (LTD). The likelihood, degree and direction of the change in synaptic efficacy depends on the history of the synapse and is referred to as ‘metaplasticity’. We provide direct experimental evidence for an involvement of group I mGluRs in metaplasticity in CA1 hippocampal synapses. Bath application of a low concentration of the specific group I agonist 3,5‐dihydroxyphenylglycine (DHPG), which does not affect basal synaptic transmission, resulted in a leftward shift of the frequency–response function for the induction of LTD and LTP in naïve synapses. DHPG resulted in the induction of LTP at frequencies which induced LTD in control slices. These alterations in the induction of LTD and LTP resemble the metaplastic changes observed in previously depressed synapses. In addition, in the presence of DHPG additional potentiation could be induced after LTP had apparently been saturated. These findings provide strong evidence for an involvement of group I mGluRs in the regulation of metaplasticity in the CA1 field of the hippocampus.     

The PTEN phosphatase is essential for long-term depression of hippocampal synapses

Activity-induced long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission are two types of enduring changes in neuronal connections that are believed to underlie learning and memory functions. Here we show that CA1 synapses in hippocampal slices from PTEN-deficient mice exhibit LTP, but are resistant to LTD. PTEN reduces phosphatidylinositol-3-kinase (PI₃-K) activity, and pharmacological inhibition of PI₃-K restores LTD in PTEN-deficient mice, suggesting that inhibition of PI₃-K by PTEN is necessary for LTD induction. These findings demonstrate a pivolate role for PTEN in LTD, and suggest that alterations in PTEN could have an impact on learning and memory processes. Authors contributed equally.     

Mice lacking the adenosine A1 receptor have normal spatial learning and plasticity in the CA1 region of the hippocampus, but they habituate more slowly

Using mice with a targeted disruption of the adenosine A1 receptor (A1R), we examined the role of A1Rs in hippocampal long-term potentiation (LTP), long-term depression (LTD), and memory formation. Recordings from the Shaffer collateral-CA1 pathway of hippocampal slices from adult mice showed no differences between theta burst and tetanic stimulation-induced LTP in adenosine A1 receptor knockout (A1R-/-), heterozygote (A1R+/-), and wildtype (A1R+/+) mice. However, paired pulse facilitation was impaired significantly in A1R-/- slices as compared to A1R+/+ slices. LTD in the CA1 region was unaffected by the genetic manipulation. The three genotypes showed similar memory acquisition patterns when assessed for spatial reference and working memory in the Morris water maze tasks at 9 months of age. However, 10 months later A1R-/- mice showed some deficits in the 6-arm radial tunnel maze test. The latter appeared, however, not due to memory deficits but to decreased habituation to the test environment. Taken together, we observe normal spatial learning and memory and hippocampal CA1 synaptic plasticity in adult adenosine A1R knockout mice, but find modifications in arousal-related processes, including habituation, in this knockout model.     

Hippocampal long-term depression: master or minion in declarative memory processes?

The neural mechanisms for the formation of declarative memory (memory for facts and events) are believed to be integrated from processes mediated by hippocampal long-term potentiation (LTP) and long-term depression (LTD). Traditionally, LTP has been designated as the main mediator of spatial memory storage in the hippocampus, whereas LTD has been assigned an auxiliary role in signal-to-noise regulation or in forgetting. It has recently become apparent, however, that LTD contributes directly to hippocampal information storage. In fact, LTD could dominate in the processing of precise spatial characteristics. Accumulating evidence supports the idea that LTP and LTD enable distinct and separate forms of information storage, which together facilitate the generation of a spatial cognitive map.     

Priming of long-term potentiation induced by activation of metabotropic glutamate receptors coupled to phospholipase C

Activation of metabotropic glutamate receptors (mGluRs) with 1-aminocyclopentane-1S,3R-dicarboxylic acid 20 min prior to tetanus facilitates, or “primes,” subsequent induction of long-term potentiation (LTP; Cohen and Abraham, J Neurophysiol 1996;76:953–962). In the present study, we investigated the receptor specificity and associated second messenger pathways involved in the mGluR priming effect by using field potentials recorded from area CA1 of rat hippocampal slices. In controls, mild theta-burst or high-frequency (100 Hz) stimulation induced 16% and 21% LTP, respectively. A 10-min application of the group I mGluR agonist 3,5-dihydroxyphenylglycine (DHPG) caused a transient depression of synaptic responses but a significant enhancement of subsequent LTP for both tetanus protocols (45% and 41% LTP, respectively). Maximal LTP, induced by stronger tetanization protocols, was not enhanced by DHPG, nor was mild LTP facilitated by post-tetanic application of DHPG. Priming with agonists selective for group II or III mGluRs had no effect on LTP. The mGluR antagonists L-2-amino-3-phosphonopropionic acid and 1-aminoindan-1,5-dicarboxylic acid inhibited the LTP facilitatory effect of DHPG but not the transient response depression, whereas α-methyl-4-carboxyphenylglycine produced the opposite effects. Priming with N-methyl-D-aspartate or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid did not facilitate LTP induction. Prior activation of muscarinic acetylcholine receptors produced at best a weak priming effect. Inhibition of phospholipase C by U-73122 completely abolished the priming of LTP by DHPG. We conclude that mGluR priming of LTP results from biochemical cascades triggered by activation of phospholipase C coupled to group I mGluRs. Hippocampus 1998;8:160–170. © 1998 Wiley-Liss, Inc.     

Antagonism of D1/D5 receptors prevents long‐term depression (LTD) and learning‐facilitated LTD at the perforant path–dentate gyrus synapse in freely behaving rats

Hippocampal synaptic plasticity, in the form of long‐term potentiation (LTP) and long‐term depression (LTD), enables spatial memory formation, whereby LTP and LTD are likely to contribute different elements to the resulting spatial representation. Dopamine, released from the ventral tegmental area particularly under conditions of reward, acts on the hippocampus, and may specifically influence the encoding of information into long‐term memory. The dentate gyrus (DG), as the “gateway” to the hippocampus is likely to play an important role in this process. D1/D5 dopamine receptors are importantly involved in the regulation of synaptic plasticity thresholds in the CA1 region of the hippocampus and determine the direction of change in synaptic strength that occurs during novel spatial learning. Here, we explored whether D1/D5‐receptors influence LTD that is induced in the DG following patterned afferent stimulation of the perforant path of freely behaving adult rats, or influence LTD that occurs in association with spatial learning. We found that LTD that is induced by afferent stimulation, and LTD that is facilitated by learning about novel landmark configurations, were both prevented by D1/D5‐receptor antagonism, whereas agonist activation of the D1/D5‐receptor had no effect on basal tonus or short‐term depression. Other studies have reported that in the DG, D1/D5‐receptor agonism or antagonism do not affect LTP, but agonism prevents depotentiation. These findings suggest that the dopaminergic system, acting via D1/D5‐receptors, influences information gating by the DG and modulates the direction of change in synaptic strength that underlies information storage in this hippocampal substructure. Information encoded by robust forms of LTD is especially dependent on D1/D5‐receptor activation. Thus, dopamine acting on D1/D5‐receptors is likely to support specific experience‐dependent encoding, and may influence the content of hippocampal representations of experience. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

The effect of acute stress on LTP and LTD induction in the hippocampal CA1 region of anesthetized rats at three different ages

Not all experiences are memorized equally well. Especially, some types of stress are unavoidable in daily life and the stress experience can be memorized for life. Previous evidence has showed that synaptic plasticity, such as long-term potentiation (LTP) that may be the major cellular model of the mechanism underlying learning and memory, is influenced by behavioral stress. However, the effect of behavioral stress on age-related synaptic plasticity in vivo was primarily known. Here we found that the LTP induction in the hippocampal CA1 region of anesthetized rats obviously showed inverted-U shape related to ages (4, 10 and 74 weeks old rats), but low-frequency stimulation was unable to induce reliable long-term depression (LTD) in these animals. Furthermore, acute elevated platform (EP) stress enabled reliable LTD significantly and completely blocked LTP induction at these ages. Importantly, LTD after exposure to acute EP stress showed similar magnitude over these ages. The present results that stress enables LTD but impairs LTP induction at these three ages strengthen a view that stress experience-dependent LTD (SLTD) may underlie stress form of aberrant memories.     

Local facilitation of hippocampal metabotropic glutamate receptor-dependent long-term depression by corticosterone and dexamethasone

Long-term potentiation and long-term depression (LTD) of synaptic efficacy, two major forms of synaptic plasticity, are believed to underlie learning processes and memory storage. We have recently shown that acute stress, through corticosterone release and stimulation of glucocorticoid receptors (GRs), facilitates the LTD elicited by the group 1 metabotropic glutamate receptor (mGluR) agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) in hippocampal CA1 neurons. However, it is unknown whether sustained corticosterone release, per se, is also able to facilitate DHPG-elicited LTD in control (i.e. unstressed) conditions, and if so, whether it acts on local (i.e. hippocampal) or distant GRs. Here, we show that a brief application of 100 nM corticosterone to rat hippocampal slices lowers the threshold for DHPG-elicited LTD, an effect mimicked by the local application of the GR agonist dexamethasone. These results show that high corticosterone release facilitates hippocampal CA1 mGluR-dependent LTD, and does so through local GRs.     

Time-dependent induction of depotentiation in the dentate gyrus of freely moving rats: involvement of group 2 metabotropic glutamate receptors

Depotentiation comprises a reversal of tetanization-induced long-term potentiation (LTP) which occurs following low-frequency stimulation (LFS) in the hippocampus in vivo. Although depotentiation has been consistently demonstrated in the CA1 region, no positive reports of the existence of depotentiation in the dentate gyrus in vivo have occurred. This study therefore investigated whether depotentiation is possible in the dentate gyrus in vivo. We found that depotentiation can be induced, but it is very tightly dependent on the interval between tetanization and LFS. Thus, LFS given 2 or 5 min following tetanization produced significant depotentiation, whereas LFS given 10-30 min following tetanization had no significant effect on the expression of LTP. Depotentiation occurred in two phases: a transient depression of evoked responses to below pre-tetanization values, which occurred in the first 60 min following LFS, and a recovery of this response to a stable level of synaptic transmission which comprised a significant reduction in the magnitude of LTP. Group 2 metabotropic glutamate receptors (mGluRs) play an important role in the expression of long-term depression in vivo. We therefore investigated whether group 2 mGluRs contribute to depotentiation. The group 2 antagonist (2S)-alpha-ethylglutamic acid (EGLU) inhibited the early transient depression at a concentration which inhibits LTD in vivo, but did not block the expression of depotentiation. EGLU also inhibited the transient depression induced by 5 Hz given alone. Increasing the concentration of EGLU prevented depotentiation, however. The group 2 agonist (S)-4-carboxy-3-hydroxyphenyl- glycine (4C3HPG) inhibited LTP and enhanced depotentiation. These data suggest a role for group 2 mGluRs in depotentiation.