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.     

Endogenous hippocampal LTD that is enabled by spatial object recognition requires activation of NMDA receptors and the metabotropic glutamate receptor,mGlu5

Learning‐facilitated synaptic plasticity describes the ability of hippocampal synapses to respond with persistent plasticity to afferent stimulation when coupled with a spatial learning event, whereby the afferent stimulation normally produces short‐term plasticity or no change in synaptic strength if given in the absence of novel learning. Recently, it was reported that in the mouse hippocampus intrinsic long‐term depression (LTD > 24 h) occurs when test‐pulse afferent stimulation is coupled with a novel spatial learning. It is not known to what extent this phenomenon shares molecular properties with synaptic plasticity that is typically induced by means of patterned electrical afferent stimulation. In previous work, we showed that a novel spatial object recognition task facilitates LTD at the Schaffer collateral—CA1 synapse of freely behaving adult mice, whereas reexposure to the familiar spatial configuration ～24 h later elicited no such facilitation. Here we report that treatment with the NMDA receptor antagonist, (±)‐3‐(2‐Carboxypiperazin‐4‐yl)‐propanephosphonic acid (CPP), or antagonism of metabotropic glutamate (mGlu) receptor, mGlu5, using 2‐methyl‐6‐(phenylethynyl) pyridine (MPEP), completely prevented LTD under the novel learning conditions. Behavioral assessment during re‐exposure after application of the antagonists revealed that the animals did not remember the object during novel exposure and treated them as if they were novel. Under these circumstances, where the acquisition of novel spatial information was involved, LTD was facilitated. Our data support that the endogenous LTD that is enabled through novel spatial learning in adult mice is critically dependent on the activation of both the NMDA receptors and mGlu5. © 2012 Wiley Periodicals, Inc.     

The 5‐hydroxytryptamine4 receptor enables differentiation of informational content and encoding in the hippocampus

Long‐term synaptic plasticity, represented by long‐term depression (LTD) and long‐term potentiation (LTP) comprise cellular processes that enable memory. Neuromodulators such as serotonin regulate hippocampal function, and the 5‐HT₄‐receptor contributes to processes underlying cognition. It was previously shown that in the CA1‐region, 5‐HT₄‐receptors regulate the frequency‐response relationship of synaptic plasticity: patterned afferent stimulation that has no effect on synaptic strength (i.e., a θm‐frequency), will result in LTP or LTD, when given in the presence of a 5‐HT₄‐agonist, or antagonist, respectively. Here, we show that in the dentate gyrus (DG) and CA3 regions of freely behaving rats, pharmacological manipulations of 5‐HT₄‐receptors do not influence responses generated at θm‐frequencies, but activation of 5‐HT₄‐receptors prevents persistent LTD in mossy fiber (mf)‐CA3, or perforant path‐DG synapses. Furthermore, the regulation by 5‐HT₄‐receptors of LTP is subfield‐specific: 5‐HT₄‐receptor‐activation prevents mf‐CA3‐LTP, but does not strongly affect DG‐potentiation. These data suggest that 5‐HT₄‐receptor activation prioritises information encoding by means of LTP in the DG and CA1 regions, and suppresses persistent information storage in mf‐CA3 synapses. Thus, 5‐HT₄‐receptors serve to shape information storage across the hippocampal circuitry and specify the nature of experience‐dependent encoding. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

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.     

Aberrant NMDA‐dependent LTD after perinatal ethanol exposure in young adult rat hippocampus

Irreversible cognitive deficits induced by ethanol exposure during fetal life have been ascribed to a lower NMDA‐dependent synaptic long‐term potentiation (LTP) in the hippocampus. Whether NMDA‐dependent long‐term depression (LTD) may also play a critical role in those deficits remains unknown. Here, we show that in vitro LTD induced with paired‐pulse low frequency stimulation is enhanced in CA1 hippocampus field of young adult rats exposed to ethanol during brain development. Furthermore, single pulse low frequency stimulation, ineffective at this age (LFS600), induced LTD after ethanol exposure accompanied with a stronger response than controls during LFS600, thus revealing an aberrant form of activity‐dependent plasticity at this age. Blocking NMDA receptor or GluN2B containing NMDA receptor prevented both the stronger response during LFS600 and LTD whereas Zinc, an antagonist of GluN2A containing NMDA receptor, was ineffective on both responses. In addition, LFS600‐induced LTD was revealed in controls only with a reduced‐Mg²⁺ medium. In whole dissected hippocampus CA1 field, perinatal ethanol exposure increased GluN2B subunit expression in the synaptic compartment whereas GluN2A was unaltered. Using pharmacological tools, we suggest that LFS600 LTD was of synaptic origin. Altogether, we describe a new mechanism by which ethanol exposure during fetal life induces a long‐term alteration of synaptic plasticity involving NMDA receptors, leading to an aberrant LTD. We suggest this effect of ethanol may reflect a delayed maturation of the synapse and that aberrant LTD may also participates to long‐lasting cognitive deficits in fetal alcohol spectrum disorder. © 2015 Wiley Periodicals, Inc.     

Low‐frequency‐induced synaptic potentiation: A paradigm shift in the field of memory‐related plasticity mechanisms?

Long‐term potentiation (LTP) and long‐term depression (LTD) are two forms of synaptic plasticity thought to play functional roles in learning and memory processes. It is generally assumed that the direction of synaptic modifications (i.e., up‐ or down‐regulation of synaptic strength) depends on the specific pattern of afferent inputs, with high frequency activity or stimulation effectively inducing LTP, while low‐frequency patterns often elicit LTD. This dogma (“high frequency‐LTP, low frequency‐LTD”) has recently been challenged by evidence demonstrating low frequency stimulation (LFS)‐induced synaptic potentiation in the rodent hippocampus and amygdala. Extensive work in the past decades has focused on deciphering the mechanisms by which high frequency stimulation of afferent fiber systems results in LTP. With this review, we will compare and contrast the well‐known synaptic and cellular mechanisms underlying classical, high‐frequency‐induced LTP to those mediating the more recently discovered phenomena of LFS‐induced synaptic enhancement. In addition, we argue that LFS protocols provide a means to more accurately mimic some endogenous, oscillatory activity patterns present in hippocampal and extra‐hippocampal (especially neocortical) circuits during periods of memory consolidation. Consequently, LFS‐induced synaptic potentiation offers a novel and important avenue to investigate cellular and systems‐level mechanisms mediating the encoding, consolidation, and transfer of information throughout multiple forebrain networks implicated in learning and memory processes. © 2009 Wiley‐Liss, Inc.     

Hippocampal long‐term depression in freely behaving mice requires the activation of beta‐adrenergic receptors

In the intact mouse hippocampus patterned afferent stimulation does not lead to long‐term depression (LTD) at Schaffer collateral (Sc)‐CA1 synapses, but the same synapses express robust LTD (<24 h) if test‐pulse or patterned afferent experience is coupled with novel spatial learning. This suggests that the failure of sole afferent stimulation to elicit LTD relates to the absence of neuromodulatory input related to increased arousal or novelty during learning. Locus coeruleus (LC) firing increases during novel experience, and in rats patterned stimulation of the LC together with test‐pulse stimulation of Sc‐CA1 synapses leads to robust LTD in vivo. This effect is mediated by beta‐adrenergic receptors. Here, we explored if activation of beta‐adrenergic receptors supports the expression of LTD in freely behaving mice. We also explored if beta‐adrenergic receptors contribute to endogenous LTD that is expressed following spatial learning. Patterned stimulation of Sc‐CA1 synapses at 3 Hz (200 pulses) resulted in short‐term depression (STD). Pretreatment with isoproterenol, an agonist of beta‐adrenergic receptors, resulted in robust LTD (<24 h). Test‐pulse stimulation under control conditions elicited field potentials that were stable for the 24‐h monitoring period. Coupling of test‐pulses with a novel spatial object recognition task resulted in robust endogenous LTD (<24 h). Pretreatment with propranolol, a beta‐adrenergic receptor antagonist, completely prevented endogenous LTD that was enabled by learning and prevented object recognition learning itself. These data indicate that the absence of LTD in freely behaving mice, under standard recording conditions, does not reflect an inability of mice to express LTD, rather it is due to the absence of a noradrenalin tonus. Our data also support that spatial object recognition requires beta‐adrenergic receptor activation. Furthermore, LTD that is enabled by novel spatial learning critically depends on activation of beta‐adrenergic receptors that are presumably activated by noradrenalin released by the LC in response to the novel experience. © 2013 Wiley Periodicals, Inc.     

Maladaptive striatal plasticity and abnormal reward‐learning in cervical dystonia

In monogenetic generalized forms of dystonia, in vitro neurophysiological recordings have demonstrated direct evidence for abnormal plasticity at the level of the cortico‐striatal synapse. It is unclear whether similar abnormalities contribute to the pathophysiology of cervical dystonia, the most common type of focal dystonia. We investigated whether abnormal cortico‐striatal synaptic plasticity contributes to abnormal reward‐learning behavior in patients with focal dystonia. Forty patients and 40 controls performed a reward gain and loss avoidance reversal learning task. Participant's behavior was fitted to a computational model of the basal ganglia incorporating detailed cortico‐striatal synaptic learning rules. Model comparisons were performed to assess the ability of four hypothesized receptor specific abnormalities of cortico‐striatal long‐term potentiation (LTP) and long‐term depression (LTD): increased or decreased D1:LTP/LTD and increased or decreased D2: LTP/LTD to explain abnormal behavior in patients. Patients were selectively impaired in the post‐reversal phase of the reward task. Individual learning rates in the reward reversal task correlated with the severity of the patient's motor symptoms. A model of the striatum with decreased D2:LTP/ LTD best explained the patient's behavior, suggesting excessive D2 cortico‐striatal synaptic depotentiation could underpin biased reward‐learning in patients with cervical dystonia. Reversal learning impairment in cervical dystonia may be a behavioral correlate of D2‐specific abnormalities in cortico‐striatal synaptic plasticity. Reinforcement learning tasks with computational modeling could allow the identification of molecular targets for novel treatments based on their ability to restore normal reward‐learning behavior in these patients.     

Methamphetamine‐induced enhancement of hippocampal long‐term potentiation is modulated by NMDA and GABA receptors in the shell–accumbens

Addictive drugs modulate synaptic transmission in the meso‐corticolimbic system by hijacking normal adaptive forms of experience‐dependent synaptic plasticity. Psychostimulants such as METH have been shown to affect hippocampal synaptic plasticity, albeit with a less understood synaptic mechanism. METH is one of the most addictive drugs that elicit long‐term alterations in the synaptic plasticity in brain areas involved in reinforcement learning and reward processing. Dopamine transporter (DAT) is one of the main targets of METH. As a substrate for DAT, METH decreases dopamine uptake and increases dopamine efflux via the transporter in the target brain regions such as nucleus accumbens (NAc) and hippocampus. Due to cross talk between NAc and hippocampus, stimulation of NAc has been shown to alter hippocampal plasticity. In this study, we tested the hypothesis that manipulation of glutamatergic and GABA‐ergic systems in the shell‐NAc modulates METH‐induced enhancement of long term potentiation (LTP) in the hippocampus. Rats treated with METH (four injections of 5 mg/kg) exhibited enhanced LTP as compared to saline‐treated animals. Intra‐NAc infusion of muscimol (GABA receptor agonist) decreased METH‐induced enhancement of dentate gyrus (DG)‐LTP, while infusion of AP5 (NMDA receptor antagonist) prevented METH‐induced enhancement of LTP. These data support the interpretation that reducing NAc activity can ameliorate METH‐induced hippocampal LTP through a hippocampus‐NAc‐VTA circuit loop. Synapse 70:325–335, 2016 . © 2016 Wiley Periodicals, Inc.     

Properties of 4 Hz stimulation‐induced parallel fiber–Purkinje cell presynaptic long‐term plasticity in mouse cerebellar cortex in vivo

Cerebellar parallel fiber–Purkinje cell (PF–PC) long‐term synaptic plasticity is important for the formation and stability of cerebellar neuronal circuits, and provides substrates for motor learning and memory. We previously reported both presynaptic long‐term potentiation (LTP) and long‐term depression (LTD) in cerebellar PF–PC synapses in vitro. However, the expression and mechanisms of cerebellar PF–PC synaptic plasticity in the cerebellar cortex in vivo are poorly understood. In the present study, we studied the properties of 4 Hz stimulation‐induced PF–PC presynaptic long‐term plasticity using in vivo the whole‐cell patch‐clamp recording technique and pharmacological methods in urethane‐anesthetised mice. Our results demonstrated that 4 Hz PF stimulation induced presynaptic LTD of PF–PC synaptic transmission in the intact cerebellar cortex in living mice. The PF–PC presynaptic LTD was attenuated by either the N‐methyl‐D‐aspartate receptor antagonist, D‐aminophosphonovaleric acid, or the group 1 metabotropic glutamate receptor antagonist, JNJ16259685, and was abolished by combined D‐aminophosphonovaleric acid and JNJ16259685, but enhanced by inhibition of nitric oxide synthase. Blockade of cannabinoid type 1 receptor activity abolished the PF–PC LTD and revealed a presynaptic PF–PC LTP. These data indicate that both endocannabinoids and nitric oxide synthase are involved in the 4 Hz stimulation‐induced PF–PC presynaptic plasticity, but the endocannabinoid‐dependent PF–PC presynaptic LTD masked the nitric oxide‐mediated PF–PC presynaptic LTP in the cerebellar cortex in urethane‐anesthetised mice.     

Spatial olfactory learning facilitates long‐term depression in the hippocampus

Recently, it has emerged that visual spatial exploration facilitates synaptic plasticity at different synapses within the trisynaptic network. Particularly striking is the finding that visuospatial contexts facilitate hippocampal long‐term depression (LTD), raising the possibility that this form of plasticity may be important for memory formation. It is not known whether other sensory modalities elicit similar permissive effects on LTD. Here, we explored if spatial olfactory learning facilitates LTD in the hippocampus region of freely behaving rats. Patterned afferent stimulation of the Schaffer collaterals elicited short‐term depression (STD) (<1 h) of evoked responses in the Stratum radiatum of the CA1 region. Coupling of this protocol with novel exploration of a spatial constellation of olfactory cues facilitated short‐term depression into LTD that lasted for over 24 h. Facilitation of LTD did not occur when animals were re‐exposed 1 week later to the same odors in the same spatial constellation. Evaluation of learning behavior revealed that 1 week after the 1st odor exposure, the animals remembered the odors and their relative positions. These data support that the hippocampus can use nonvisuospatial resources, and specifically can use spatial olfactory information, to facilitate LTD and to generate spatial representations. The data also support that a tight relationship exists between the processing of spatial contextual information and the expression of LTD in the hippocampus. © 2013 Wiley Periodicals, Inc.     

Frequency dependency of NMDA receptor‐dependent synaptic plasticity in the hippocampal CA1 region of freely behaving mice

Hippocampal synaptic plasticity in the form of long‐term potentiation (LTP) and long‐term depression (LTD) is likely to enable synaptic information storage in support of memory formation. The mouse brain has been subjected to intensive scrutiny in this regard; however, a multitude of studies has examined synaptic plasticity in the hippocampal slice preparation, whereas very few have addressed synaptic plasticity in the freely behaving mouse. Almost nothing is known about the frequency or N‐methyl‐D‐aspartate receptor (NMDAR) dependency of hippocampal synaptic plasticity in the intact mouse brain. Therefore, in this study, we investigated the forms of synaptic plasticity that are elicited at different afferent stimulation frequencies. We also addressed the NMDAR dependency of this phenomenon. Adult male C57BL/6 mice were chronically implanted with a stimulating electrode into the Schaffer collaterals and a recording electrode into the Stratum radiatum of the CA1 region. To examine synaptic plasticity, we chose protocols that were previously shown to produce either LTP or LTD in the hippocampal slice preparation. Low‐frequency stimulation (LFS) at 1 Hz (900 pulses) had no effect on evoked responses. LFS at 3 Hz (ranging from 200 up to 2 × 900 pulses) elicited short‐term depression (STD, <45 min). LFS at 3 Hz (1,200 pulses) elicited slow‐onset potentiation, high‐frequency stimulation (HFS) at 100 Hz (100 or 200 pulses) or at 50 Hz was ineffective, whereas 100 Hz (50 pulses) elicited short‐term potentiation (STP). HFS at 100 Hz given as 2 × 30, 2 × 50, or 4 × 50 pulses elicited LTP (>24 h). Theta‐burst stimulation was ineffective. Antagonism of the NMDAR prevented STD, STP, and LTP. This study shows for the first time that protocols that effectively elicit persistent synaptic plasticity in the slice preparation elicit distinctly different effects in the intact mouse brain. Persistent LTD could not be elicited with any of the protocols tested. Plasticity responses are NMDAR dependent, suggesting that these phenomena are relevant for hippocampus‐dependent learning. © 2012 Wiley Periodicals, Inc.     

Intrinsic cellular and molecular properties of in vivo hippocampal synaptic plasticity are altered in the absence of key synaptic matrix molecules

Hippocampal synaptic plasticity comprises a key cellular mechanism for information storage. In the hippocampus, both long‐term potentiation (LTP) and long‐term depression (LTD) are triggered by synaptic Ca²⁺‐elevations that are typically mediated by the opening of voltage‐gated cation channels, such as N‐methyl‐d ‐aspartate receptors (NMDAR), in the postsynaptic density. The integrity of the post‐synaptic density is ensured by the extracellular matrix (ECM). Here, we explored whether synaptic plasticity is affected in adult behaving mice that lack the ECM proteins brevican, neurocan, tenascin‐C, and tenascin‐R (KO). We observed that the profiles of synaptic potentiation and depression in the dentate gyrus (DG) were profoundly altered compared to plasticity profiles in wild‐type littermates (WT). Specifically, synaptic depression was amplified in a frequency‐dependent manner and although late‐LTP (>24 hr) was expressed following strong afferent tetanization, the early component of LTP (<75 min post‐tetanization) was absent. LTP (>4 hr) elicited by weaker tetanization was equivalent in WT and KO animals. Furthermore, this latter form of LTP was NMDAR‐dependent in WT but not KO mice. Scrutiny of DG receptor expression revealed significantly lower levels of both the GluN2A and GluN2B subunits of the N‐methyl‐d ‐aspartate receptor, of the metabotropic glutamate receptor, mGlu5 and of the L‐type calcium channel, Ca_v1.3 in KO compared to WT animals. Homer 1a and of the P/Q‐type calcium channel, Ca_v1.2 were unchanged in KO mice. Taken together, findings suggest that in mice that lack multiple ECM proteins, synaptic plasticity is intact, but is fundamentally different.     

Effects of endogenous and exogenous D1/D5 dopamine receptor activation on LTP in ventral and dorsal CA1 hippocampal synapses

Hippocampus is importantly involved in dopamine‐dependent behaviors and dopamine is a significant modulator of synaptic plasticity in the hippocampus. Moreover, the dopaminergic innervation appears to be disproportionally segregated along the hippocampal longitudinal (dorsoventral) axis with unknown consequences for synaptic plasticity. In this study we examined the actions of endogenously released dopamine and the effects of exogenous D1/D5 dopamine receptor agonists on theta‐burst stimulation‐induced long‐term potentiation (LTP) of field excitatory synaptic potential (fEPSP) at Schaffer collateral‐CA1 synapses in slices from dorsal (DH) and ventral hippocampus (VH). Furthermore, we quantified D1 receptor mRNA and protein expression levels in DH and VH. We found that blockade of D1/D5 receptors by SCH 23390 (20 μM) significantly reduced the magnitude of LTP in both DH and VH similarly suggesting that dopamine endogenously released during TBS, presumably mimicking low activity of DA neurons, exerts a homogeneous modulation of LTP along the hippocampal long axis. Moderate to high concentrations of the selective partial D1/D5 receptor agonist SKF 38393 (50‐150 μM) did not significantly change LTP in either hippocampal segment. However, the full D1 receptor selective agonist SKF 82958 (10 μM) significantly enhanced LTP in VH but not DH. Furthermore, the expression of D1 receptor mRNA and protein was considerably higher in VH compared with DH. These results suggest that the dynamic range of D1/D5 receptor‐mediated dopamine effects on LTP may be higher in VH than DH and that VH may be specialized to acquire information about behaviorally relevant strong stimuli signaled by the dopamine system.     

Interaction of DHPG‐LTD and synaptic‐LTD at senescent CA3‐CA1 hippocampal synapses

The susceptibility, but not the magnitude, of long‐term depression (LTD) induced by hippocampal CA3‐CA1 synaptic activity (synaptic‐LTD) increases with advanced age. In contrast, the magnitude of LTD induced by pharmacological activation of CA3‐CA1 group I metabotropic glutamate receptors (mGluRs) increases during aging. This study examined the signaling pathways involved in induction of LTD and the interaction between paired‐pulse low frequency stimulation‐induced synaptic‐LTD and group I mGluR selective agonist, (RS)‐3,5‐dihydroxyphenylglycine (DHPG, 100 µM)‐induced DHPG‐LTD in hippocampal slices obtained from aged (22–24 months) male Fischer 344 rats. Prior induction of synaptic‐LTD did not affect induction of DHPG‐LTD; however, prior induction of the DHPG‐LTD occluded synaptic‐LTD suggesting that expression of DHPG‐LTD may incorporate synaptic‐LTD mechanisms. Application of individual antagonist for the group I mGluR (AIDA), the N‐methyl‐d ‐aspartate receptor (NMDAR) (AP‐5), or L‐type voltage‐dependent Ca²⁺ channel (VDCC) (nifedipine) failed to block synaptic‐LTD and any two antagonists severely impaired synaptic‐LTD induction, indicating that activation of any two mechanisms is sufficient to induce synaptic‐LTD in aged animals. For DHPG‐LTD, AIDA blocked DHPG‐LTD and individually applied NMDAR or VDCC attenuated but did not block DHPG‐LTD, indicating that the magnitude of DHPG‐LTD depends on all three mechanisms. © 2014 Wiley Periodicals, Inc.     

Differential effects of strain, circadian cycle, and stimulation pattern on LTP and concurrent LTD in the dentate gyrus of freely moving rats

Because long‐term potentiation (LTP) and long‐term depression (LTD) are thought to be involved in learning and memory, it is important to delineate factors that modulate their induction and persistence, especially as studied in freely moving animals. Here, we investigated the effects of rat strain, circadian cycle, and high‐frequency stimulation (HFS) pattern on LTP and concurrently induced LTD in the dentate gyrus (DG). Comparison of two commonly used rat strains revealed that medial perforant path field EPSP‐population spike (E‐S) coupling and LTP were greater in Long‐Evans than Sprague‐Dawley rats. Circadian cycle experiments conducted in Long‐Evans rats revealed greater E‐S coupling and enhanced LTP during the dark phase. Interestingly, concurrent LTD in the lateral perforant path did not significantly differ across strains or circadian cycle. Testing HFS protocols during the dark phase revealed that theta burst stimulation (100 Hz bursts at 5 Hz intervals) was ineffective in eliciting either LTP or concurrent LTD in DG, whereas 400 Hz bursts delivered at theta (5 Hz) or delta (1 Hz) frequencies produced substantial LTP and concurrent LTD. Thus, these natural and experimental factors regulate granule cell excitability, and differentially affect LTP and concurrent LTD in the DG of freely moving rats. © 2011 Wiley Periodicals, Inc.     

Antagonism of group III metabotropic glutamate receptors results in impairment of LTD but not LTP in the hippocampal CA1 region, and prevents long-term spatial memory

Recently it has emerged that hippocampal long-term depression (LTD) may play an important role in the acquisition and storage of spatial memories. This form of synaptic plasticity is tightly regulated by metabotropic glutamate receptors (mGluRs) that negatively couple to adenylyl cyclase. Activation of group III mGluRs is necessary for persistent hippocampal LTD, but is not required for depotentiation or long-term potentiation (LTP) in the dentate gyrus in vivo. In the CA1 region antagonism of group III mGluRs prevents LTD in vivo. Effects on LTP in vivo are as yet unknown. We investigated the effects of group III mGluR antagonism on LTP and LTD at Schaffer collateral-CA1 synapses, and on spatial learning in the eight-arm radial maze. Daily application of the group III mGluR antagonist (R,S)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG) resulted in impairment of long-term (reference) memory, with effects becoming apparent 4 days after training and drug treatment began. Short-term (working) memory was unaffected throughout the 10-day study. Application of CPPG prevented LTD, but not LTP, in the CA1 region. These data suggest that activation of group III mGluRs is required for the establishment of spatial long-term memory. Their exclusive role in mediating hippocampal LTD provides correlational evidence for a role for LTD in the type of spatial learning studied.     

Endogenous inhibition of hippocampal LTD and depotentiation by vasoactive intestinal peptide VPAC1 receptors

Vasoactive intestinal peptide (VIP), an important modulator of hippocampal synaptic transmission, influences exploration and hippocampal‐dependent learning in rodents. Homosynaptic long‐term depression (LTD) and depotentiation are two plasticity phenomena implicated in learning of behavior flexibility and spatial novelty detection. In this study, we investigated the influence of endogenous VIP on LTD and depotentiation induced by low‐frequency stimulation (1 Hz, 900 pulses) of the hippocampal CA1 area in vitro in juvenile and young adult rats, respectively. LTD and depotentiation were enhanced by the VIP receptor antagonist Ac‐Tyr¹, D‐Phe² GRF (1–29), and the selective VPAC₁ receptor antagonist, PG 97–269, but not the selective VPAC₂ receptor antagonist, PG 99–465. This action was mimicked by an anti‐VIP antibody, suggesting that VIP, and not pituitary adenylate cyclase‐activating polypeptide (PACAP), is the endogenous mediator of these effects. Selective inhibition of PAC1 receptors with PACAP (6–38) enhanced depotentiation, but not LTD. VPAC₁ receptor blockade also revealed LTD in young adult rats, an effect abolished by the GABA_A antagonist bicuculline, evidencing an involvement of GABAergic transmission. We conclude that inhibition of LTD and depotentiation by endogenous VIP occurs through VPAC₁ receptor‐mediated mechanisms and suggest that disinhibition of pyramidal cell dendrites is the most likely physiological mechanism underlying this effect. As such, VPAC₁ receptor ligands may be considered promising pharmacological targets for treatment of cognitive dysfunction in diseases involving altered GABAergic circuits and pathological saturation of LTP/LTD like Down's syndrome and temporal lobe epilepsy. © 2014 Wiley Periodicals, Inc.     

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.     

Acute nicotine treatment prevents rem sleep deprivation‐induced learning and memory impairment in rat

Rapid eye movement (REM) sleep deprivation (SD) is implicated in impairment of spatial learning and memory and hippocampal long‐term potentiation (LTP). An increase in nicotine consumption among habitual smokers and initiation of tobacco use by nonsmokers was observed during SD. Although nicotine treatment was reported to attenuate the impairment of learning and memory and LTP associated with several mental disorders, the effect of nicotine on SD‐induced learning and memory impairment has not been studied. Modified multiple platform paradigm was used to induce SD for 24 or 48 h during which rats were injected with saline or nicotine (1 mg kg^?1 s.c.) twice a day. In the radial arm water maze (RAWM) task, 24‐ or 48‐h SD significantly impaired learning and short‐term memory. In addition, extracellular recordings from CA1 and dentate gyrus (DG) regions of the hippocampus in urethane anesthetized rats showed a significant impairment of LTP after 24‐ and 48‐h SD. Treatment of normal rats with nicotine for 24 or 48 h did not enhance spatial learning and memory or affect magnitude of LTP in the CA1 and DG regions. However, concurrent, acute treatment of rats with nicotine significantly attenuated SD‐induced impairment of learning and STM and prevented SD‐induced impairment of LTP in the CA1 and DG regions. These results show that acute nicotine treatment prevented the deleterious effect of sleep loss on cognitive abilities and synaptic plasticity. © 2010 Wiley‐Liss, Inc.