Amyloid β‐protein fragments 25–35 and 31–35 potentiate long‐term depression in hippocampal CA1 region of rats in vivo

Amyloid β‐protein (Aβ) is thought to be responsible for the deficit of learning and memory in Alzheimer's disease (AD), possibly through interfering with synaptic plasticity in the brain. It has been reported that Aβ fragments suppress the long‐term potentiation (LTP) of synaptic transmission. However, it is unclear whether Aβ fragments can regulate long‐term depression (LTD), an equally important form of synaptic plasticity in the brain. The present study investigates the effects of Aβ fragments on LTD induced by low frequency stimulation (LFS) in the hippocampus in vivo. Our results showed that (1) prolonged 1–10 Hz of LFS all effectively elicited LTD, which could persist for at least 2 h and be reversed by high frequency stimulation (HFS); (2) the effectiveness of LTD induction depended mainly on the number of pulses but not the frequency of LFS; (3) pretreatment with Aβ fragment 25–35 (Aβ_25–35, 12.5 and 25 nmol) did not change baseline field excitatory postsynaptic potentials but dose‐dependently potentiated LTD; (4) Aβ fragment 31–35 (Aβ_31–35), a shorter Aβ fragment than Aβ_25–35, also dose‐dependently strengthened LFS‐induced hippocampal LTD. Thus, the present study demonstrates the enhancement of hippocampal LTD by Aβ in in vivo condition. We propose that Aβ‐induced potentiation of LTD, together with the suppression of LTP, will result in the impairment of cognitive function of the brain. Synapse 63:206–214, 2009. © 2008 Wiley‐Liss, 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.     

Long-term depression in horizontal slices of the rat lateral amygdala

Long-term depression (LTD) is an enduring decrease in synaptic efficacy and is thought to underlie memory. In contrast to investigations of plasticity mechanisms in the amygdala in rat coronal slices, this study was done in horizontal slices. Field excitatory postsynaptic potentials (fEPSPs) and EPSPs, respectively, were recorded extracellularly and intracellularly from the lateral nucleus of the amygdala (LA). We show that low-frequency stimulation (LFS) induces LTD in the LA, when stimulation electrodes were located in the LA. No significant differences were found between females and males. In dependence of strain variations, a reduction of GABAergic inhibition either reduced the magnitude of LTD or was a prerequisite for the induction of extracellularly recorded LA-LTD. Theta pulse stimulation (TPS) of afferents within the LA caused a weaker LTD than LFS. Theta burst stimulation (TBS) given 20 min after the end of LFS reversed LTD, whereas high-frequency stimulation (HFS) resulted in long-term potentiation (LTP) that was significantly stronger than that obtained in naive slices. Therefore, primed induction of LTD facilitates high-frequency-induced LTP in the rat lateral amygdala. NMDARs as well as group II mGluRs were involved in the mediation of LA-LTD. In contrast to data obtained by stimulation of afferents running within the LA, LFS of the external capsule fibers induced a weak LA-LTD, and TPS was not able to induce LTD. This study showed for the first time that LTD can be induced in the LA by standard LFS (900 pulses at 1 Hz) and that LTP stimuli reversed LTD. The results also provide further evidence for the broad sensitivity of synaptic plasticity mechanisms to the history of prior activity.     

Long-term potentiation and depression of synaptic transmission in rat posterior cingulate cortex

We used stimulation of corpus callosum (CAL) and the subiculo-cingulate tract (SCT), in an in vitro brain slice preparation, to study activity-dependent changes in synaptic efficacy in posterior cingulate cortex (PCC). SCT stimulation monosynaptically excites the apical dendrites of deep laminae (V–VI) pyramidal neurons, while CAL afferents drive these same cells via synapses on their basal dendrites. In contrast, most superficial laminae (II/III–IV) pyramids appear to be driven polysynaptically via ascending axonal collaterals of deep pyramids. In slices retaining these connectivities, we contrasted characteristics of synaptic plasticity in superficial vs deep laminae field and intracellular potentials evoked by conditioning stimuli given at frequencies of 100, 20, 8, 5 and 1 Hz. Tetanic stimulation (100 Hz) of SCT or CAL yielded homosynaptic long-term potentiation (LTP) of each pathway, while stimulus trains of 8–20 Hz did not. 1–5 Hz stimulation of SCT and CAL elicited homosynaptic long-term depression (LTD) of synaptic strength in each pathway. Associative LTD was induced by interleaving 5 Hz pulses to the SCT pathway with 100 Hz θ-burst stimulation of CAL, but was not induced when these stimulus loci were switched. Heterosynaptic non-associative LTD was also observed in the alternate pathway following tetanization of either SCT or CAL. In all cases, LTP and LTD were observed only in deep laminae recordings. In contrast, superficial records showed only paired-pulse facilitation and short-term post-tetanic potentiation. In in vivo experiments in anaesthetized rats, PCC responses to SCT stimulation were contrasted with responses to stimulation of anteroventral and anterodorsal thalamic nuclei (AV/AD). SCT-elicited field potentials closely resembled those evoked in the slice, with maximal amplitude tuned to the 4–8 Hz frequency band. AV/VD stimulation elicited field potentials which were not frequency tuned. Overall, these data suggest that the acute circuit properties of PCC superficial laminae, modulated by thalamic input and synaptic plasticity in deep laminae, can transform hippocampal synaptic inflow before relaying it to extracingulate targets.     

Target-cell-specific bidirectional synaptic plasticity at hippocampal output synapses

It is commonly accepted that the hippocampus is critically involved in the explicit memory formation of mammals. The subiculum is the principal target of CA1 pyramidal cells and thus serves as the major relay station for the outgoing hippocampal information. Pyramidal cells in the subiculum can be classified according to their firing properties into burst-spiking and regular-spiking cells. In the present study we demonstrate that burst-spiking and regular-spiking cells show fundamentally different forms of low frequency-induced synaptic plasticity in rats. In burst-spiking cells, low-frequency stimulation (at 0.5–5 Hz) induces frequency-dependent long-term depression (LTD) with a maximum at 1 Hz. This LTD is dependent on the activation of NMDAR and masks an mGluR-dependent long-term potentiation (LTP). In contrast, in regular-spiking cells low-frequency stimulation induces an mGluR-dependent LTP that masks an NMDAR-dependent LTD. Both processes depend on postsynaptic Ca²⁺-signaling as BAPTA prevents the induction of synaptic plasticity in both cell types. Thus, mGluR-dependent LTP and NMDAR-dependent LTD occur simultaneously at CA1-subiculum synapses and the predominant direction of synaptic plasticity relies on the cell type investigated. Our data indicate a novel mechanism for the sliding-threshold model of synaptic plasticity, in which induction of LTP and LTD seems to be driven by the relative activation state of NMDAR and mGluR. Our observation that the direction of synaptic plasticity correlates with the discharge properties of the postsynaptic cell reveals a novel and intriguing mechanism of target specificity that may serve in tuning the significance of neuronal information by trafficking hippocampal output onto either subicular burst-spiking or regular-spiking cells.     

Different synaptic stimulation patterns influence the local androgenic and estrogenic neurosteroid availability triggering hippocampal synaptic plasticity in the male rat

Electrophysiological recordings were used to investigate the role of the local synthesis of 17β‐estradiol (E2) and 5α‐dihydrotestosterone (DHT) on synaptic long‐term effects induced in the hippocampal CA1 region of male rat slices. Long‐term depression (LTD) and long‐term potentiation (LTP), induced by different stimulation patterns, were examined under the block of the DHT synthesis by finasteride (FIN), and the E2 synthesis by letrozole (LET). We used low frequency stimulation (LFS) for LTD, high frequency stimulation (HFS) for LTP, and intermediate patterns differing in duration or frequency. We found that FIN reverted the LFS‐LTD into LTP and enhanced LTP induced by intermediate and HFSs. These effects were abolished by exogenous DHT at concentration higher than the basal one, suggesting a stimulus dependent increase in DHT availability. No effect on the synaptic responses was observed giving DHT alone. Moreover, we found that the inhibition of E2 synthesis influenced the HFS‐LTP by reducing its amplitude, and the exogenous E2 either enhanced HFS‐LTP or reverted the LFS‐LTD into LTP. The equivalence of the E2 concentration for rescuing the full HFS‐LTP under LET and reverting the LFS‐LTD into LTP suggests an enhancement of the endogenous E2 availability that is specifically driven by the HFS. No effect of FIN or LET was observed on the responses to stimuli that did not induce either LTD or LTP. This study provides evidence that the E2 and DHT availability combined with specific stimulation patterns is determinant for the sign and amplitude of the long‐term effects.     

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.     

Fear memories induce a switch in stimulus response and signaling mechanisms for long-term potentiation in the lateral amygdala

Activity-dependent modification of synapses is fundamental for information storage in the brain and underlies behavioral learning. Fear conditioning is a model of emotional memory and anxiety that is expressed as an enduring increase in synaptic strength in the lateral amygdala (LA). Here we analysed synaptic plasticity in the rat cortico-LA pathway during maintenance of fear memory. We show for the first time that the stimulus frequency for synaptic potentiation is switched during maintenance of fear memory, and the underlying signaling mechanisms are altered in the cortico-LA pathway. In slices from fear-conditioned animals, high-frequency stimulation-induced (HFS) long-term potentiation (LTP) was attenuated, whereas low-frequency stimulation (LFS) elicited a long-lasting potentiation. HFS generates robust LTP that is dependent on N-methyl-d-aspartate receptor (NMDAR) and L-type voltage-gated calcium channel (VGCC) activation in control animals, whereas in fear-conditioned animals HFS LTP is NMDAR- and VGCC-independent. LFS-LTP is partially NMDAR-dependent, but VGCCs are necessary for potentiation in fear memory. Collectively, these results show that during maintenance of fear memory the stimulus requirements for amygdala afferents and critical signaling mechanisms for amygdala synaptic potentiation are altered, suggesting that cue-engaged synaptic mechanisms in the amygdala are dramatically affected as a result of emotional learning.     

Diabetes mellitus concomitantly facilitates the induction of long-term depression and inhibits that of long-term potentiation in hippocampus

Memory impairments, which occur regularly across species as a result of ageing, disease (such as diabetes mellitus) and psychological insults, constitute a useful area for investigating the neurobiological basis of learning and memory. Previous studies in rats found that induction of diabetes (with streptozotocin, STZ) impairs long‐term potentiation (LTP) but enhances long‐term depression (LTD) induced by high‐ (HFS) and low‐frequency stimulations (LFS), respectively. Using a pairing protocol under whole‐cell recording conditions to induce synaptic plasticity at Schaffer collateral synapses in hippocampal CA1 slices, we show that LTD and LTP have similar magnitudes in diabetic and age‐matched control rats. But, in diabetic animals, LTD is induced at more polarized and LTP more depolarized membrane potentials (V_ms) compared with controls: diabetes produces a 10 mV leftward shift in the threshold for LTD induction and 10 mV rightward shift in the LTD–LTP crossover point of the voltage–response curve for synaptic plasticity. Prior repeated short‐term potentiations or LTP are known to similarly, though reversibly, lower the threshold for LTD induction and raise that for LTP induction. Thus, diabetes‐ and activity‐dependent modulation of synaptic plasticity (referred to as metaplasticity) display similar phenomenologies. In addition, compared with naïve synapses, prior induction of LTP produces a 10 mV leftward shift in V_ms for inducing subsequent LTD in control but not in diabetic rats. This could indicate that diabetes acts on synaptic plasticity through mechanisms involved in metaplasticity. Persistent facilitation of LTD and inhibition of LTP may contribute to learning and memory impairments associated with diabetes mellitus.     

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.     

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.     

Differential regulation of synaptic plasticity of the hippocampal and the hypothalamic inputs to the anterior thalamus

The hippocampus projects to the anterior thalamic nuclei both directly and indirectly via the mammillary bodies, but little is known about the electrophysiological properties of these convergent pathways. Here we demonstrate, for the first time, the presence of long‐term plasticity in anterior thalamic nuclei synapses in response to high‐ and low‐frequency stimulation (LFS) in urethane‐anesthetized rats. We compared the synaptic changes evoked via the direct vs. the indirect hippocampal pathways to the anterior thalamus, and found that long‐term potentiation (LTP) of the thalamic field response is induced predominantly through the direct hippocampal projections. Furthermore, we have estimated that that long‐term depression (LTD) can be induced only after stimulation of the indirect connections carried by the mammillothalamic tract. Interestingly, basal synaptic transmission mediated by the mammillothalamic tract undergoes use‐dependent, BDNF‐mediated potentiation, revealing a distinct form of plasticity specific to the diencephalic region. Our data indicate that the thalamus does not passively relay incoming information, but rather acts as a synaptic network, where the ability to integrate hippocampal and mammillary body inputs is dynamically modified as a result of previous activity in the circuit. The complementary properties of these two parallel pathways upon anterior thalamic activity reveal that they do not have duplicate functions. © 2009 Wiley‐Liss, Inc.     

Modulatory metaplasticity induced by pregnenolone sulfate in the rat hippocampus: A leftward shift in LTP/LTD‐frequency curve

We recently have found that an acute application of the neurosteroid pregnenolone sulfate (PREGS) at 50 μM to rat hippocampal slices induces a long‐lasting potentiation (LLP_PREGS) via a sustained ERK2/CREB activation at perforant‐path/granule‐cell synapses in the dentate gyrus. This study is a follow up to investigate whether the expression of LLP_PREGS influences subsequent frequency‐dependent synaptic plasticity. Conditioning electric stimuli (CS) at 0.1–200 Hz were given to the perforant‐path of rat hippocampal slices expressing LLP_PREGS to induce long‐term potentiation (LTP) and long‐term depression (LTD). The largest LTP was induced at about 20 Hz‐CS, which is normally a subthreshold frequency, and the largest LTD at 0.5 Hz‐CS, resulting in a leftward‐shift of the LTP/LTD‐frequency curve. Furthermore, the level of LTP at 100 Hz‐CS was significantly attenuated to give band‐pass filter characteristics of LTP induction with a center frequency of about 20 Hz. The LTP induced by 20 Hz‐CS (termed 20 Hz‐LTP) was found to be postsynaptic origin and dependent on L‐type voltage‐gated calcium channel (L‐VGCC) but not on N‐methyl‐D ‐aspartate receptor (NMDAr). Moreover, the induction of 20 Hz‐LTP required a sustained activation of ERK2 that had been triggered by PREGS. In conclusion, the transient elevation of PREGS is suggested to induce a modulatory metaplasticity through a sustained activation of ERK2 in an L‐VGCC dependent manner. © 2009 Wiley‐Liss, 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.     

Short-term and long-term plasticity interaction in human primary motor cortex

Repetitive transcranial magnetic stimulation (rTMS) over primary motor cortex (M1) elicits changes in motor evoked potential (MEP) size thought to reflect short‐ and long‐term forms of synaptic plasticity, resembling short‐term potentiation (STP) and long‐term potentiation/depression (LTP/LTD) observed in animal experiments. We designed this study in healthy humans to investigate whether STP as elicited by 5‐Hz rTMS interferes with LTP/LTD‐like plasticity induced by intermittent and continuous theta‐burst stimulation (iTBS and cTBS). The effects induced by 5‐Hz rTMS and iTBS/cTBS were indexed as changes in MEP size. We separately evaluated changes induced by 5‐Hz rTMS, iTBS and cTBS applied alone and those induced by iTBS and cTBS delivered after priming 5‐Hz rTMS. Interactions between 5‐Hz rTMS and iTBS/cTBS were investigated under several experimental conditions by delivering 5‐Hz rTMS at suprathreshold and subthreshold intensity, allowing 1 and 5 min intervals to elapse between 5‐Hz rTMS and TBS, and delivering one and ten 5‐Hz rTMS trains. We also investigated whether 5‐Hz rTMS induces changes in intracortical excitability tested with paired‐pulse transcranial magnetic stimulation. When given alone, 5‐Hz rTMS induced short‐lasting and iTBS/cTBS induced long‐lasting changes in MEP amplitudes. When M1 was primed with 10 suprathreshold 5‐Hz rTMS trains at 1 min before iTBS or cTBS, the iTBS/cTBS‐induced after‐effects disappeared. The 5‐Hz rTMS left intracortical excitability unchanged. We suggest that STP elicited by suprathreshold 5‐Hz rTMS abolishes iTBS/cTBS‐induced LTP/LTD‐like plasticity through non‐homeostatic metaplasticity mechanisms. Our study provides new information on interactions between short‐term and long‐term rTMS‐induced plasticity in human M1.     

Prenatal morphine exposure enhances seizure susceptibility but suppresses long-term potentiation in the limbic system of adult male rats

The present study examined the effects of prenatal morphine exposure on NMDA-dependent seizure susceptibility in the entorhinal cortex (EC), and on activity-dependent synaptic plasticity at Schaffer collateral and perforant path synapses in the hippocampus. During perfusion with Mg(2+)-free ACSF, an enhancement of epileptiform discharges was found in the EC of slices from prenatally morphine-exposed male rats. A submaximal tetanic stimulation (2x50 Hz/1 s) in control slices elicited LTP at the Schaffer collateral-CA1 synapses, but neither LTP nor LTD was evoked at the perforant path-DG synapses. In slices from prenatally morphine-exposed adult male rats, long-term potentiation of synaptic transmission was not observed at Schaffer collateral-CA1 synapses, while the submaximal tetanus now elicited frank LTD of synaptic EPSPs at perforant path synapses. These data suggest that prenatal morphine exposure enhances the susceptibility of entorhinal cortex to the induction of epileptiform activity, but shifts long-term plasticity of hippocampal synapses in favor of LTD.     

Blockade of BDNF signaling turns chemically‐induced long‐term potentiation into long‐term depression

Long‐term potentiation (LTP) is accompanied by increased spine density and dimensions triggered by signaling cascades involving activation of the neurotrophin brain‐derived neurotrophic factor (BDNF) and cytoskeleton remodeling. Chemically‐induced long‐term potentiation (c‐LTP) is a widely used cellular model of plasticity, whose effects on spines have been poorly investigated. We induced c‐LTP by bath‐application of the N‐methyl‐d ‐aspartate receptor (NMDAR) coagonist glycine or by the K⁺ channel blocker tetraethylammonium (TEA) chloride in cultured hippocampal neurons and compared the changes in dendritic spines induced by the two models of c‐LTP and determined if they depend on BDNF/TrkB signaling. We found that both TEA and glycine induced a significant increase in stubby spine density in primary and secondary apical dendrites, whereas a specific increase in mushroom spine density was observed upon TEA application only in primary dendrites. Both TEA and glycine increased BDNF levels and the blockade of tropomyosin‐receptor‐kinase receptors (TrkRs) by the nonselective tyrosine kinase inhibitor K‐252a or the selective allosteric TrkB receptor (TrkBR) inhibitor ANA‐12, abolished the c‐LTP‐induced increase in spine density. Surprisingly, a blockade of TrkBRs did not change basal spontaneous glutamatergic transmission but completely changed the synaptic plasticity induced by c‐LTP, provoking a shift from a long‐term increase to a long‐term depression (LTD) in miniature excitatory postsynaptic current (mEPSC) frequency. In conclusion, these results suggest that BDNF/TrkB signaling is necessary for c‐LTP‐induced plasticity in hippocampal neurons and its blockade leads to a switch of c‐LTP into chemical‐LTD (c‐LTD). © 2013 Wiley Periodicals, Inc.     

Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation

Short, high frequency stimulation bursts (4 pulses at 100 Hz) were applied to Schaffer/commissural projections to the CA1 field of rat hippocampal slices at 0.1, 0.2, 1.0 or 2.0-s intervals to assess their efficacy in eliciting long-term potentiation (LTP). Bursts repeated at 2-s intervals induced very little LTP; shorter repetition intervals reliably elicited LTP, with the 200-ms repetition interval producing the greatest potentiation. A short-term potentiation effect, which was maximal 20 s after the last burst and decayed within 10 min, was affected differently by the stimulation parameters than was LTP, suggesting that the two phenomena are due to different processes. The results indicate that patterns of stimulation resembling spike discharge patterns of hippocampal neurons in animals in exploratory situations are effective in inducing LTP and suggest temporal constraints on the mechanisms involved in triggering synaptic plasticity.     

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.     

Bidirectional redistribution of AMPA but not NMDA receptors after perforant path simulation in the adult rat hippocampus in vivo

Long-term potentiation (LTP) in vitro reveals dynamic regulation of synaptic glutamate receptors. AMPA receptors may be inserted into synapses to increase neurotransmission, whereas NMDA receptors may redistribute within the synapse to alter the probability of subsequent plasticity. To date, the only evidence for these receptor dynamics in the hippocampus is from the studies of dissociated neurons and hippocampal slices taken from young animals. Although synaptic plasticity is induced easily, the extent of AMPA and NMDA receptor mobility after LTP is unknown in the adult, intact hippocampus. To test whether AMPA or NMDAR subunits undergo activity-dependent modifications in adult hippocampal synapses, we induced LTP at perforant path-dentate gyrus (DG) synapses in anesthetized adult rats, using high frequency stimulation (HFS), verified layer-specific Arc induction, and analyzed the distribution of postsynaptic AMPA and NMDAR subunits, using immunogold electron microscopy. The number of synapses with AMPA receptor labeling increased with LTP-inducing HFS in the stimulated region of the dendrite relative to the nonstimulated regions. The opposite trend was noted with low frequency stimulation (LFS). Moreover, HFS increased and LFS decreased the ratio of synaptic to extrasynaptic AMPA receptor labeling in the postsynaptic membrane. In contrast, HFS did not significantly alter NMDAR labeling. Thus, LTP in the adult hippocampus in vivo selectively enhanced AMPA but not NMDAR labeling specifically in synapses undergoing activity-dependent plasticity relative to the remainder of the dendritic tree. The results suggest a mechanism by which rapid adjustments in synaptic strength can occur through localized AMPA receptor mobility and that this process may be competitive across the dendritic tree.