Surprising similarity between mechanisms mediating low (1 Hz)-and high (100 Hz)-induced long-lasting synaptic potentiation in CA1 of the intact hippocampus

It is generally assumed that long lasting synaptic potentiation (long-term potentiation, LTP) and depression (long-term depression, LTD) result from distinct patterns of afferent activity, with high and low frequency activity favouring LTP and LTD, respectively. However, a novel form of N-methyl-d-aspartate (NMDA) receptor-dependent synaptic potentiation in the hippocampal CA1 area in vivo induced by low frequency afferent stimulation has recently been demonstrated. Here, we further characterize the mechanisms mediating this low frequency stimulation (LFS)-induced LTP in area CA1 of intact, urethane-anesthetized preparations. Consistent with previous reports, alternating, low frequency (1 Hz) stimulation of CA1 afferents originating in the contralateral CA3 area and the medial septum resulted in gradually developing, long lasting (>2 h) LTP of field excitatory postsynaptic potentials (fEPSPs) recorded in CA1. Local application of the protein synthesis inhibitor anisomycin in CA1 blocked LFS-induced LTP, as did application of H89, an inhibitor of protein kinase A. Given the apparent overlap in molecular mechanisms mediating LFS-LTP and “classic” high-frequency stimulation (HFS)-induced LTP in CA1, we examined the relation between these forms of LTP by means of occlusion experiments. LFS, delivered to synapses saturated by initial HFS, resulted in a gradually developing LTD, rather than the normally seen LTP. Conversely, initial induction of LFS-LTP reduced the amount of subsequent HFS-LTP. Together, these experiments reveal a surprising similarity in the molecular mechanisms (dependence on NMDA receptors, protein kinase A, protein synthesis) mediating LTP induced by highly distinct (1 vs. 100 Hz) induction protocols. Importantly, these findings further challenge the “high-frequency-LTP, low-frequency LTD” dogma by demonstrating that this dichotomy does not account for all types of plasticity phenomena at central synapses.     

Properties of subsequent induction of long-term potentiation and/or depression in one synaptic input in apical dendrites of hippocampal CA1 neurons in vitro

The hippocampus is a prominent structure to study mechanisms of learning and memory at the cellular level. Long-term potentiation (LTP) as well as long-term depression (LTD) are the major cellular models which could underlie learning and memory formation. LTP and LTD consist of at least two phases, an early protein synthesis-independent transient stage (<4 h; E-LTP, E-LTD) as well as a prolonged phase (>4 h; L-LTP, L-LTD) requiring the synthesis of new proteins. It is known that during E-LTP the further induction of longer lasting LTP is precluded. However, if E-LTP is transformed into L-LTP, the same synapses now allow the induction of LTP again. We reproduced the LTP-results first and then investigated whether hippocampal LTP or LTD also prevents the establishment of subsequent LTD-induction in the same synaptic input. We show that the prior induction of LTP or LTD does not prevent a short-term depression (STD) but occludes LTD in apical dendrites of CA1 neurons in hippocampal slices in vitro during the early phase of LTP or LTD. However, LTD can again be induced in addition to STD after the establishment of L-LTP or L-LTD, that is about 4 h after the induction of the first event in the same synaptic input. We suggest that the neuronal input preserves the capacity for STD immediately after an initial potentiation or depression, but for the onset of additional longer lasting LTD in the same synaptic input, the establishment of the late plasticity form of the preceding event is critical.     

Two-deoxyglucose-induced long-term potentiation in slices of rat dentrate gyrus

In keeping with previous observations in the CA1 and the somatosensory neocortex of the brain of rat, 20-min applications of 2-deoxy-D-glucose (2DG; 10 mM, replacing glucose) induced a long-term potentiation (LTP)-like enhancement of field excitatory synaptic potentials (fEPSPs) in the dentate region of hippocampal slices. The effects of 2DG were not identical at synapses of medial and lateral perforant paths (MPP and LPP). At MPP synapses, there was no post-2DG early depression of fEPSPs and the potentiation reached +78.6 +/- 5.7 % (+/- standard error of the mean) 40 min after the return to glucose. In the presence of 50 microM D-amino-phosphono valerate (APV; an N-methyl-D-aspartate [NMDA] receptor antagonist), a marked post-2DG depression appeared and the subsequent LTP was reduced to +34.7 +/- 2.8 % (for both 2DG- and APV-treatment P<0.001 by ANOVA-2W). At LPP synapses, even under control conditions, there was a sharp post-2DG depression followed by LTP (+62.2 +/- 5.7 %) and APV had little effect on either the post-2DG depression or LTP, reducing the latter by only 24 % [the 2DG treatment was very significant (P<0.001) but not the APV treatment]. Thus, 2DG evokes both NMDAR-dependent and -independent components of LTP in the perforant pathways. In view of these findings, the consumption of 2DG could have significant effects on synaptic plasticity and cognitive function.     

Opiate withdrawal modifies synaptic plasticity in subicular-nucleus accumbens pathway in vivo

Subiculum receives output of hippocampal CA1 neurons and projects glutamatergic synapses onto nucleus accumbens (NAc), the subicular-NAc pathway linking memory and reward system. It is unknown whether morphine withdrawal influences synaptic plasticity in the subicular-NAc pathway. Here, we recorded the field excitatory postsynaptic potential (EPSP) within the shell of NAc by stimulating ventral subiculum in anesthetized adult rats. We found that high frequency stimulation (HFS, 200 Hz) induced long-term potentiation (LTP) but low frequency stimulation (LFS, 1 Hz) failed to induce long-term depression (LTD) in control animals. However, behavioral stress enabled LFS to induce a reliable LTD (sLTD) that was dependent on the glucocorticoid receptors. Both LTP and sLTD were prevented by the N-methyl-d-aspartate receptor antagonist AP-5. After repeated morphine treatment for 12 days, acute withdrawal (12 h) impaired LTP but had no effect on sLTD; prolonged withdrawal (4 days) restored the LTP but impaired the sLTD. Remarkably, basal synaptic efficacy reflected by baseline EPSP amplitude was potentiated in acute withdrawal but was depressed in prolonged withdrawal. Thus, acute and prolonged opiate withdrawal may cause endogenous LTP and LTD in the subicular-NAc pathway that occludes the subsequent induction of synaptic plasticity, demonstrating adaptive changes of the NAc functions during opiate withdrawal.     

Effects of GABAergic inhibition on neocortical long-term potentiation in the chronically prepared rat

Long-term potentiation (LTP) is a form of activity-dependent synaptic plasticity that is a candidate cellular mechanism for some forms of learning and memory. Although GABAergic synaptic inhibition plays a critical role in regulating of synaptic plasticity, there is still little known about the GABAergic modulation on LTP induction in chronic preparation. In the present study we examined the effect of GABA_A agonist, diazepam (DZM), and antagonist, picrotoxin (PTX) on the induction of LTP in the somatosensory cortex of freely moving rats for a long-term period. In adult rats a bipolar stimulating and recording electrode were implanted into corpus callusom and somatosensory cortex, respectively. Two weeks after the surgery, evoked field potential responses were recorded before, during (12 days), and after (1 month) induction period of LTP by high-frequency stimulation. The LTP characteristics were compared between control, DZM and PTX groups during the time course of recording in each rat. Administration of DZM prior to train, blocked the induction of neocortical LTP, while the PTX increased the development of LTP making the highest differential levels of LTP about 12 days after the initiation of LTP induction. Our findings suggest that the augmentation of LTP by PTX can be explained by an interaction between excitatory and inhibitory pathways. Suppression of neocortical inhibitory inputs by PTX causes enhancement in LTP induction. These results suggest that GABAergic system has an important role in synaptic plasticity and long-term modification of somatosensory cortex in freely moving rat.     

Arginine vasopressin prevents amyloid β protein-induced impairment of long-term potentiation in rat hippocampus in vivo

Amyloid β protein (Aβ) is thought to be responsible for the loss of memory in Alzheimer's disease (AD). A significant decrease in [Arg⁸]-vasopressin (AVP) in the AD brain has been found. However, it is unclear whether the decrease in AVP is involved in Aβ-induced impairment of memory and whether AVP can protect against Aβ-induced neurotoxicity. The present study examines the effects of intracerebroventricular (i.c.v.) injection of AVP on hippocampal long-term potentiation (LTP), a synaptic model of memory, and investigates the potential protective function of AVP in Aβ-induced LTP impairment. The results showed that (1) i.c.v. injection of different concentrations of AVP or Aβ_25–35 did not affect the baseline field excitatory postsynaptic potentials (fEPSPs); (2) AVP administration alone induced a significant increase in HFS-induced LTP, while Aβ_25–35 significantly suppressed HFS-induced LTP; (3) Aβ_25–35-induced LTP suppression was significantly prevented by the pretreatment with AVP; (4) paired-pulse facilitation did not change after separate application or co-application of AVP and Aβ_25–35. These results indicate that AVP can potentiate hippocampal synaptic plasticity and dose-dependently prevent Aβ_25–35-induced LTP impairment. Thus, the present study provides further insight into the mechanisms by which Aβ impairs synaptic plasticity and suggests an important approach in the treatment of AD.     

PKMζ knockdown disrupts post-ischemic long-term potentiation via inhibiting postsynaptic expression of aminomethyl phosphonic acid receptors

Post-ischemic long-term potentiation(i-LTP) is a pathological form of plasticity that was observed in glutamate receptor-mediated neurotransmission after stroke and may exert a detrimental effect via facilitating excitotoxic damage.The mechanism underlying i-LTP,however,remains less understood.By employing electrophysiological recording and immunofluorescence assay on hippocampal slices and cultured neurons,we found that protein kinase Mζ(PKMζ),an atypical protein kinase C isoform,was involved in enhancing aminomethyl phosphonic acid(AMPA) receptor(AMPAR) expression after i-LTP induction.PKMζ,knockdown attenuated postsynaptic expression of AMPA receptors and disrupted i-LTP.Consistently,we observed less neuronal death of cultured hippocampal cells with PKMζ,knockdown.Meanwhile,these findings indicate that PKMζ plays an important role in i-LTP by regulating postsynaptic expression of AMPA receptors.This work adds new knowledge to the mechanism of i-LTP,and thus is helpful to find the potential target for clinical therapy of ischemic stroke.     

Age-dependent decline in supragranular long-term synaptic plasticity by increased inhibition during the critical period in the rat primary visual cortex

Supragranular long-term potentiation (LTP) and depression (LTD) are continuously induced in the pathway from layer 4 during the critical period in the rodent primary visual cortex, which limits the use of supragranular long-term synaptic plasticity as a synaptic model for the mechanism of ocular dominance (OD) plasticity. The results of the present study demonstrate that the pulse duration of extracellular stimulation to evoke a field potential (FP) is critical to induction of LTP and LTD in this pathway. LTP and LTD were induced in the pathway from layer 4 to layer 2/3 in slices from 3-wk-old rats when FPs were evoked by 0.1- and 0.2-ms pulses. LTP and LTD were induced in slices from 5-wk-old rats when evoked by stimulation with a 0.2-ms pulse but not by stimulation with a 0.1-ms pulse. Both the inhibitory component of FP and the inhibitory/excitatory postsynaptic potential amplitude ratio evoked by stimulation with a 0.1-ms pulse were greater than the values elicited by a 0.2-ms pulse. Stimulation with a 0.1-ms pulse at various intensities that showed the similar inhibitory FP component with the 0.2-ms pulse induced both LTD and LTP in 5-wk-old rats. Thus extracellular stimulation with shorter-duration pulses at higher intensity resulted in greater inhibition than that observed with longer-duration pulses at low intensity. This increased inhibition might be involved in the age-dependent decline of synaptic plasticity during the critical period. These results provide an alternative synaptic model for the mechanism of OD plasticity.     

Chronic brain inflammation impairs two forms of long-term potentiation in the rat hippocampal CA1 area

Neuroinflammation plays an important role in the progression of Alzheimer's disease (AD) and is characterized by the presence of activated microglia. We investigated whether chronic neuroinflammation affects the induction of N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) and NMDAR-independent LTP which is expressed by voltage-dependent calcium channel (VDCC). Chronic neuroinflammation was induced by administration of lipopolysaccharide (LPS) (28 days, 0.35 μg/h) to the fourth ventricle. The Morris water maze test was conducted to measure the memory impairment and then excitatory postsynaptic potentials were recorded extracelluarly from stratum radiatum in the rat hippocampal CA1 area to examine the changes in synaptic plasticity induced by LPS infusion. Chronic administration of LPS induced remarkable memory impairment. The field recording experiments revealed that the induction of both NMDAR-dependent LTP and NMDAR-independent LTP were impaired in the hippocampal Schaffer collateral-CA1 synapse in animals chronically infused with LPS. The present results show that chronic neuroinflammation can lead to the impaired spatial memory and attenuation of VDCC-dependent LTP as well as NMDAR-dependent LTP. The attenuation of synaptic plasticity may be caused by the impairment of both NMDAR and L-type Ca²⁺ via elevated levels of inflammatory proteins, which may underlie aspects of dementia.     

Properties of long-term synaptic plasticity and metaplasticity in organotypic slice cultures of rat hippocampus

The aim of this study was to investigate whether synaptic plasticity and metaplasticity in slice cultures of the young rat hippocampus were comparable to previously reported synaptic plasticity and metaplasticity in acute adult hippocampal slices. This is relevant since differences do exist between the preparations as a result of age and the ex vivo maintenance. We prepared and maintained slice cultures from 5- to 6-day-old rats according to the porous membrane method. After 12–16 days in vitro, extracellular low-frequency stimulation (LFS) and high-frequency stimulation (HFS) protocols were applied to the Schaffer collaterals, and extracellular field potentials were recorded in area CA1. LFS and HFS induced long-term depression (LTD) and long-term potentiation (LTP), respectively. LTP could be reversed by LFS, as could LTD by HFS 60 min after induction. Plotting the amount of LTD and LTP versus stimulation protocol demonstrated frequency-dependence of the sign and extent of plasticity. Priming activation of group 1 metabotropic glutamate receptors (mGluRs) with DHPG facilitated subsequent LTP, revealing a metaplastic effect similar to that observed in acute slices. Immunohistochemistry for group 1 mGluR subtypes mGluR1α and mGluR5 showed both receptors to be present in these cultures. We conclude that synaptic plasticity and mGluR-mediated metaplasticity are largely comparable to those effects found in acute in vitro techniques.     

Stress-facilitated LTD induces output plasticity through synchronized-spikes and spontaneous unitary discharges in the CA1 region of the hippocampus

Long-term potentiation (LTP) and long-term depression (LTD) of the excitatory synaptic inputs plasticity in the hippocampus is believed to underlie certain types of learning and memory. Especially, stressful experiences, well known to produce long-lasting strong memories of the event themselves, enable LTD by low frequency stimulation (LFS, 3 Hz) but block LTP induction by high frequency stimulation (HFS, 200 Hz). However, it is unknown whether stress-affected synaptic plasticity has an impact on the output plasticity. Thus, we have simultaneously studied the effects of stress on synaptic plasticity and neuronal output in the hippocampal CA1 region of anesthetized Wistar rats. Our results revealed that stress increased basal power spectrum of the evoked synchronized-spikes and enabled LTD induction by LFS. The induction of stress-facilitated LTD but not LFS induced persistent decreases of the power spectrum of the synchronized-spikes and the frequency of the spontaneous unitary discharges; However, HFS induced LTP in non-stressed animals and increased the power spectrum of the synchronized-spikes, without affecting the frequency of the spontaneous unitary discharges, but HFS failed to induce LTP in stressed animals without affecting the power spectrum of the synchronized-spikes and the frequency of the spontaneous unitary discharges. These observations that stress-facilitated LTD induces the output plasticity through the synchronized-spikes and spontaneous unitary discharges suggest that these types of stress-related plasticity may play significant roles in distribution, amplification and integration of encoded information to other brain structures under stressful conditions.     

Nerve growth factor favours long-term depression over long-term potentiation in layer II–III neurones of rat visual cortex

Nerve growth factor (NGF) has been shown to regulate plasticity in the visual cortex of monocularly deprived animals. However, to date, few attempts have been made to investigate the role of NGF in synaptic plasticity at the cellular level. In the study reported here we looked at the effects of exogenously applied NGF on synaptic plasticity of layer II–III regular spiking (RS) neurones in visual cortex of 16- to 18-day-old rats. We found that local application of NGF converted high frequency stimulation (HFS)-induced long-term potentiation (LTP) into long-term depression (LTD). We showed that this shift of synaptic plasticity was also obtained with bath application of NGF during HFS. Application of NGF subsequent to HFS left LTP unaffected, conferring temporal constraints on NGF efficacy. NGF effects on LTP were mediated by TrkA receptors. Indeed, blockade of TrkA by monoclonal antibody prevented NGF from inducing LTD following HFS. Low frequency stimulation (LFS) elicited LTD in RS cells. We found that NGF or blockade of NGF signalling by anti-TrkA antibody did not change the amplitude of the LTD induced by LFS. Thus, the NGF effect is selective for synaptic modifications induced by HFS in RS cells. The present results indicate that NGF may modulate the sign of long-term changes of synaptic efficacy in response to high frequency inputs.     

Synapse-specific mGluR1-dependent long-term potentiation in interneurones regulates mouse hippocampal inhibition

Hippocampal CA1 inhibitory interneurones control the excitability and synchronization of pyramidal cells, and participate in hippocampal synaptic plasticity. Pairing theta-burst stimulation (TBS) with postsynaptic depolarization, we induced long-term potentiation (LTP) of putative single-fibre excitatory postsynaptic currents (EPSCs) in stratum oriens/alveus (O/A) interneurones of mouse hippocampal slices. LTP induction was absent in metabotropic glutamate receptor 1 (mGluR1) knockout mice, was correlated with the postsynaptic presence of mGluR1a, and required a postsynaptic Ca²⁺ rise. Changes in paired-pulse facilitation and coefficient of variation indicated that LTP expression involved presynaptic mechanisms. LTP was synapse specific, occurring selectively at synapses modulated by presynaptic group II, but not group III, mGluRs. Furthermore, the TBS protocol applied in O/A induced a long-term increase of polysynaptic inhibitory responses in CA1 pyramidal cells, that was absent in mGluR1 knockout mice. These results uncover the mechanisms of a novel form of interneurone synaptic plasticity that can adaptively regulate inhibition of hippocampal pyramidal cells.     

Involvement of the adenosine neuromodulatory system in the benzodiazepine-induced depression of excitatory synaptic transmissions in rat hippocampal neurons in vitro

We investigated whether adenosine neuromodulation is involved in a benzodiazepine (midazolam)-induced depression of excitatory synaptic transmissions in the CA1 and dentate gyrus (DG) regions in rat hippocampal slices. Field excitatory postsynaptic potentials (fEPSPs), evoked by electrical stimulation of the CA1-Schaffer collateral or the DG-perforant path, were recorded with extracellular microelectrodes from CA1-stratum radiatum or DG-stratum moleculare in oxygenated ACSF. The initial slope of the fEPSPs was analyzed for assessing the drug effects. Midazolam (1 microM) transiently depressed CA1- and DG-fEPSPs. The fEPSPs were depressed to approximately 75% of the control values, and then gradually recovered. The depression was not affected by bicuculline, a GABAA receptor antagonist, although it was completely antagonized by aminophylline, an adenosine receptor antagonist. Dipyridamole (5 microM), an adenosine uptake inhibitor, depressed the fEPSPs in a similar manner to midazolam. An adenosine deaminase inhibitor, EHNA, also transiently depressed the fEPSPs, but in a different manner. Exogenous adenosine persistently depressed the fEPSPs. The effects of the drugs were not significantly different in the CA1 and DG regions. The results suggest that midazolam (1 microM) depresses excitatory synaptic transmissions through the adenosine neuromodulatory system by inhibiting adenosine uptake in the CA1 and DG regions of the hippocampus.     

Hippocampal long-term synaptic plasticity and signal amplification of NMDA receptors

The direction of plasticity at CA3-CA1 hippocampal synapses is determined by the strength of afferent stimulation. Weak stimuli lead to long-term depression (LTD) and strong stimuli to long-term potentiation (LTP), but both require activation of synaptic N-methyl-D-aspartate receptors (NMDARs). These receptors are therefore necessary and required for the induction of plasticity at CA3-CA1 synapses even though they carry little of the current responsible for the basal excitatory post-synaptic potential (EPSP). The influx of Ca(2+) via NMDARs triggers the subsequent and persistent changes in the expression of alpha-amino-3-hydroxy-5 methylisoxazole-4-proprionic acid receptors (AMPARs) and these receptors are responsible for the major part of the basal EPSP. The degree of activity of NMDARs is determined in part by extracellular Mg(2+) and by the co-agonists for this receptor, glycine and D-serine. During strong stimulation, a relief of the voltage-dependent block of NMDARs by Mg(2+) provides a positive feedback for NMDAR Ca(2+) influx into postsynaptic CA1 spines. In this review, we discuss how the induction of LTP at CA3-CA1 synapses requires further signal amplification of NMDAR activity. We discuss how the regulation of NMDARs by protein kinases and phosphatases is brought into play. Evidence is presented that Src family kinases (SFKs) play a "core" role in the induction of LTP by enhancing the function and expression of NMDARs. At CA3-CA1 synapses, NMDARs are largely composed of NR1 (NMDA receptor subunit 1)-NR2A or NR1-NR2B containing subunits. Recent, but controversial, evidence has correlated NR1-NR2A receptors with the induction of LTP and NR1-NR2B receptors with LTD. However, LTP can be induced by activation of either subtype of NMDAR and the ratio of NR2A:NR2B receptors has been proposed as an alternative determinant of the direction of synaptic plasticity. Many transmitters and signal pathways can modify NMDAR function and expression and, for a given stimulus strength, they can potentially lead to a change in the balance between LTP and LTD. As opposed to the "core" mechanisms of LTP and LTD, the resulting alterations in this balance underlie "meta-plasticity." Thus, in addition to their contribution to core mechanisms, we will also discuss how Src-family kinases could preferentially target NR1-NR2A or NR1-NR2B receptors to alter the relative contribution of these receptor subtypes to synaptic plasticity.     

Dopamine gates LTP induction in lateral amygdala by suppressing feedforward inhibition

Fear conditioning involves the induction of long-term potentiation (LTP) of excitatory synaptic transmission in the lateral amygdala, a brain structure which is tightly controlled by GABAergic inhibition. Here we show that dopamine gates the induction of LTP in the mouse lateral amygdala by suppressing feedforward inhibition from local interneurons. Our findings provide a cellular mechanism for the dopaminergic modulation of fear conditioning and indicate that suppression of feedforward inhibition represents a key mechanism for the induction of associative synaptic plasticity in the lateral amygdala.     

Visualization of changes in presynaptic function during long-term synaptic plasticity.

Controversy exists regarding the site of modification of synaptic transmission during long-term plasticity in the mammalian hippocampus. Here we used a fluorescent marker of presynaptic activity, FM 1-43, to directly image changes in presynaptic function during both short-term and long-term forms of plasticity at presynaptic boutons of CA3-CA1 excitatory synapses in acute hippocampal slices. We demonstrated enhanced presynaptic function during long-term potentiation (LTP) induced either chemically (with tetraethylammonium), or by high-frequency (200-Hz) electrical stimulation. Both of these forms of LTP required activation of L-type voltage-gated calcium channels and NMDA receptors in the postsynaptic CA1 neuron. These results thus implied that a long-lasting increase in the efficacy of synaptic transmission is likely to depend, at least in part, on enhanced transmitter release from the presynaptic neuron.     

The facilitating effect of systemic administration of Kv7/M channel blocker XE991 on LTP induction in the hippocampal CA1 area independent of muscarinic activation

A large amount of in vitro studies demonstrate suppression of M-current in hippocampal neurons by Kv7/M channel blocker results in depolarization of membrane potential and release of neurotransmitters, such as acetylcholine and glutamate, suggesting that Kv7/M channel may play important roles in regulating synaptic plasticity. In the present study, we examined the in vivo effect of Kv7/M channel inhibition on the long-term potentiation (LTP) induction at basal dendrites in hippocampal CA1 area of urethane-anaesthetized rats. The Kv7/M channel was inhibited by intraperitoneal injection of XE991 (10 mg/kg) and the LTP of field excitatory postsynaptic potential (fEPSP) was induced by supra-threshold high frequency stimulation (S1 HFS). A weak protocol which was just below the threshold for evoking LTP was used as sub-threshold high frequency stimulation (S2 HFS). XE991 did not significantly alter the slope of fEPSP and the magnitude of LTP induced by S1 HFS, suggesting that Kv7/M channel inhibition had little or no effect on glutamatergic transmission under basal conditions. However, XE991 could make S2 HFS evoke LTP even after the application of the muscarinic cholinergic (mACh) receptor antagonist scopolamine, suggesting that Kv7/M channel inhibition lowered the threshold for LTP induction and the effect was independent of muscarinic activation. Based on the above findings, we concluded that the facilitating effect of XE991 on LTP induction is not mediated by its ability to enhance the release of acetylcholine; therefore, Kv7/M channel blockers may provide a therapeutic benefit to cholinergic deficiency-related cognitive impairment, e.g., Alzheimer's disease.     

Synapses between parallel fibres and stellate cells express long-term changes in synaptic efficacy in rat cerebellum

Various forms of synaptic plasticity underlying motor learning have already been well characterized at cerebellar parallel fibre (PF)–Purkinje cell (PC) synapses. Inhibitory interneurones play an important role in controlling the excitability and synchronization of PCs. We have therefore tested the possibility that excitatory synapses between PFs and stellate cells (SCs) are also able to exhibit long-term changes in synaptic efficacy. In the present study, we show that long-term potentiation (LTP) and long-term depression (LTD) were induced at these synapses by a low frequency stimulation protocol (2 Hz for 60 s) and that pairing this low frequency stimulation protocol with postsynaptic depolarization induced a marked shift of synaptic plasticity in favour of LTP. This LTP was cAMP independent, but required nitric oxide (NO) production from pre- and/or postsynaptic elements, depending on the stimulation or pairing protocol used, respectively. In contrast, LTD was not dependent on NO production but it required activation of postsynaptic group II and possibly of group I metabotropic glutamate receptors. Finally, stimulation of PFs at 8 Hz for 15 s also induced LTP at PF–SC synapses. But in this case, LTP was cAMP dependent, as was also observed at PF–PC synapses for presynaptic LTP induced in the same conditions. Thus, long-term changes in synaptic efficacy can be accomplished by PF–SCs synapses as well as by PF–PC synapses, suggesting that both types of plasticity might co-operate during cerebellar motor learning.     

Epileptiform activity in rat hippocampus strengthens excitatory synapses

Although epileptic seizures are characterized by excessive excitation, the role of excitatory synaptic transmission in the induction and expression of epilepsy remains unclear. Here, we show that epileptiform activity strengthens excitatory hippocampal synapses by increasing the number of functional (RS)-α-amino-3hydroxy-5methyl-4-isoxadepropionate (AMPA)-type glutamate receptors in CA3–CA1 synapses. This form of synaptic strengthening occludes long-term potentiation (LTP) and enhances long-term depression (LTD), processes involved in learning and memory. These changes in synaptic transmission and plasticity, which are fully blocked with N -methyl-D-aspartate (NMDA) receptor antagonists, may underlie epilepsy induction and seizure-associated memory deficits.