Prepubertal castration‐associated developmental changes in sigma‐1 receptor gene expression levels regulate hippocampus area CA1 activity during adolescence

The functional relevance of sigma‐1 (σ₁) receptor expression in the rat hippocampal CA1 during adolescence (i.e., 35–60 days old) was explored. A selective antagonist for the σ₁ receptor subtype, BD‐1047, was applied to study hippocampal long‐term potentiation (LTP) and spatial learning performance. Changes in the expression of the σ₁ receptor subtype and its function were compared between castrated and sham‐castrated rats. Castration reduced the magnitude of both field excitatory postsynaptic potential (fEPSP)‐LTP and population spike (PS)‐LTP at 35 days (d). BD‐1047 decreased PS‐LTP in sham‐castrated rats, whereas BD‐1047 reversed the effect of castration on fEPSP‐LTP at 35 d. In addition, BD1047 impaired spatial learning and augmented σ₁ receptor mRNA levels in castrated rats at 35 d. Surprisingly, neither castration nor BD1047 had an effect on fEPSP‐LTP and PS‐LTP, spatial learning ability or gene expression levels at 45 d. Castration had no effect on fEPSP‐LTP but reduced PS‐LTP at 60 d. BD1047 increased the magnitude of fEPSP‐LTP, but had no effect on PS‐LTP in castrated rats at 60 d. However, BD1047 reduced spatial learning ability, and σ₁ receptor mRNA levels were decreased in castrated rats at 60 d. This study shows that σ₁ receptors play a role in the regulation of both CA1 synaptic efficacy and spatial learning performance. The regulatory role of σ₁ receptors in activity‐dependent CA1‐LTP is locality‐ and age‐dependent, whereas its role in spatial learning ability is only age‐dependent. Prepubertal castration‐associated changes in the expression and function of the σ₁ receptor during adolescence may play a developmental role in the regulation of hippocampal area CA1 activity and plasticity. © 2016 Wiley Periodicals, Inc.     

Epileptogenic insult alters endogenous adenosine control on long‐term changes in synaptic strength by theta pattern stimulation in hippocampus area CA1

The impact of theta patterning of the stimulation on the kindling effects of pentylenetetrazol (PTZ) was studied in rat hippocampus area CA1 in vitro. A potential involvement of adenosine A1 receptors was also examined. Primed‐bursts stimulation (PBs) and theta pulse stimulation (TPS) were used as patterned activities. Stimulus patterns were applied to the Schaffer collateral afferents of hippocampal slices from both control and PTZ‐kindled rats, the field excitatory postsynaptic potentials (fEPSP) and population spikes (PS) were simultaneously recorded from stratum radiatum and stratum pyramidale, respectively. Experiments were carried out in the presence or absence of the adenosine A1 receptor antagonist CPX. The following changes in kindled vs. control slices were observed. PBs was unable to produce both fEPSP LTP and PS LTP in untreated slices. When A1 receptor antagonist CPX was applied before PBs, both fEPSP LTP and PS LTP were elicited. PS LTP was selectively depressed by TPS (applied at 60 min after LTP induction) exclusively when A1 receptors were blocked, while TPS failed to depress PS LTP in untreated PBs‐exposed slices. These findings suggest that seizing entails lasting changes in hippocampus area CA1 so that LTP induction by PBs is masked due to intensive adenosine release which in turn prevents TPS to induce PS LTD in epileptic CA1 network. Synapse, 2010. © 2010 Wiley‐Liss, Inc.     

Repetitive systemic morphine alters activity‐dependent plasticity of schaffer–collateral–CA1 pyramidal cell synapses: Involvement of adenosine A1 receptors and adenosine deaminase

The effectiveness of O‐pulse stimulation (TPS) for the reversal of O‐pattern primed bursts (PB)‐induced long‐term potentiation (LTP) were examined at the Schaffer–collateral–CA1 pyramidal cell synapses of hippocampal slices derived from rats chronically treated with morphine (M‐T). The results showed that slices derived from both control and M‐T rats had normal field excitatory postsynaptic potential (fEPSP)‐LTP, whereas PS‐LTP in slices from M‐T rats was significantly greater than that from control slices. When morphine was applied in vitro to slices derived from rats chronically treated with morphine, the augmentation of PS‐LTP was not seen. TPS given 30 min after LTP induction failed to reverse the fEPSP‐ or PS‐LTP in both groups of slices. However, TPS delivered in the presence of long‐term in vitro morphine caused the PS‐LTP reversal. This effect was blocked by the adenosine A1 receptor (A1R) antagonist CPX (200 nM) and furthermore was enhanced by the adenosine deaminase (ADA) inhibitor EHNA (10 μM). Interestingly, TPS given 30 min after LTP induction in the presence of EHNA (10 μM) can reverse LTP in morphine‐exposed control slices in vitro. These results suggest adaptive changes in the hippocampus area CA1 in particular in adenosine system following repetitive systemic morphine. Chronic in vivo morphine increases A1R and reduces ADA activity in the hippocampus. Consequently, adenosine can accumulate because of a stimulus train‐induced activity pattern in CA1 area and takes the opportunity to work as an inhibitory neuromodulator and also to enable CA1 to cope with chronic morphine. In addition, adaptive mechanisms are differentially working in the dendrite layer rather than the somatic layer of hippocampal CA1. © 2014 Wiley Periodicals, Inc.     

Cocaine enhancement of long‐term potentiation in the CA1 region of rat hippocampus: Lamina‐specific mechanisms of action

There is an expanding body of work characterizing dopaminergic modulation of synaptic plasticity in the hippocampus CA1 region, an area known to be involved in learning and memory. However, in vitro studies to date have focused almost exclusively on the proximal and distal apical dendritic layers (strata radiatum and lacunosum moleculare, respectively). In this report, we establish that dopaminergic activity can enhance long‐term potentiation (LTP) in the basal dendritic layer (stratum oriens) of CA1 in the rat hippocampal slice preparation. Application of the D_1/5 agonist SKF38393 (20 μM) significantly increased the magnitude of basal LTP of the fEPSP response following high‐frequency stimulation of the Schaffer collateral/commissural inputs in the stratum oriens layer. In addition, endogenous dopamine (DA) activity facilitated by the presence of cocaine (6 μM) was also capable of enhancing the magnitude of basal LTP. Prior application of the D_1/5 antagonist SKF83566 (2 μM) prevented this effect of cocaine, indicating that endogenously released dopamine was exerting its LTP‐enhancing effect in stratum oriens via activation of D_1/5 receptors. This final result stands in contrast with the previously characterized effects of cocaine on apical LTP in the stratum radiatum, which instead have been shown to require D₃ receptor activation. These observations demonstrate that dopaminergic mechanisms resulting in the enhancement of hippocampal LTP are lamina specific at Schaffer collateral/commissural synapses in the CA1 region. Synapse 2010. © 2010 Wiley‐Liss, Inc.     

Maintenance of long‐term potentiation in hippocampal mossy fiber—CA3 pathway requires fine‐tuned MMP‐9 proteolytic activity

Mechanisms of synaptic plasticity involve proteolytic activity mediated by a complex system of proteases, including members of metalloproteinase (MMP) family. In particular, MMP‐9 is critical in LTP maintenance in the Schaffer collateral‐CA1 pathway and in the acquisition of hippocampus‐dependent memory. Recent studies from this laboratory revealed that in the mossy fiber‐CA3 (MF‐CA3) projection, where LTP induction and expression are largely presynaptic, MMPs blockade disrupts LTP maintenance and that LTP induction is associated with increased MMP‐9 expression. Here we used acute brain slices from MMP‐9 knock‐out mice and transgenic rats overexpressing MMP‐9 to determine how manipulations in endogenous MMP‐9 affect LTP in the MF‐CA3 projection. Both types of transgenic models showed a normal basal synaptic transmission and short‐term plasticity. Interestingly, the maintenance of LTP induced in slices from knock‐out mice and overexpressing rats was nearly abolished. However, in the presence of active MMP‐9, a gradual fEPSP autopotentiation was observed and tetanization evoked a marked LTP in knock‐out mice. Additionally, in MMP‐9‐treated slices from wild‐type mice, fEPSP autopotentiation also occurred and partially occluded LTP. This indicates that exogenous protease can restore LTP in null mice whereas in the wild‐type, MMP‐9 excess impairs LTP. We expected that LTP maintenance in transgenic rats could be re‐established by a partial MMP blockade but non‐saturating concentrations of MMP inhibitor were ineffective. In conclusion, we demonstrate that LTP maintenance in MF‐CA3 pathway requires fine‐tuned MMP‐9 activity and raises the possibility that altered MMP‐9 level might be detrimental for cognitive processes as observed in some neuropathologies. © 2013 Wiley Periodicals, Inc.     

Presynaptic Ultrastructural Plasticity Along CA3→CA1 Axons During Long‐Term Potentiation in Mature Hippocampus

In area CA1 of the mature hippocampus, synaptogenesis occurs within 30 minutes after the induction of long‐term potentiation (LTP); however, by 2 hours many small dendritic spines are lost, and those remaining have larger synapses. Little is known, however, about associated changes in presynaptic vesicles and axonal boutons. Axons in CA1 stratum radiatum were evaluated with 3D reconstructions from serial section electron microscopy at 30 minutes and 2 hours after induction of LTP by theta‐burst stimulation (TBS). The frequency of axonal boutons with a single postsynaptic partner was decreased by 33% at 2 hours, corresponding perfectly to the 33% loss specifically of small dendritic spines (head diameters <0.45 μm). Docked vesicles were reduced at 30 minutes and then returned to control levels by 2 hours following induction of LTP. By 2 hours there were fewer small synaptic vesicles overall in the presynaptic vesicle pool. Clathrin‐mediated endocytosis was used as a marker of local activity, and axonal boutons containing clathrin‐coated pits showed a more pronounced decrease in presynaptic vesicles at both 30 minutes and 2 hours after induction of LTP relative to control values. Putative transport packets, identified as a cluster of less than 10 axonal vesicles occurring between synaptic boutons, were stable at 30 minutes but markedly reduced by 2 hours after the induction of LTP. APV blocked these effects, suggesting that the loss of axonal boutons and presynaptic vesicles was dependent on N‐methyl‐D‐aspartic acid (NMDA) receptor activation during LTP. These findings show that specific presynaptic ultrastructural changes complement postsynaptic ultrastructural plasticity during LTP. J. Comp. Neurol. 521:3898–3912, 2013. © 2013 Wiley Periodicals, Inc.     

17β estradiol recruits GluN2B‐containing NMDARs and ERK during induction of long‐term potentiation at temporoammonic‐CA1 synapses

When circulating 17β estradiol (E2) is elevated to proestrous levels, hippocampus‐dependent learning and memory is enhanced in female rodents, nonhuman primates, and women due to heightened synaptic function at hippocampal synapses. We previously reported that proestrous‐like levels of E2 administered to young adult ovariectomized (OVX) female rats increases the magnitude of LTP at CA3 Schaffer collateral (SC)‐CA1 synapses only when dendritic spine density, the NMDAR/AMPAR ratio, and current mediated by GluN2B‐containing NMDA receptors (NMDARs) are simultaneously increased. We also reported that this increase in GluN2B‐mediated NMDAR current in area CA1 is causally related to the E2‐induced increase in novel object recognition, tying together heightened synaptic function with improved learning and memory. In addition to SC inputs, innervation from the entorhinal cortex in the temporoammonic (TA) pathway onto CA1 distal dendrites in stratum lacunosum‐moleculare is critical for spatial memory formation and retrieval. It is not known whether E2 modulates TA‐CA1 synapses similarly to SC‐CA1 synapses. Here, we report that 24 hours post‐E2 injection, dendritic spine density on CA1 pyramidal cell distal dendrites and current mediated by GluN2B‐containing NMDARs at TA‐CA1 synapses is increased, similarly to our previous findings at SC‐CA1 synapses. However, in contrast to SC‐CA1 synapses, AMPAR transmission at TA‐CA1 synapses is significantly increased, and there is no effect on the LTP magnitude. Pharmacological blockade of GluN2B‐containing NMDARs or ERK activation, which occurs downstream of synaptic but not extrasynaptic GluN2B‐containing NMDARs, attenuates the LTP magnitude only in slices from E2‐treated rats. These data show that E2 recruits a causal role for GluN2B‐containing NMDARs and ERK signaling in the induction of LTP, cellular mechanisms not required for LTP induction at TA‐CA1 synapses in vehicle‐treated OVX female rats. © 2015 Wiley Periodicals, Inc.     

Afferent high strength tetanizations favour potentiation of the NMDA vs. AMPA receptor-mediated component of field EPSP in CA1 hippocampal slices of rats

Long-term potentiation (LTP) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated components of 'dual-component' field excitatory postsynaptic potentials (fEPSP-A and fEPSP-N) was studied in the CA1 stratum radiatum in hippocampal slices of rats. Relative degrees of LTP of these fEPSP components were compared for tetanizations with low and high strengths. Magnitudes of fEPSP-A and fEPSP-N were estimated in parallel with a least-square fitting of a short-latent (0.1-8.8 ms) fragment of evoked responses by a weighted sum of 'basic' fEPSP-A and fEPSP-N, obtained during a short preliminary application of d-2-amino-5-phosphonovalerate (APV). We found that low-strength tetanizations selectively potentiated fEPSP-A, while high strength tetanizations potentiated both fEPSP components. These results demonstrate in the experiments with parallel measurements of fEPSP-A and fEPSP-N that LTP of these components differ depending on the strength of afferent tetanization. Unequal potentiation of the commissural-collateral and excitatory local-circuit synapses, which presumably contain different amounts of the AMPA and NMDA receptors, is discussed as the most probable explanation for these results.     

Long-term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors

A series of ω-phosphono-α-car?ylic acids were tested as antagonists of excitatory amino acid depolarizations and long-term potentiation (LTP) in region CA1 of rat hippocampal slices. The 5- and 7-phosphono compounds (±AP5and±AP7) blocked N-methyl-D-aspartate (NMDA) depolarizations and prevented the induction of LTP of the synaptic field potential and population spike components of the Schaffer collateral response.±AP5and±AP7 did not reduce kainate or quisqualate depolarizations and did not affect unpoten synaptic response amplitude.±AP5, ±AP6and±AP8 did not block amino acid excitant responses or LTP.These results demonstrate that NMDA receptors present in hippocampal region CA1 are not necessary for normal synaptic transmission, but are involved in the initiation of long-term synaptic plasticity.     

Effects of melatonin on synaptic transmission and long-term potentiation in two areas of mouse hippocampus

We have examined the effects of melatonin on synaptic transmission and long-term potentiation (LTP) in the Schaffer Collateral-CA1 and the mossy fiber-CA3 pathways in mouse hippocampus brain slices. Melatonin (0.1-1 mM) application had different actions on both the field excitatory postsynaptic potentials (fEPSPS) and LTP in the CA1 as compared to the CA3. In CA1, 0.1 mM melatonin blocked LTP, while 1 mM melatonin also depressed the fEPSP. In CA3, neither 0.1 nor 1 mM melatonin altered the fEPSP, whereas both concentrations only slightly reduced LTP. These results demonstrate that melatonin significantly alters synaptic transmission and LTP in the CA1 but has only modest actions in CA3.     

Synaptic transmission and hippocampal long-term potentiation in transgenic mice expressing FAD-linked presenilin 1

Mutations in two related genes, presenilin 1 and presenilin 2 (PS1 and PS2), cause a subset of early-onset familial Alzheimer's disease (FAD). PS1 is expressed in a variety of neuronal and peripheral tissues, including neuronal populations known to be at risk in Alzheimer's disease such as CA1 hippocampal neurons. To examine whether FAD-linked mutations in PS1 directly influence the physiology of learning and memory, we measured the field excitatory postsynaptic potential (fEPSP) at the Schaffer collateral-CA1 synapse in hippocampal slices. Basal synaptic transmission and long-term potentiation (LTP) were examined in neurons of transgenic mice expressing wild-type human PS1 (WtTg) and FAD-linked A246E PS1 variant (MTg) and in neurons of nontransgenic littermates (NTg). Several measures of basal synaptic transmission were unaltered in WtTg and MTg compared to NTg mice, including maximum fEPSP slope, maximum fEPSP amplitude, maximum fiber volley amplitude, and the function relating fiber volley amplitude to fEPSP slope, an index of basal synaptic strength. In addition, paired-pulse facilitation was not changed. However, upon theta burst stimulation or high-frequency stimulation, input-specific LTP in MTg animals had a larger initial amplitude and was more persistent than that in WtTg or NTg animals. These data suggest that the FAD-linked A246E variant of PS1 leads to higher degree of LTP induction in mice.     

Long-term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors

A series of ω-phosphono-α-car☐ylic acids were tested as antagonists of excitatory amino acid depolarizations and long-term potentiation (LTP) in region CA1 of rat hippocampal slices. The 5- and 7-phosphono compounds (±AP5and±AP7) blocked N-methyl-D-aspartate (NMDA) depolarizations and prevented the induction of LTP of the synaptic field potential and population spike components of the Schaffer collateral response.±AP5and±AP7 did not reduce kainate or quisqualate depolarizations and did not affect unpoten synaptic response amplitude.±AP5, ±AP6and±AP8 did not block amino acid excitant responses or LTP.These results demonstrate that NMDA receptors present in hippocampal region CA1 are not necessary for normal synaptic transmission, but are involved in the initiation of long-term synaptic plasticity.     

Curcuminoids rescue long-term potentiation impaired by amyloid peptide in rat hippocampal slices

Curcuminoids are vital constituent of turmeric, with therapeutic potential in the treatment of Alzheimer's disease. Electrically, stimulus train-elicited plastic changes in hippocampal CA1 excitability were used as an experimental paradigm to study the effects of curcuminoid mixture and individual components on functional failure induced by Aβ peptide in vitro. Electrical stimulation was applied on Schaffer collaterals, and population spikes (PS) were recorded from stratum pyramidale. To induce long-term potentiation (LTP) of PS, primed burst stimulation (PBs) was used. Aβ peptide inhibited PS LTP induction. Sinking PS LTP due to Aβ peptide was rescued when curcuminoid mixture was applied before PBs only at lower dose (0.1 μM) resulting in PS potentiation to 127.42% ± 1.83% at 5 min and 123.98% ± 1.06% at 60-min post-PBs. Similarly, when bisdemethoxycurcumin was applied, PS LTP was induced and lasted only at a single dose (0.1 μM). Demethoxycurcumin was effective at a middle dose (1 μM), so that the PS amplitude was changed to 140.15% ± 2.68% and 129.82% ± 0.44% at 5 and 60 min, respectively. PS LTP was effectively induced in the presence of curcumin at middle and high doses (1 and 30 μM) with resultant PS LTP to 155.68% ± 1.23% and 127.72% ± 1.23%, respectively, at 60-min post-PBs. These results showed that curcuminoids can restore susceptibility for plastic changes in CA1 excitability that is injured by exposure to Aβ peptide and rescue sinking PS LTP in Aβ-peptide-exposed hippocampal CA1 neurons.     

Alternating low frequency stimulation of medial septal and commissural fibers induces NMDA-dependent, long-lasting potentiation of hippocampal synapses in urethane-anesthetized rats

Recent evidence indicates that some synapses exhibit long-lasting synaptic potentiation in response to low frequency (1 Hz) stimulation, similar to long-term potentiation (LTP) following high frequency induction protocols. Here, the authors characterize a form of long-lasting synaptic potentiation in the hippocampal CA1 area following alternating, single pulse stimulation of the medial septum (MS) and hippocampal CA3 commissural fibers (MS-H LTP). In urethane-anesthetized rats, alternating single pulse stimulation of the MS and CA3 (50 pulses each at 0.5 Hz, 1,000 ms interstimulus interval [ISI]) produced gradual increases of field excitatory postsynaptic potential (fEPSP) amplitude in CA1 ( approximately 123% of baseline), while MS or CA3 stimulation alone was ineffective. The fEPSP enhancement was long-lasting (>4h) and repeated episodes of alternating MS-CA3 stimulation tended to result in greater levels of potentiation than those elicited by a single episode. Surprisingly, ISIs of 500, 750, and 1,500 ms did not result in significant changes in fEPSP amplitude, while an ISI of 100 ms produced synaptic depression. MS-H LTP was resistant to systemic administration of nicotinic and muscarinic receptor antagonists (scopolamine, mecamylamine), but abolished by systemic MK-801 (0.5 mg/kg, i.p.) or local CA1 application of AP-V (10 mM), indicative of a critical role of hippocampal NMDA receptors in this effect. Paired-pulse facilitation experiments revealed a gradually developing, significant inverse correlation between fEPSP enhancement and decrease in paired-pulse facilitation ratio, suggesting a role of changes in presynaptic transmitter release. Together, these data demonstrate a novel form of long-lasting synaptic enhancement in CA1 neurons in response to low frequency activity in separate afferent systems, an activity that might mimic some aspects of natural discharge patterns during the acquisition or consolidation of memory processes in hippocampal circuits.     

Galantamine enhancement of long‐term potentiation is mediated by calcium/calmodulin‐dependent protein kinase II and protein kinase C activation

Galantamine, a novel Alzheimer's drug, is known to inhibit acetylcholinesterase activity and potentiate nicotinic acetylcholine receptor (nAChR) in the brain. We previously reported that galantamine potentiates the NMDA‐induced currents in primary cultured rat cortical neurons. We now studied the effects of galantamine on long‐term potentiation (LTP) in the rat hippocampal CA1 regions. The field excitatory postsynaptic potentials (fEPSPs) were induced by stimulation of the Schaffer collateral/commissural pathways in the hippocampal CA1 region. Treatment with 0.01–10 μM galantamine did not affect the slope of fEPSPs in the CA1 region. Galantamine treatment increased calcium/calmodulin‐dependent protein kinase II (CaMKII) and protein kinase Cα (PKCα) activities with a bell‐shaped dose–response curve peaked at 1 μM, thereby increasing the phosphorylation of AMPA receptor, myristoylated alanine‐rich protein kinase C, and NMDA receptor as downstream substrates of CaMKII and/or PKCα. By contrast, galatamine treatment did not affect protein kinase A activity. Consistent with the bell‐shaped CaMKII and PKCα activation, galantamine treatment enhanced LTP in the hippocampal CA1 regions with the same bell‐shaped dose–response curve. Furthermore, LTP potentiation induced by galantamine treatment at 1 μM was closely associated with both CaMKII and PKC activation with concomitant increase in phosphorylation of their downstream substrates except for synapsin I. In addition, the enhancement of LTP by galantamine was accompanied with α7‐type nAChR activation. These results suggest that galantamine potentiates NMDA receptor‐dependent LTP through α7‐type nAChR activation, by which the postsynaptic CaMKII and PKC are activated. © 2009 Wiley‐Liss, Inc.     

Chronic failure in the maintenance of long-term potentiation following fluid percussion injury in the rat

Traumatic brain injury (TBI) can produce chronic cognitive learning/memory deficits that are thought to be mediated, in part, by impaired hippocampal function. Experimentally induced TBI is associated with deficits in hippocampal synaptic plasticity (long-term potentiation, or LTP) at acute post-injury intervals but plasticity has not been examined at long-term survival periods. The present study was conducted to assess the temporal profile of LTP after injury and to evaluate the effects of injury severity on plasticity. Separate groups of rats were subjected to mild (1.1-1.4 atm), moderate (1.8-2.1 atm), or severe (2.2-2.7 atm) fluid percussion (FP) injury (or sham surgery) and processed for hippocampal electrophysiology in the first or eighth week after injury. LTP was defined as a lasting increase in field excitatory post-synaptic potential (fEPSP) slope in area CA1 following tetanic stimulation of the Schaffer collaterals. The fEPSP slope was measured for 60 min after tetanus. Assessment of LTP at the acute interval (6 days) revealed modest peak slope potentiation values (129-139%), which declined in each group (including sham) over the hour-long recording session and did not differ between groups. Eight weeks following injury, slices from all groups exhibited robust maximal potentiation (134-147%). Levels of potentiation among groups were similar at the 5-min test interval but differed significantly at the 30- and 60-min test intervals. Whereas sham slices showed stable potentiation for the entire 60-min assessment period, slices in all of the injury groups exhibited a significant decline in potentiation over this period. These experiments reveal a previously unknown effect of TBI whereby experimentally induced injury results in a chronic inability of the CA1 hippocampus to maintain synaptic plasticity. They also provide evidence that sham surgical procedures can significantly influence hippocampal physiology at the acute post-TBI intervals. The results have implications for the mechanisms underlying the impaired synaptic plasticity following TBI.     

Long-term enhancement of postsynaptic excitability after brief exposure to Mg2(+)-free medium in normal and epileptic mice

Brief exposure to Mg2(+)-free medium (MFM) enhanced the population response of CA1 neurons to stratum radiatum stimulation in hippocampal slices from normal (+/?) and epileptic tottering (tg/tg) mice. The enhancement was maintained in both groups for at least 2 h following reperfusion with normal medium (NM). Excitability curves obtained from the extracellular records suggest that, while both synaptic activation and postsynaptic excitability are enhanced during MFM perfusion, only the latter enhancement is maintained at significant levels after reperfusion with NM. The long-term increase in postsynaptic excitability was comparable in strength to that produced by long-term potentiation (LTP) inducing tetanic stimuli, was accompanied by an increase in the slope of the population spike/field excitatory postsynaptic potential (PS/fEPSP) curve and did not appear to depend on the induction of epileptiform activity by MFM. Both the short- and the long-term effects of MFM on synaptic activation and postsynaptic excitability were qualitatively similar in normal and epileptic mice and any quantitative differences were not statistically significant. Thus, epileptogenesis in the tottering mutant may not involve a change in the NMDA receptor-mediated control of excitability, at least in the CA1 area of hippocampus.     

Induction of long-term potentiation in the basolateral amygdala does not depend on NMDA receptor activation.

Long-term potentiation (LTP) can be induced in the lateral and basolateral amygdala by stimulating synaptic afferents in the external capsule (EC). We examined the sensitivity of amygdaloid LTP to the NMDA receptor antagonist 2-amino-5-phosphonopentanoate (AP5), which is known to block LTP induction in the Schaffer collateral/CA1 synapses in the hippocampus. While relatively high concentrations (100 microM) of DL-AP5 were effective in preventing LTP induction in the lateral and basolateral amygdala in vitro, the same concentrations also significantly depressed synaptic responses to low-frequency stimulation. Furthermore, at 50 microM, a concentration sufficient to block both synaptic responses mediated by NMDA receptors and LTP induction in the hippocampus and neocortex, AP5 did not affect the probability of inducing LTP in the amygdala. Application of 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), which blocks non-NMDA excitatory amino acid receptors, reduced the monosynaptic response to EC stimulation by 85%. The remaining CNQX-insensitive response did not appear to be mediated by NMDA-type receptors, since it was not reduced by 50 or 100 microM AP5, and showed none of the voltage sensitivity characteristic of NMDA responses. These data suggest that while the induction of LTP in the amygdala produced by EC stimulation is blocked by high doses of AP5, plasticity at these synapses probably does not require activation of NMDA receptors.     

Differences in hippocampal synaptic plasticity in rats with inborn high or low learning ability may be related to different sensitivity of aspartate receptors.

Rats with an inborn high (HP) or low (LP) learning capacity were used to study the sensitivity to the blocking effect of 2-amino-phosphonopentanoic acid (AP5; 10 and 20 microM) on long-term potentiation (LTP) produced in hippocampal slices by a 1-s tetanus at 200 Hz. The potential evoked by stimulation of the perforant path was recorded from the granule cell layer of the dentate gyrus in 400 microns slices perfused with standard Krebs' solution or the AP5. Under perfusion with 10 microM of AP5, in 100% of slices from HP rats, LTP generation was not blocked; when AP5 20 microM was used, in 85% of the cases LTP was not blocked. In 60% of slices from LP rats, AP5 10 microM and in 100% of the cases at 20 microM AP5 blocked LTP generation. These results are coherent with the hypothesis that the different inborn learning ability of HP and LP rats is related to the different population or sensitivity of N-methyl-D-aspartate (NMDA) receptors.