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PubMed1999

Effects of bifemelane on incomplete cerebral ischaemia-induced reduction of long-term potentiation in rat hippocampal neurones in vivo.

In the present study, we investigated the effects of bifemelane on the reduction of hippocampal long-term potentiation after transient ischaemia. Bilateral common carotid arteries were clamped for 10 min. in halothane-anaesthetized rats. Thirty min. before occlusion, bifemelane (25 mg/kg, intraperitoneally) or saline was administered to the rats. Four days after occlusion, we measured long-term potentiation in Schaffer collateral-CA1 synapses and perforant path-dentate gyrus synapses in vivo. Long-term potentiation was significantly reduced in both the Schaffer collateral-CA1 and perforant path-dentate gyrus synapses in the saline-injected group. However bifemelane decreased the ischaemia-induced reduction of long-term potentiation in perforant path-dentate gyrus synapses, but not in Schaffer collateral-CA1 synapses. The findings suggest that bifemelane deserves further attention with regard to possible protective role in ischaemia.

Animals↗
PubMed2000

Development of the entorhino-hippocampal projection: guidance by Cajal-Retzius cell axons.

The entorhinal cortex gives rise to a massive projection to the hippocampus and fascia dentata. In the rat, this projection forms early in development with first entorhinal axons reaching the hippocampus around embryonic day (E) 17. From the very beginning, the entorhinal axons recognize their appropriate termination zones in the hippocampus proper and fascia dentata, i.e., stratum lacunosum-moleculare and the outer molecular layer of the dentate. This is remarkable, because at the time of entorhinal fiber ingrowth, the definitive target cells of entorhinal axons, pyramidal cells and granule cells, are not yet fully developed, and the majority of their distal dendritic tips have not yet reached these layers. This raises the question as to the cellular and molecular signals guiding the entorhinal axons to and keeping them in their target layers. Here we hypothesize that early generated Cajal-Retzius (CR) cells located in stratum lacunosum-moleculare and the outer molecular layer of the dentate, and in particular their axons projecting to the entorhinal cortex, provide a template that is used by the entorhinal axons to find their target layers in the hippocampus.

Aging↗
PubMed2005

Synaptic fatigue at the naive perforant path-dentate granule cell synapse in the rat.

Synaptic activation at low frequency is often used to probe synaptic function and synaptic plasticity, but little is known about how such low-frequency activation itself affects synaptic transmission. In the present study, we have examined how the perforant path-dentate granule cell (PP-GC) synapse adapts to low-frequency activation from a previously non-activated (naive) state. Stimulation at 0.2 Hz in acute slices from developing rats (7-12 days old) caused a gradual depression of the AMPA EPSC (at -80 mV) to about half within 50 stimuli. This synaptic fatigue was unaffected by the NMDA and metabotropic glutamate (mGlu) receptor antagonists d-AP5 and LY-341495. A smaller component of this synaptic fatigue was readily reversible when switching to very low-frequency stimulation (0.033-0.017 Hz) and is attributed to a reversible decrease in release probability, which is probably due to depletion of readily releasable vesicles. Thus, it was expressed to the same extent by AMPA and NMDA EPSCs, and was associated with a decrease in quantal content (measured as 1/CV(2)) with no change in the paired-pulse ratio. The larger component of the synaptic fatigue was not readily reversible, was selective for AMPA EPSCs and was associated with a decrease in 1/CV(2), thus probably representing silencing of AMPA signalling in a subset of synapses. In adult rats (> 30 days old), the AMPA silencing had disappeared while the low-frequency depression remained unaltered. The present study has thus identified two forms of synaptic plasticity that contribute to fatigue of synaptic transmission at low frequencies at the developing PP-GC synapse; AMPA silencing and a low-frequency depression of release probability.

Animals↗
PubMed2003

Pharmacological characterization and identification of amino acids involved in the positive modulation of metabotropic glutamate receptor subtype 2.

In the present study, we describe the characterization of a positive allosteric modulator at metabotropic glutamate subtype 2 receptors (mGluR2). N-(4-(2-Methoxyphenoxy)-phenyl-N-(2,2,2-trifluoroethylsulfonyl)-pyrid-3-ylmethylamine (LY487379) is a selective positive allosteric modulator at human mGluR2 and is without activity at human mGluR3. Furthermore, LY487379 has no intrinsic agonist or antagonist activity at hmGluR2, as determined by functional guanosine 5'(gamma-[35S]thio)triphosphate ([35S]GTPgammaS) binding, single-cell Ca2+ imaging, and electrophysiological studies. However, LY487379 markedly potentiated glutamate-stimulated [35S]GTPgammaS binding in a concentration-dependent manner at hmGluR2, shifting the glutamate dose-response curve leftward by 3-fold and increasing the maximum levels of [35S]GTPgammaS stimulation. This effect of LY487479 was also observed to a greater extent on the concentration-response curves to selective hmGluR2/3 agonists. In radioligand binding studies to rat cortical membranes, LY487379 increased the affinity of the radiolabeled agonist, [3H]DCG-IV, without affecting the binding affinity of the radiolabeled antagonist, [3H]LY341495. In rat hippocampal slices, coapplication of LY487379 potentiated synaptically evoked mGluR2 responses. Finally, to elucidate the site of action, we systematically exchanged segments and single amino acids between hmGluR2 and hmGluR3. Substitution of Ser688 and/or Gly689 in transmembrane IV along with Asn735 located in transmembrane segment V, with the homologous amino acids of hmGluR3, completely eliminated LY487379 allosteric modulation of hmGluR2. We propose that this allosteric binding site defines a pocket that is different from the orthosteric site located in the amino terminal domain.

Allosteric Regulation↗
PubMed2002

Postsynaptic Induction of BDNF-Mediated Long-Term Potentiation.

Brain-derived neurotrophic factor (BDNF) and other neurotrophins are critically involved in long-term potentiation (LTP). Previous reports point to a presynaptic site of neurotrophin action. By imaging dentate granule cells in mouse hippocampal slices, we identified BDNF-evoked Ca2+ transients in dendrites and spines, but not at presynaptic sites. Pairing a weak burst of synaptic stimulation with a brief dendritic BDNF application caused an immediate and robust induction of LTP. LTP induction required activation of postsynaptic Ca2+ channels and N-methyl-d-aspartate receptors and was prevented by the blockage of postsynaptic Ca2+ transients. Thus, our results suggest that BDNF-mediated LTP is induced postsynaptically. Our finding that dendritic spines are the exclusive synaptic sites for rapid BDNF-evoked Ca2+ signaling supports this conclusion.

Action Potentials↗
PubMed2003

Asymmetrical allocation of NMDA receptor epsilon2 subunits in hippocampal circuitry.

Despite its implications for higher order functions of the brain, little is currently known about the molecular basis of left-right asymmetry of the brain. Here we report that synaptic distribution of N-methyl-D-aspartate (NMDA) receptor GluRepsilon2 (NR2B) subunits in the adult mouse hippocampus is asymmetrical between the left and right and between the apical and basal dendrites of single neurons. These asymmetrical allocations of epsilon2 subunits differentiate the properties of NMDA receptors and synaptic plasticity between the left and right hippocampus. These results provide a molecular basis for the structural and functional asymmetry of the mature brain.

Animals↗
PubMed2006

Storage of spatial information by the maintenance mechanism of LTP.

Analogous to learning and memory storage, long-term potentiation (LTP) is divided into induction and maintenance phases. Testing the hypothesis that the mechanism of LTP maintenance stores information requires reversing this mechanism in vivo and finding out whether long-term stored information is lost. This was not previously possible. Recently however, persistent phosphorylation by the atypical protein kinase C isoform, protein kinase Mzeta (PKMz), has been found to maintain late LTP in hippocampal slices. Here we show that a cell-permeable PKMz inhibitor, injected in the rat hippocampus, both reverses LTP maintenance in vivo and produces persistent loss of 1-day-old spatial information. Thus, the mechanism maintaining LTP sustains spatial memory.

Animals↗
PubMed1998

Impaired spatial learning after saturation of long-term potentiation.

If information is stored as activity-driven increases in synaptic weights in the hippocampal formation, saturation of hippocampal long-term potentiation (LTP) should impair learning. Here, rats in which one hippocampus had been lesioned were implanted with a multielectrode stimulating array across and into the angular bundle afferent to the other hippocampus. Repeated cross-bundle tetanization caused cumulative potentiation. Residual synaptic plasticity was assessed by tetanizing a naïve test electrode in the center of the bundle. Spatial learning was disrupted in animals with no residual LTP (<10 percent) but not in animals that were capable of further potentiation. Thus, saturation of hippocampal LTP impairs spatial learning.

Animals↗
PubMed2003

Reduced synaptic plasticity in the lateral perforant path input to the dentate gyrus of aged C57BL/6 mice.

Hippocampal slices obtained from C57BL/6 mice (3-25 mo) were used to investigate the effects of aging on excitatory postsynaptic potentials (EPSPs) elicited in dentate gyrus with lateral perforant path stimulation. The maximal amplitude of the EPSP, as well as the degree of paired-pulse facilitation, was significantly reduced in animals aged 12 mo or more compared with younger animals (<12 mo). Although all animals showed equivalent short-term potentiation (STP) in response to high-frequency stimulation, this did not translate into a long-lasting increase in synaptic efficacy in the older animals. A significant degree of long-term potentiation (LTP) of synaptic efficacy was only observed in animals <12 mo of age when measured 30 min after induction. Blocking GABAA-mediated inhibition significantly enhanced STP in younger and older animals; however, a significant degree of LTP was again only observed in slices taken from younger animals. These data indicate that the lateral perforant path input to the dentate gyrus is altered by the aging process, and that this results in a reduction in the capacity of this input to exhibit long-lasting synaptic plasticity.

Aging↗
PubMed2005

Inhibition of perforant path input to the CA1 region by serotonin and noradrenaline.

Bath-applied monoamines-dopamine (DA), serotonin (5-HT), and noradrenaline (NE)-strongly suppress the perforant path (PP) input to CA1 hippocampal region with very little effect on the Schaffer collaterals (SC) input. The effect of DA action on PP field excitatory postsynaptic potential (fEPSP) has been characterized in detail, but relatively little is known about the NE and 5-HT effects. Here we show that the maximal inhibition of the PP fEPSP by NE is approximately 55%, whereas 5-HT inhibition is weaker ( approximately 35%). The half-maximal inhibitory concentration of both 5-HT and NE is approximately 1 muM. Neither NE nor 5-HT affected paired-pulse facilitation, suggesting that the effect is not presynaptic. This is in contrast to DA, which does have a presynaptic effect. The NE effect was blocked by alpha2 antagonists, whereas the alpha1 antagonist corynanthine and beta-antagonist propranolol were ineffective. The effect of 5-HT was mimicked by the agonist, 5-carboxamidotryptamine maleate (5-CT), and not affected by adrenergic and dopaminergic antagonists. To determine the 5-HT receptors involved, we tested a number of 5-HT antagonists, but none produced a complete suppression of the 5-HT effect. Of these, only the 5-HT7 and 5-HT2 antagonists produced weak but significant inhibition of 5-HT effect. We conclude that NE inhibits the PP fEPSP through postsynaptic action on alpha2-adrenoceptors and that 5-HT7, 5-HT2, and some other receptor may be involved in 5-HT action in PP.

Adrenergic alpha-Antagonists↗
PubMed2004

Medial perforant path inhibition mediated by mGluR7 is reduced after status epilepticus.

Metabotropic glutamate receptor (mGluR)-mediated inhibition within the dentate gyrus is altered after epilepsy. Whether these changes occur during the developmental period of the disease (i.e., the latent period) has not yet been investigated. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the lateral (LPP) and medial perforant path (MPP) simultaneously in adult mouse hippocampal slices 3-9 days after pilocarpine (PILO)-induced status epilepticus. Genetically manipulated mice (mGluR8 knockout and mGluR4/8 double knockout) and pharmacologically selective agonists were used to identify specific mGluR subtypes affected after PILO. Pharmacological activation of mGluR7 by L-AP4 in both wild-type and mGluR4/8 double knockout mice selectively reduced fEPSPs in the MPP, but not LPP, and this level of inhibition was significantly reduced 3-9 days after PILO-induced SE. Activation of mGluR2/3 reversibly depressed the fEPSP slopes in both the MPP and LPP, but no alterations were noted after PILO. mGluR8 activation selectively inhibited evoked responses in the LPP, but not in the MPP, and this level of inhibition did not change after PILO treatment. These data suggest that reduced presynaptic inhibition mediated by mGluR7, but not mGluR2/3 or mGluR8, may play a role during the latent period in generating hyperexcitability in the dentate and thereby contribute to epileptogenesis.

Animals↗
PubMed2002

Limbic network interactions leading to hyperexcitability in a model of temporal lobe epilepsy.

In mouse brain slices that contain reciprocally connected hippocampus and entorhinal cortex (EC) networks, CA3 outputs control the EC propensity to generate experimentally induced ictal-like discharges resembling electrographic seizures. Neuronal damage in limbic areas, such as CA3 and dentate hilus, occurs in patients with temporal lobe epilepsy and in animal models (e.g., pilocarpine- or kainate-treated rodents) mimicking this epileptic disorder. Hence, hippocampal damage in epileptic mice may lead to decreased CA3 output function that in turn would allow EC networks to generate ictal-like events. Here we tested this hypothesis and found that CA3-driven interictal discharges induced by 4-aminopyridine (4AP, 50 microM) in hippocampus-EC slices from mice injected with pilocarpine 13-22 days earlier have a lower frequency than in age-matched control slices. Moreover, EC-driven ictal-like discharges in pilocarpine-treated slices occur throughout the experiment (< or = 6 h) and spread to the CA1/subicular area via the temporoammonic path; in contrast, they disappear in control slices within 2 h of 4AP application and propagate via the trisynaptic hippocampal circuit. Thus, different network interactions within the hippocampus-EC loop characterize control and pilocarpine-treated slices maintained in vitro. We propose that these functional changes, which are presumably caused by seizure-induced cell damage, lead to seizures in vivo. This process is facilitated by a decreased control of EC excitability by hippocampal outputs and possibly sustained by the reverberant activity between EC and CA1/subiculum networks that are excited via the temporoammonic path.

4-Aminopyridine↗
PubMed2002

Somatostatin depresses long-term potentiation and Ca2+ signaling in mouse dentate gyrus.

The selective loss of somatostatin (SST)-containing interneurons from the hilus of the dentate gyrus is a hallmark of epileptic hippocampus. The functional consequence of this loss, including its contribution to postseizure hyperexcitability, remains unclear. We address this issue by characterizing the actions of SST in mouse dentate gyrus using electrophysiological techniques. Although the majority of dentate SST receptors are located in the outer molecular layer adjacent to lateral perforant path (LPP) synapses, we found no consistent action of SST on standard synaptic responses generated at these synapses. However, when SST was present during application of high-frequency trains that normally generate long-term potentiation (LTP), the induction of LTP was impaired. SST did not alter the maintenance of LTP when applied after its induction. To examine the mechanism by which SST inhibits LTP, we recorded from dentate granule cells and examined the actions of this neuropeptide on synaptic transmission and postsynaptic currents. Unlike findings in the CA1 hippocampus, we observed no postsynaptic actions on K(+) currents. Instead, SST inhibited Ca(2+)/Ba(2+) spikes evoked by depolarization. This inhibition was dependent on N-type Ca(2+)currents. Blocking these currents also blocked LTP, suggesting a mechanism through which SST may inhibit LTP. Our results indicate that SST reduction of dendritic Ca(2+) through N-type Ca(2+) channels may contribute to modulation of synaptic plasticity at LPP synapses. Therefore the loss of SST function postseizure could result in abnormal synaptic potentiation that contributes to epileptogenesis.

Action Potentials↗
PubMed2004

Contribution of Ih and GABAB to synaptically induced afterhyperpolarizations in CA1: a brake on the NMDA response.

CA1 pyramidal cells receive two major excitatory inputs: the perforant path (PP) terminates in the most distal dendrites, whereas the Schaffer collaterals (SC) terminate more proximally. We have examined the mechanism of the afterhyperpolarization (AHP) that follows single subthreshold excitatory postsynaptic potentials (EPSPs) in these inputs. The AHPs were not reduced by a GABAA antagonist or by agents that block Ca2+ entry. Application of the Ih blocker, ZD7288, partially blocked the AHP in the PP; the substantial remaining component was blocked by 2-hydroxysaclofen, a GABAB antagonist. In contrast, the AHP in the SC depends nearly completely on Ih, with almost no GABAB component. Thus postsynaptic GABAB receptors appear to be preferentially involved at distal synapses, consistent with the spatial distribution of GABAB receptors and g protein-coupled inward rectifying potassium (GIRK) channels. GABAB does, however, play a role at proximal synapses through presynaptic suppression of glutamate release, a mechanism that is much weaker at distal synapses. Experiments were conducted to explore the functional role of the AHP in the PP, which has a higher N-methyl-D-aspartate (NMDA)/AMPA ratio than the SC. Blockade of the AHP converted a response that had a small NMDA component to one that had a large component. These results indicate that the Ih and postsynaptic GABAB conductances act as a brake on distally generated NMDA responses.

Animals↗
PubMed2002

Long-term potentiation in direct perforant path projections to the hippocampal CA3 region in vivo.

The perforant path constitutes the primary projection system relaying information from the neocortex to the hippocampal formation. Long-term synaptic potentiation (LTP) in the perforant path projections to the dentate gyrus is well characterized. However, surprisingly few studies have addressed the mechanisms underlying LTP induction in the direct perforant path projections to the hippocampus. Here we investigate the role of N-methyl-D-aspartate (NMDA) and opioid receptors in the induction of LTP in monosynaptic medial and lateral perforant path projections to the CA3 region in adult pentobarbital sodium-anesthetized rats. Similar to LTP observed at the medial perforant path-dentate gyrus synapse, medial perforant path-CA3 synapses display LTP that is blocked by both local and systemic administration of the competitive NMDA receptor antagonist (+/-)-3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid [(+/-)-CPP]. By contrast, LTP induced at the lateral perforant path-CA3 synapses is not blocked by either local or systemic administration of this NMDA receptor antagonist. The induction of LTP at lateral perforant path-CA3 synapses, which is blocked by the opioid receptor antagonist naloxone, is also blocked by the selective mu opioid receptor antagonist Cys(2)-Tyr(3)-Orn(5)-Pen(7)-amide (CTOP), but not the selective delta opioid receptor antagonist naltrindole (NTI). CTOP was without effect on the induction of medial perforant path-CA3 LTP. The selective sensitivity of lateral perforant path-CA3 LTP to mu-opioid receptor antagonists corresponds with the distribution of mu-opioid receptors within the stratum lacunosum-moleculare of area CA3 where perforant path projections to CA3 terminate. These data indicate that both lateral and medial perforant path projections to the CA3 region display LTP, and that LTP induction in medial and lateral perforant path-CA3 synapses are differentially sensitive to NMDA receptor and mu-opioid receptor antagonists. This suggests a role for opioid, but not NMDA receptors in the induction of LTP at lateral perforant path projections to the hippocampal formation.

Animals↗
PubMed1997

Conditions for the induction of long-term potentiation and long-term depression by conjunctive pairing in the dentate gyrus in vitro.

Conditions for the induction of long-term potentiation and long-term depression by conjunctive pairing in the dentate gyrus in vitro. J. Neurophysiol. 78: 2569-2573, 1997. The conditions under which long-term potentiation (LTP) and long-term depression (LTD) of excitatory postsynaptic currents were induced by the conjunctive pairing-type protocol of afferent stimulation and postsynaptic depolarization were studied in the medial perforant pathway-granule cell synapse of the dentate gyrus in vitro. The conjunctive pairing of 1-Hz afferent stimulation and steady state postsynaptic depolarization to 0 mV did not induce LTP or LTD. Inhibition of LTD induction with a phosphatase inhibitor or ruthenium red resulted in induction of LTP after the conjunctive pairing. Such LTP induction was N-methyl--aspartate dependent. Conversely, inhibition of LTP induction with a kinase inhibitor resulted in LTD induction after the conjunctive pairing. Thus the failure to induce LTP or LTD with the pairing protocol involving depolarization to 0 mV membrane potential was due to simultaneous activation of intracellular processes that generate the induction of LTP and LTD. Increasing the frequency of afferent stimulation to 200 Hz, even for just eight stimuli, resulted in LTP induction. The studies show that two factors govern the induction of LTP/LTD, membrane potential and frequency of afferent stimulation, with either increased depolarization or increased afferent stimulation favoring LTP induction.

2-Amino-5-phosphonovalerate↗
PubMed1998

Electrophysiological and pharmacological characterization of the direct perforant path input to hippocampal area CA3.

Monosynaptic perforant path responses evoked by subicular stimulation were recorded from CA3 pyramidal cells of rat hippocampal slices. These monosynaptic responses were isolated by using low intensities of stimulation and by placing a cut through the mossy fibers. Perforant path-evoked responses consisted of both excitatory and inhibitory components. Excitatory postsynaptic currents (EPSCs) were mediated by both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acidreceptors (AMPAR) and N-methyl--aspartate receptors (NMDAR). Inhibitory postsynaptic currents consisted of gamma-aminobutyric acid-A (GABAA-) and -B (GABAB)-receptor-mediated components. At membrane potentials more positive than -60 mV and at physiological [Ca2+]/[Mg2+] ratios, >30% of perforant path evoked EPSC was mediated by NMDARs. This value varied as a function of the membrane voltage and external [Mg2+]. Two types of responses were observed after low-intensity stimulation of the perforant path. The first type of response showed paired-pulse facilitation and was reduced by 2-amino-4-phosphonobutyric acid (AP4). The second type of response showed paired-pulse depression and was reduced by baclofen. Electrophysiological and pharmacological characteristics of these two types of responses are similar to the properties of lateral and medial perforant path-evoked EPSPs in the dentate gyrus.

Aminobutyrates↗