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PubMed2001

Combination of hypothyroidism and stress abolishes early LTP in the CA1 but not dentate gyrus of hippocampus of adult rats.

Clinical experience suggests that both hypothyroidism and stress interfere with mental concentration and memory. This electrophysiological study examined the effect of hypothyroidism and stress, separately or combined, on long-term potentiation (LTP), a widely accepted cellular model for learning and memory. Measurements of early LTP (E-LTP) were carried out in the hippocampus of urethane-anesthetized adult Wistar rats. Hypothyroidism was achieved by thyroidectomy, and the 'intruder' stress was used as a model of chronic psychosocial stress. Stimulating electrodes were placed in the left CA3 region and right angular bundle and a recording electrode was placed in the right CA1 or the dentate gyrus (DG). The results showed that in the CA1 region of the hippocampus, hypothyroid or stress partially blocked E-LTP. However, when hypothyroidism and stress were combined, they eliminated E-LTP. In contrast, no significant change in E-LTP was seen in the DG of the three groups of rats. These results suggest that impaired memory because of hypothyroidism or stress may be related to impairment of the E-LTP in the Schaffer collateral synapses but not of that of the perforant path synapses.

Animals↗
PubMed2002

Presynaptic group III mGluR modulation of short-term plasticity in the lateral perforant path of the dentate gyrus in vitro.

Modulation of short-term plasticity by activation of group III metabotropic glutamate receptors (mGluR) was investigated in the lateral perforant path of the dentate gyrus of the rat hippocampus in vitro. Brief trains of stimulation (10 stimuli at 1-100 Hz) evoked short-term depression of field excitatory postsynaptic potentials (EPSPs), with a steady-state level of short-term depression being attained after approximately 5 stimuli. The steady-state level of depression was frequency-dependent, increasing linearly between 1 and 200 Hz. The curve relating transmitter release per unit time to frequency of stimulation increased linearly up to a limiting frequency of 20-50 Hz, and then flattened at higher frequencies. Activation of group III mGluR by the selective agonist L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) had two distinct actions. Firstly, the test EPSP evoked at low test frequencies was inhibited, and secondly, short-term depression evoked at high frequencies was reduced in a frequency and agonist concentration-dependent manner. Short-term facilitation became prominent at high stimulation frequencies as short-term depression was inhibited by activation of group III mGluR. Activation of group III mGluR also shifted the limiting frequency to higher values.

Animals↗
PubMed2002

Nefiracetam induces a long-lasting facilitation of hippocampal postsynaptic responses in mice lacking the NMDA receptor epsilon1 subunit.

The present study was designed to assess whether the facilitatory action of nefiracetam, a pyrrolidone derivative, on hippocampal postsynaptic responses is dependent upon N-methyl-D-aspartate (NMDA) receptors or not, by monitoring population spikes (PSs) in the dentate gyrus of hippocampal slices from mice lacking the NMDA receptor epsilon1 subunit. Nefiracetam (1 microM) induced a sustained facilitation of postsynaptic responses in the dentate gyrus of hippocampal slices from wild-type mice. The facilitation occluded the potentiation induced by high-frequency stimulation at the perforant path, and vice versa, suggesting a common mechanism between them. The perforant path long-term potentiation (LTP) was not induced in epsilon1 subunit knock-out mice, but nefiracetam (1 microM) persistently potentiated PS amplitude, reaching 280% of basal levels 50 min after 10-min treatment, similar to the potentiation achieved with wild-type mice. The results of the present study, thus, suggest that nefiracetam exerts its facilitatory action on hippocampal postsynaptic responses in an NMDA receptor-independent manner.

Animals↗
PubMed2003

Associational sprouting in the mouse fascia dentata after entorhinal lesion in vitro.

Collateral sprouting is a form of neuronal plasticity observed in brain following injury. In order to establish an in vitro model of collateral sprouting, entorhino-hippocampal slice cultures were prepared from brain of C57BL/6 mouse pups (P1-4) and incubated for 14-16 days in vitro. Thereafter, entorhino-hippocampal fibers were cut and the outer molecular layer of the fascia dentata was denervated. At this age, entorhino-hippocampal fibers do not regenerate, as could be shown using anterograde tracing with Miniruby. Sprouting of associational mossy cell axons was monitored using calretinin-immunocytochemistry. Control and lesioned entorhino-hippocampal slices were studied at 1, 5, and 10 days postlesion. Whereas only the inner portion of the molecular layer was occupied by calretinin-positive mossy cell axons in controls and after 1 and 5 days postlesion, the entire width of the molecular layer was occupied by associational fibers by 10 days postlesion. Thus, robust sprouting of associational mossy cell axons occurs in response to entorhinal denervation in vitro. Using organotypic entorhino-hippocampal slices of genetically engineered mice, this sprouting model can be used to identify molecules involved in the regulation of sprouting following brain injury.

Animals↗
PubMed1997

Metabotropic glutamate receptors modulate synaptic transmission in the perforant path: pharmacology and localization of two distinct receptors.

Metabotropic glutamate receptors (mGluRs) have emerged as an interesting family of eight different receptor subtypes that can be divided into three groups according to their pharmacology and sequence similarity. In the present study, the specific mGluR agonists (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD) and L(+)-2-amino-4-phosphonobutyric acid (L-AP4) depressed field excitatory postsynaptic potentials (fEPSPs) in the rat dentate gyrus evoked by perforant path stimulation in a concentration-dependent, rapid and reversible manner (EC50: L-AP4 5.9 +/- 1.6 microM, (1S,3R)-ACPD 80 +/- 34 microM). In a 'paired-pulse' stimulation protocol, the first fEPSP showed a stronger reduction, resulting in 'paired-pulse' facilitation. The effects of L-AP4 but not of (1S,3R)-ACPD could be antagonized by the group III mGluR antagonists (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4) and (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG). Moreover, (1S,3R)-ACPD was still potently depressing fEPSPs after preperfusion of near saturating concentrations of L-AP4. Together, the results suggest that both substances act on different mGluRs. The effects of (1S,3R)-ACPD could not be further differentiated by selective group I or group II mGluR agonists. Although (2S,1'S,2'S)-2-carboxycyclopropylglycine (L-CCG-I) blocked fEPSPs at concentrations >> 1 microM, these effects, as well as L-AP4 effects, were potently antagonized by MAP4. This suggests that mGluR8 might be responsible for the actions of L-AP4 and L-CCG-I. The two different mGluRs showed a distinct distribution when fEPSPs were recorded simultaneously in the outer and middle molecular layer (OML/MML): The L-AP4 sensitive receptor, possibly mGluR8, seems to be located in the OML while (1S,3R)-ACPD showed its main effect in the MML.

Aminobutyrates↗
PubMed1997

5-HT inhibits lateral entorhinal cortical neurons of the rat in vitro by activation of potassium channel-coupled 5-HT1A receptors.

Serotonin (1-40 microM) reduced input resistance by 20.6 +/- 6% and hyperpolarized stellate and pyramidal neurons of layers two and three of the lateral entorhinal cortex. 5-Carboxamidotryptamine, a 5-HT1 agonist, and the selective 5-HT1A agonist 8-hydroxy-dipropylaminotetralin mimicked the action of serotonin. The reversal potential of 5-HT-mediated hyperpolarizations was sensitive to the extracellular K+ concentration, indicating a potassium conductance change. Serotonin treatment suppressed excitatory amino acid-mediated synaptic potentials (by 48%, Kd = 6.9 microM) and responses to exogenously applied glutamate (70.1 +/- 17% of control, n = 7), but did not alter paired-pulse facilitation, indicating a postsynaptic site of action. Intracellular application of QX-314, a blocker of potassium conductance, significantly reduced depression of synaptic potentials by 5-HT agonists. In cells filled with QX-314, responses to exogenously applied glutamate were not reduced by serotonin or 5-carboxamidotryptamine application. These results indicate that the observed conductance increase associated with 5-HT application accounts for most if not all of the observed depressant effects of 5-HT1A agonists on excitatory amino acid-mediated neurotransmission.

2-Amino-5-phosphonovalerate↗
PubMed1997

The effects of fimbria/fornix transections on perforant path kindling and mossy fiber sprouting.

Various clinical and experimental studies of epilepsy have described synaptic reorganization in the dentate gyrus of hippocampus, in the form of collateral sprouting of the mossy fibers. These reports have led to the hypothesis that reorganized mossy fibers form a functional excitatory feedback circuit that contributes to local circuit hyperexcitability and chronic seizures. Much of the evidence supporting the sprouting hypothesis has been derived from kindling. We recently reported that transection of the fimbria/fornix (FF), which produces chronic epileptiform activity in the hippocampus, also induces mossy fiber sprouting in the inner molecular layer of the dentate gyrus. In the present study, we attempted to determine whether mossy fiber sprouting contributes to epileptiform activity, by examining the effects FF transections on perforant path (PP) kindling and associated mossy fiber sprouting. We found that FF transections and PP kindling produced moderate levels of sprouting, whereas the combination of the two treatments produced significantly denser sprouting. FF transections had mixed effects on kindling: afterdischarge thresholds were decreased and clonus and afterdischarge durations were increased, suggesting increased local excitation, whereas the kindling of behavioral seizures was delayed, suggesting decreased epileptogenesis.

Analysis of Variance↗
PubMed1997

Changes in paired-pulse depression during the triggering of seizures by 2 Hz dentate gyrus stimulation: effect of the kindling.

In this study, seizures in the dentate gyrus were triggered by 2 Hz electrical stimulation while, at the same time, serial changes in paired-pulse depression was measured in free-moving rats. The perforant path was stimulated by paired pulses 25 ms apart and recordings were made in the dentate gyrus. We also observed the effect of kindling procedure on this change of evoked field potential. Paired-pulse depression started to fail following the onset of epileptic afterdischarge, both before and after kindling. As kindling progressed, paired-pulse depression increased in the initial part of the stimulus train, and also the time delay from the start of the stimulation to when paired-pulse depression started to fail increased significantly. These findings suggest that the collapse of local early, presumably GABAA-mediated, inhibition may occur after the dentate gyrus seizure onset and development of kindling epileptogenesis does not weaken but, on the contrary, enhances this local inhibitory function. Finally we propose that seizures triggered by 2 Hz electrical stimulation constitutes a useful model for examining physiological or biochemical changes during seizure initiation of awake, free-moving animals since it provides long (usually several seconds or more) latency from the start of stimulation to seizure onset.

Animals↗
PubMed1998

Intracerebroventricular norepinephrine potentiation of the perforant path-evoked potential in dentate gyrus of anesthetized and awake rats: A role for both alpha- and beta-adrenoceptor activation.

Norepinephrine (NE) applied iontophoretically to the dentate gyrus in vivo, and bath applied to hippocampal slices in vitro, produces potentiation of the perforant path-evoked potential. beta-receptors mediate exogenous NE potentiation in vitro, while alpha-receptors are implicated in exogenous effects in vivo. The present study uses intracerebroventricular (i.c.v.) NE to mimic in vitro bath conditions in vivo. Short-term NE potentiation was reliably seen with 10 microg [+/-] NE in 2 microl of 0.9% saline i.c.v. Long-term potentiation occurred with higher doses of NE. The beta-agonist isoproterenol and the alpha-agonist phenylephrine also produced potentiation. Long-term effects were common with isoproterenol. The beta-antagonist metoprolol and the alpha-antagonist phentolamine attenuated NE potentiation. The results suggest that both alpha- and beta-receptors could play a role in NE potentiation in dentate gyrus in vivo. In awake animals, 10 microg NE i.c.v. reproduced the potentiation pattern seen in anesthetized rats. NE potentiation in awake rats was independent of behavioral variation.

Adrenergic alpha-Agonists↗
PubMed1998

Transplanted embryonic entorhinal neurons make functional synapses in adult host hippocampus.

Grafts of embryonic entorhinal cortex (EC) or non-entorhinal cortex (NEC) were placed into the hippocampus of adult rats with transection of the perforant paths. Graft-host connectivity was investigated at 4-6 months post-transplantation by recording extracellular evoked responses in hippocampal slice preparations. Electrical stimulation of the grafts evoked excitatory postsynaptic potentials (EPSPs) in the outer molecular layer of the dentate gyrus, and the stratum lacunosum moleculare of CA1, CA3, and elicited population spikes in the granule cell layer and the pyramidal cell layer of CA1, but not CA3. While the latencies and the forms of these evoked response were similar to those in matched control slices from the normal animals, the amplitudes were smaller than normal controls. However, in the slices with NEC grafts, no such responses were recorded when stimulus was applied in similar position in the grafts. The findings suggest that grafted entorhinal neurons make viable synaptic connections with the host hippocampus.

Animals↗
PubMed1998

Development of spontaneous seizures over extended electrical kindling. I. Electrographic, behavioral, and transfer kindling correlates.

The present study was aimed at evaluating an extended kindling model of spontaneous epilepsy. Behavioral and electrographic responses to repeated kindling of either the perforant path or amygdala were monitored for up to 300 trials. Kindling initially led to generalized convulsions equivalent to the level 5 seizure on the rating scale developed by Racine. The evoked seizures became progressively more complex with additional kindling, which was described by a 10-stage classification system. The highest stage (stage 10) was achieved when the kindling stimulation evoked two or more bouts of level 5 seizures combined with running and jumping fits. These more complex seizures developed over the course of amygdala, but not perforant path kindling. Electrographic seizures from both the amygdala and dentate gyrus increased in duration and amplitude during the early phase of kindling, but did not correlate with motor seizure development beyond level 5. During the late phase of kindling, the dentate gyrus afterdischarge amplitude decreased and became dissociated from the behavioral seizures. Manifestations of spontaneously recurring seizures were seen in the majority of animals, but spontaneous seizures of level 4 or greater were observed in only five rats. The second part of this study examined kindling transfer effects, the efficacy of kindling a new site after the completion of the initial (in this case extended) kindling protocol. The effect depended on both primary and secondary site location. When the amygdala served as primary site, perforant path transfer was complete in some animals but absent in others. No transfer occurred in the opposite direction, from the perforant path to the amygdala. Finally, transfer effects in the dentate gyrus, which was tested as tertiary site, were complete. Previous studies have found weaker transfer effects in the dentate when kindling to the standard stage 5 level.

Animals↗
PubMed1998

An incomplete cerebral ischemia produced a delayed dysfunction in the rat hippocampal system.

We investigated whether functional changes occur with incomplete cerebral ischemia which do not lead to neural cell death. If functional changes are recognized, it is necessary to clarify whether they occur immediately after ischemia or after a lag of a few days similar to the pathological changes. Long-term potentiation (LTP) in both the Schaffer collateral-CA1 and the perforant path-dentate gyrus synapses in halothane-anesthetized rats were examined 1 day and 4 days after 10 min clamping of the bilateral common carotid arteries. LTP was substantially attenuated after clamping of the bilateral common carotid arteries. In Schaffer-CA1 synapses, the inhibition of LTP was significant on both the 1 day and 4 days after-clamping group. In perforant path-dentate gyrus synapses, LTP was significantly inhibited on only the 4 days after-clamping group. These results suggest that functional damages may occur with incomplete ischemia without any histological damages. In the 1 day after-clamping group, LTP was reduced, but the changes in LTP differed from the inhibition of the 4 days after-clamping group. Therefore, a so-called delayed dysfunction might exist in the hippocampal neurons, despite absence of pathological changes.

Action Potentials↗
PubMed1998

Monosynaptic activation of CA3 by the medial perforant path.

The functional projection of the medial perforant path (MPP) to different CA3 subfields was studied in urethan-anesthetized rats using current source density analysis. MPP stimulation resulted in an early-latency (presumed monosynaptic) sink with onset of 2-3 ms at the distal apical dendritic layer of CA3 (stratum lacunosum molecule) and a long-latency (presumed disynaptic, >7 ms) sink at stratum lucidum and radiatum of CA3. The population spike (onset 5. 3-6.1 ms), a sink at CA3 pyramidal cell layer, was observed 67% of the time (12 of 18 rats) in CA3a, 44% (8 of 18) in CA3b and 58% (7 of 12 rats) in CA3c following MPP stimulation. Population spike was not observed during presumed disynaptic excitation of CA3. Both early-latency sink (excitatory postsynaptic potential) and population spike in CA3 revealed robust paired-pulse facilitation (PPF). In contrast, little PPF was found for the MPP-evoked excitatory sink at the middle molecular layer of the dentate gyrus. The data suggested that the entorhinal cortex provides a strong monosynaptic excitation of different subfields of CA3. A direct entorhinal to CA3 input bypasses the dentate gyrus and may play a role in normal hippocampal signal processing and neural plasticity.

Action Potentials↗
PubMed1998

Self-sustaining status epilepticus after brief electrical stimulation of the perforant path.

We examined the duration of intermittent perforant path stimulation (PPS) needed to induce self-sustaining status epilepticus (SSSE) in rats. Seven-minute PPS did not induce SSSE. Some rats receiving 15 min and all animals after 30 min PPS developed SSSE that continued for hours. The animals killed 3 days after SSSE showed extensive neuronal damage. Those which were allowed to survive for 6 weeks after SSSE displayed spontaneous seizures.

Animals↗
PubMed1999

The short-acting anesthetic propofol produces biphasic effects-depression and withdrawal rebound overshoot-on some (but not all) limbic evoked potentials in the behaving rat.

Propofol, the relatively new, short-acting general anesthetic, markedly enhances the action of GABA at the GABAA receptor. To evaluate its effects on field potentials evoked in the dentate gyrus (DG) during the anesthetic and recovery periods, propofol was administered intraperitoneally to behaving rats bearing stimulating electrodes in the dorsal perforant path (DPP), where medial perforant path fibers predominate, and in the anterior piriform cortex (PC; i.e., olfactory cortex), and recording electrodes in the DG. Input from the PC reaches the DG via the lateral perforant path. Population slow waves (SWs) were evoked by paired-pulse stimulation of the PC at a 32 ms interstimulus interval (ISI) to produce paired-pulse facilitation in the awake animal. We had previously demonstrated that amplitude of SW2 (produced by the second stimulus) was greatly decreased by GABAergic drugs and increased by antiGABAergic convulsant agents. After administration of propofol, mean amplitude of SW2 decreased immediately and remained low for 30-60 min during propofol-induced sleep (as expected), then unexpectedly increased to about 1.5- to 2-fold above pretreatment levels at 2-4 h before gradually returning to pretreatment levels. In addition, the DPP was stimulated to produce either paired-pulse inhibition (20 ms ISI) or facilitation (32 ms ISI) of DG population spikes (PSs) in the awake animal. PS2 was much more inhibited during propofol-induced sleep, than during the pretreatment period, consistent with an expected marked increase in recurrent inhibition. An overshoot in PS2 amplitude was observed only occasionally during recovery, suggesting that withdrawal overshoot in amplitudes is more characteristic of PC-evoked DG SW2 potentials. The overshoot in SW2 amplitude during recovery may have been related to propofol's 'rapid on-rapid off' actions on the GABAA receptor, perhaps resulting in a phenomenon like the 'GABA withdrawal syndrome'. Such an effect, if true, may help explain the rare occurrence of seizures, especially during recovery, associated with its use clinically.

Anesthetics, Intravenous↗
PubMed1999

Analysing metabotropic glutamate group III receptor mediated modulation of synaptic transmission in the amygdala-kindled dentate gyrus of the rat.

Metabotropic glutamate receptors (mGluRs) provide a powerful control of synaptic transmission in the hippocampus and may serve as a target for drug development in human temporal lobe epilepsies. Agonists and antagonists at these receptors influence the development and propagation of seizures in some animal models of epilepsy. Experimental seizures can change the level of expression of mGluRs in the rat hippocampus. In the human dentate gyrus of patients suffering from temporal lobe epilepsy (TLE), group III mGluR mediated inhibition of synaptic transmission is almost lost in the sub-group with Ammon's horn sclerosis. We tested the modulation of synaptic transmission by the group III mGluR specific agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) in the dentate gyrus outer molecular layer in control and amygdala-kindled rats, a common model for TLE. Extracellular field potential recordings upon subthreshold stimulation of lateral perforant path fibers were measured simultaneously in the outer molecular layer and granule cell layer. Analysis of 'paired-pulse' characteristics in the absence and presence of L-AP4 and group III mGluR mediated inhibition of synaptic transmission in the lateral perforant path revealed no significant alterations in fully kindled rats. Since there is no evidence of altered L-AP4 responses, a loss of group III mGluR function, particularly that of subtype mGluR8, seems not necessary for the kindling epilepsy.

Amygdala↗
PubMed1999

Self-sustaining status epilepticus after a brief electrical stimulation of the perforant path: a 2-deoxyglucose study.

Status epilepticus remains a life-threatening condition associated with a high mortality. In order to understand the pathophysiological mechanisms underlying sustained seizures, the identification of structures involved in seizure activity allowing to define epileptic networks may be important. Thus, local cerebral metabolic rate for glucose (LCMR(glc)) was measured in a rat model of self-sustaining status epilepticus (SSSE) induced by a brief intermittent perforant path stimulation of 30 min, using the quantitative [(14)C]2-deoxyglucose autoradiographic technique. SSSE induced a generalized bilateral increase in LCMR(glcs) affecting 27 of the 42 structures studied. Largest metabolic increases (>250%) were recorded in the hippocampus, amygdala, entorhinal and piriform cortices, and lateral septum. Marked metabolic activation was also seen in basal ganglia areas such as the substantia nigra, globus pallidus and accumbens nucleus. LCMR(glcs) in brainstem, some midbrain structures, and in the neocortex were not affected by SSSE. In conclusion, a brief stimulation of the hippocampus induced a reproducible limbic SSSE in 100% of the rats, characterized by the metabolic activation of limbic and extralimbic structures, known to be involved in this type of seizures. Therefore, this new model allowing the development of a well-defined SSSE, appears to be particularly suitable for further studies on the mechanisms involved in status epilepticus.

Animals↗
PubMed1999

The neuroprotective glycine receptor antagonist GV150526 does not produce neuronal vacuolization or cognitive deficits in rats.

The neuroprotective activity of the novel glycine receptor antagonist (E)-3[(phenylcarbamoil)ethenil]-4,6-dichloroindole-2-c arboxylic acid sodium salt) (GV150526) was recently reported in a model of focal ischemia in the rat. Here it was investigated whether GV150526 treatment results in any of the adverse side effects commonly detected after injection of NMDA (N-methyl-D-aspartate) receptor antagonists. First, it was found that neuronal vacuolization in the posterior cingulate/retrosplenial area of the cortex was not induced by GV150526 (200 mg/kg, i.v.), but was evident after injection of the NMDA receptor antagonist dizocilpine (MK801) (1 mg/kg, s.c.). In a second set of experiments, the effects of GV150526 were examined on perforant path-dentate gyrus long-term potentiation in rats. GV150526 (3 mg/kg, i.v.) injected 30 min or 150 min prior to tetanization did not block potentiation of the e.p.s.p. slope and population spike amplitude. In contrast, in animals treated with MK801 (1 mg/kg, i.p.) 150 min before tetanization there was a clear block of long-term potentiation of the e.p.s.p. slope and population spike amplitude. The effects of GV150526 were also examined in the Morris Water Maze. Rats injected with GV150526 (10 mg/kg or 60 mg/kg, p.o.) did not show any impairment in learning when compared to control. MK801 (0.08 mg/kg, i.p.), on the other hand, significantly affected the ability to locate the escape platform in the Water Maze. These findings show that GV150526 is devoid of adverse side effects even at doses well above those producing a neuroprotective effect. This, drug has therapeutic potential with a much greater margin of safety than NMDA channel blockers or competitive NMDA receptor antagonists.

Action Potentials↗