Increase In Population Spike Amplitude Research Articles

Effect of a 5-HT1D receptor agonist on the reinstatement phase of the conditioned place preference test and hippocampal long-term potentiation in methamphetamine-treated rats

Methamphetamine (METH)-seeking relapse is associated with memory and synaptic plasticity changes. Serotonin is a key neuromodulator in this process. While there is a known distribution of 5-HT1D receptors in reward and memory areas, such as the hippocampus, its physiological function is currently unknown. Here, we evaluated effect of a 5-HT1D receptor agonist, PNU142633, on the reinstatement of METH-seeking behavior and long-term potentiation. Rats were implanted with a cannula into lateral ventricle, then treated with saline or METH (5 mg/kg) during the acquisition phase of the conditioned place preference (CPP) test. On day 13 of the extinction phase, METH groups were divided into four groups: METH (0: saline, 1, or 2.5 (priming METH) mg/kg; i.p.) + vehicle (5 µl/rat) or a priming dose of METH (2.5 mg/kg; i.p.) + PNU (2 µg/5 µl; i.c.v.) and their preference scores were calculated on reinstatement day (day 14). Immediately following this, electrophysiology was performed to assay the field excitatory postsynaptic potential (fEPSP) slope and population spike (PS) amplitude between groups. The results showed that CPP induction by METH gradually declined to extinction on days 12 and 13. A priming METH treatment significantly increased preference for the METH-paired chamber when compared with other groups, but pre-treatment with PNU significantly attenuated this effect. PS amplitude and fEPSP slopes in vehicle + priming METH rats were greater when compared with other groups. Furthermore, PNU attenuated the priming METH-induced increase in PS amplitude. These findings suggest that PNU can decrease synaptic transmission and prevent METH reinstatement in rats.

Involvement of Inhibitory Receptors in Modulating Dopamine Signaling and Synaptic Activity Following Acute Ethanol Exposure in Striatal Subregions.

Alcohol acts on both inhibitory and excitatory receptor systems resulting in a net increase in dopamine output in the ventral striatum (nucleus accumbens [nAc]), which is implicated in drug reward. However, the dorsal striatum may also be involved in reward-related behaviors. The objectives of this study were to investigate the role of inhibitory receptors in modulating the acute effects of ethanol (EtOH) on dopamine release and synaptic activity in the shell region of the nAc (nAcS) and dorsolateral striatum (DLS). EtOH (300 mM) was administered via reversed microdialysis in the nAcS or DLS of Wistar rats following pretreatment with glycine or GABAA receptor antagonist strychnine and bicuculline, respectively. Dopamine content in dialysate samples was quantified using high-performance liquid chromatography. In addition, local field potential recordings were performed in the nAcS and DLS in slices from Wistar rats. Population spike (PS) amplitude was measured following treatment with EtOH (50 mM) in slices pretreated with strychnine or bicuculline. Local EtOH increased dopamine levels in both regions, an effect that strychnine pretreatment inhibited in the nAcS. EtOH-induced increases in accumbal dopamine were not blocked by a low (5 μM) concentration of bicuculline, but were inhibited by pretreatment with higher bicuculline concentrations. None of the antagonists administered in the DLS prevented the EtOH-induced dopamine increase. Field potential recordings in the nAcS showed that acute EtOH produced an increase in PS amplitude which was blocked by both strychnine and bicuculline. In the DLS, EtOH induced a decrease in PS amplitude which was not influenced by strychnine or bicuculline. The current results show that changes in striatal dopamine output and synaptic activity induced by acute EtOH administration are modulated by inhibitory receptors in a subregion-specific manner.

Profile of the new pyrrolidone derivative seletracetam (ucb 44212) in animal models of epilepsy

Seletracetam is a pyrrolidone derivative with a one-log-unit higher affinity for the synaptic vesicle protein 2A (SV2A) than levetiracetam (Keppra®). This study explored its anticonvulsant properties in animal models of epilepsy. Seletracetam reduced both the amplitude and repetitive firing of population spikes induced by a high K+/low Ca2+ concentration fluid (HKLCF) in rat hippocampal slices. The reduction of HKLCF-induced increases in population spike amplitude was particularly pronounced, and occurred at ~10 times lower seletracetam concentrations than previously observed for levetiracetam. These invitro data suggest that desynchronisation of epileptiform activity may contribute significantly to the antiepileptic properties of seletracetam. Seletracetam also showed a potent anti-seizure activity in animal models mimicking partial-onset (kindled animals) and generalized epilepsy (audiogenic seizure susceptible mice and genetic absence epilepsy rats from Strasbourg (GAERS)). In amygdala-kindled rats, seletracetam increased the generalized seizure threshold current and decreased the duration of the after-discharge and the seizure severity observed at the after-discharge threshold current, and generally had a much more potent effect than previously observed for levetiracetam. Seletracetam showed no psychomimetic effects and a very high central nervous system (CNS) tolerability in both kindled and GAERS rats, markedly superior to that of levetiracetam and other antiepileptic drugs. These results suggest that seletracetam may represent an effective and very well tolerated broad-spectrum agent for the symptomatic treatment of epilepsy.

VPAC2 Receptor Activation Mediates VIP Enhancement of Population Spikes in the CA1 Area of the Hippocampus

The receptors mediating vasoactive intestinal polypeptide (VIP) enhancement of synaptic transmission to pyramidal cell bodies were investigated. RO 25-1553 (VPAC2agonist) mimicked the excitatory effect of VIP on population spike (PS) amplitude. [K15, R16, L27] VIP (1-7)/GRF (8-27) (VPAC1 agonist) caused only a small increase in PS amplitude. The effect of VPAC2 agonist (but not of the VPAC1 agonist) persisted upon blockade of GABAergic transmission and was strongly attenuated upon inhibition of PKA. In conclusion, VPAC2 receptor activation mediates VIP enhancement of PS amplitude in the hippocampus essentially through a PKA-dependent mechanism.

Hippocampal evoked potentials in novel environments: A behavioral clamping method

The hippocampus is involved in the detection of novelty and is essential for certain forms of learning about environmental events and relationships. The cellular and molecular mechanisms of one form of hippocampal synaptic plasticity, long-term potentiation (LTP), are thought to overlap significantly with the neural mechanisms of learning. In this study changes in hippocampal synaptic efficacy were measured in awake, freely behaving rats during exploration of novel environments. Because hippocampal physiology is modulated by on-going behavior, evoked potentials collected during Type 1 versus Type 2 behavior were evaluated separately. The effect of prior LTP induction at perforant path-dentate synapses on exploration-induced changes was evaluated. The results show that exploration causes an increase in population spike amplitude with no change in excitatory postsynaptic potential during Type 1 behavior that lasts longer than 5 min. Prior induction of hippocampal LTP occludes the change induced by exploration. This change is not likely to be due to a reduction of GABAergic inhibition induced by novelty.

Neural plasticity is impaired in cold-exposed hippocampal slices from senescent but not from age-matched presenescent F344 rats

Near the end of their natural life, many mammals enter a terminal state identifiable by a rapid loss of body weight resulting from hypophagia. This study extends characterization of this senescent state by comparing viability of metabolic mechanisms supporting neural plasticity in hippocampal slices from 24 to 30 month old senescent and age-matched presenescent (body-weight stable) F344 male rats. Half of the slices from each rat were incubated at 22–23 °C, and half were immersed in cool incubation medium (12–15 °C) immediately after slicing and allowed to passively warm to room temperature over ∼50 min to impose a cold stressor on recovery mechanisms. Following incubation, CA1 pyramidal cell population spike (PS) amplitudes were measured before and after tetanus. In slices incubated at 22–23 °C, the 221.0±24.2 % increase in PS amplitude following tetanus in seven slices from five senescent rats was not significantly different from the 202.5±23.8% increase in six slices from five age-matched presenescent rats. In contrast, in cold-exposed slices, the 133.8±13.1% increase in PS amplitude following tetanus in 14 slices from 10 senescent rats was significantly smaller ( p<0.05) than the 184.7±10.2% increase in 13 slices from seven age-matched presenescent rats. This smaller PS enhancement in senescent rats cannot be attributed to weight loss because robust potentiation was induced in cold-exposed slices from five food-restricted presenescent rats having a weight loss comparable to their senescent counterparts. Thus, the blunted enhancement observed in cold-exposed slices appears to be a characteristic of senescence.

(-)clausenamide improves long-term potentiation impairment and attenuates apoptosis after transient middle cerebral artery occlusion in rats

The effects of (-)clausenamide (clau) on long-term potentiation (LTP) and neuronal DNA damage were investigated in a rat model of middle cerebral artery (MCA) occlusion. Four days after reperfusion, electrophysiology records revealed reduced LTP in the ipsilateral dentate gyrus of ischemic rats, while treatment with clau (10 mg kg-1 p.o. once daily) improved LTP impairment. The fractional increase of population spike amplitude 20-50 min after tetanus was significantly larger in ischemic rats treated with clau than vehicle treated animals. Terminal deoxynucleotidyltransferase mediated dUTP end labeling (TUNEL) assay revealed occurrence of apoptosis in the ipsilateral striatum. The numbers of TUNEL-positive particles were significantly reduced after treatment with clau compared with vehicle group (78.8 ± 17.9 versus 105.8 ± 27.2). Mitochondrial rhodamine 123 accumulation showed that clau treatment (55.0 ± 8.5) elevated numbers of rhodamine 123-positive particles in the ipsilateral striatum compared with vehicle group (40.4 ± 7.5) These results demonstrate that clau can improve LTP impairment in the ipsilateral dentate gyrus and enhance cell survival in the striatum compared to the vehicle-treated rats four days following ischemic damage and its protective effect on mitochondria may partially underlie its action.

Propylthiouracil (PTU)-induced hypothyroidism in the developing rat impairs synaptic transmission and plasticity in the dentate gyrus of the adult hippocampus

Reductions in thyroid hormone during critical periods of brain development can have devastating effects on neurological function that are permanent. Neurochemical, molecular and structural alterations in a variety of brain regions have been well documented, but little information is available on the consequences of developmental hypothyroidism on synaptic function. Developing rats were exposed to the thyrotoxicant, propylthiouracil (PTU: 0 or 15 ppm), through the drinking water of pregnant dams beginning on GD18 and extending throughout the lactational period. Male offspring were allowed to mature after termination of PTU exposure at weaning on PND21 and electrophyiological assessments of field potentials in the dentate gyrus were conducted under urethane anesthesia between 2 and 5 months of age. PTU dramatically reduced thyroid hormones on PND21 and produced deficits in body weight that persisted to adulthood. Synaptic transmission was impaired as evidenced by reductions in excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitudes at a range of stimulus intensities. Long-term potentiation of the EPSP slope was impaired at both modest and strong intensity trains, whereas a paradoxical increase in PS amplitude was observed in PTU-treated animals in response to high intensity trains. These data are the first to describe functional impairments in synaptic transmission and plasticity in situ as a result of PTU treatment and suggest that perturbations in synaptic function may contribute to learning deficits associated with developmental hypothyroidism.

Evoked responses of the dentate gyrus during seizures in developing gerbils with inherited epilepsy.

When they are 1-2 mo old, domesticated Mongolian gerbils begin having initially mild seizures which become more severe with age. To evaluate the development of this increasing seizure severity, we obtained field potential responses of the dentate gyrus to paired-pulse stimulation of the perforant path during seizures. In 18 gerbils that were 1.5-8.0 mo old, 73 seizures were analyzed. We measured population spike amplitude, the slope of the field excitatory postsynaptic potential (fEPSP), and the population spike amplitude ratio (2nd/1st) to evaluate excitatory and inhibitory synaptic processes. In gerbils <2 mo old, exposure to a novel environment was followed by an increase in population spike amplitude and then by seizure onset, but population spike amplitude ratio and fEPSP slope remained at baseline levels, and multiple population spikes were never evoked. As previously reported for chronically epileptic gerbils, these findings provide little evidence of a disinhibitory seizure-initiating mechanism in the dentate gyrus when young gerbils begin having seizures. In young gerbils evoked responses changed little during the behaviorally mild seizures. In contrast, most seizures in older gerbils included generalized convulsions, postictal depression, and evoked responses that changed dramatically. In older gerbils, shortly after seizure onset the dentate gyrus became hyperexcitable. Population spike amplitude and fEPSP slope peaked, and multiple population spikes were evoked, suggesting that mechanisms for seizure amplification and spread are more developed in older gerbils. Next, dentate gyrus excitability decreased precipitously, and population spike amplitude and fEPSP slope diminished. This period of hypoexcitability began before the end of the seizure, suggesting it may contribute to seizure termination. After the convulsive phase of the seizure, older gerbils remained motionless during a period of postictal depression, and population spike amplitude remained suppressed until the abrupt switch to normal exploratory activity. These findings suggest that the mechanisms of postictal depression may suppress granule cell excitability. The population spike amplitude ratio peaked after the convulsive phase and then gradually returned to the baseline level an average of 12 min after seizure onset, suggesting that granule cell inhibition recovers within minutes after a spontaneous seizure. Although it is unclear whether the seizure-related changes in evoked responses are a cause or an effect of increased seizure severity in older gerbils, their analysis provides clues about developmental changes in the mechanisms of seizure spread and termination.

Primed-burst potentiation occludes the potentiation phenomenon and enhances the epileptiform activity induced by transient pentylenetetrazol in the CA1 region of rat hippocampal slices

The effects of pentylenetetrazol (PTZ) following induction of long-term potentiation (LTP) on population spikes in CA1 of hippocampal slices were investigated. Population spikes were evoked by activation of Schaffer collaterals with a range of stimulation intensities. LTP was induced using θ-pattern primed burst tetanic stimulation. Changes in the population spike amplitude and number of population spikes were used as indices to quantify the effects of PTZ exposure in the control (non-tetanized) and LTP (tetanized) conditions. The amplitude of population spike was measured 20 min before, during 20 min chemical application (3 mM), and also after 30 or 60 min washout period. In non-tetanized slices, the population spike input-output curve was significantly increased 20 min after PTZ application and persisted at least for 60 min. Multiple population spikes or after potentials also appeared, but did not persist. When PTZ was applied on tetanized slices, 60 min after LTP induction, the amplitude increase produced by PTZ was smaller than the increase seen in the control condition. Also LTP induction preceding PTZ exposure increased the number of population spikes evoked by stimulation of Schaffer collaterals. It is concluded that a transient PTZ application produces a long-lasting increase in population spike amplitude. Primed burst LTP occludes PTZ-induced potentiation while also increasing the epileptogenic effect of PTZ.

Long-lasting increase in cellular excitability associated with the priming of LTP induction in rat hippocampus.

The mechanisms underlying the facilitation (priming) of long-term potentiation (LTP) by prior activation of metabotropic glutamate receptors (mGluRs) were investigated in area CA1 of rat hippocampal slices. In particular, we focused on whether a long-lasting increase in postsynaptic excitability could account for the facilitated LTP. Administration of the mGluR agonist 1S, 3R-aminocyclopentanedicarboxylic acid (ACPD) produced rapid decreases in the amplitude of both the slow spike afterhyperpolarization (AHP(slow)) and spike frequency adaptation recorded intracellularly from CA1 pyramidal cells. These changes persisted after drug washout, showing only a slow decay over 20 min. ACPD also caused a leftward shift of the field EPSP-population spike relation and an overall increase in population spike amplitude, but this effect was not as persistent as the intracellularly measured alterations in cell excitability. ACPD-treated cells showed increased spike discharges during LTP-inducing tetanic stimulation, and the amplitude of the AHP(slow) was negatively correlated with the degree of initial LTP induction. The beta-adrenergic agonist isoproterenol also caused excitability changes as recorded intracellularly, whereas in extracellular experiments it weakly primed the induction but not the persistence of LTP. ACPD primed both LTP measures. Isoproterenol administration during the tetanus occluded the priming effect of ACPD on initial LTP induction but not its effect on LTP persistence. We conclude that the persistent excitability changes elicited by ACPD contributes to the priming of LTP induction but that other ACPD-triggered mechanisms must account for the facilitated persistence of LTP in the priming paradigm.

Diurnal modulation of long-term potentiation in the hamster hippocampal slice

Long-term potentiation (LTP) was examined in hippocampal slices from Syrian hamsters entrained to a LD 14:10 cycle. Population spike (PS) amplitudes from CA1 pyramidal cells were measured before (control) and after tetanizing the Schaffer/collateral commissural pathway. Slices from animals sacrificed during the day, between zeitgeber time (ZT) 0430 and 0530, were incubated, and then tetanized between ZT 1340 and 1930, where ZT=0 denotes lights on. Slices from animals sacrificed during the night, between ZT 1830 and 1930, were incubated, and tetanized between ZT 0030 and 0410. LTP, a sustained increase in PS amplitude following tetanus, was evoked in both groups. PS amplitude increased by 102.7±20.3% in animals sacrificed during the day and by 48.0±7.5% in animals sacrificed during the night ( p<0.05). Thus hamster slices prepared during the day show more robust LTP (a doubling of PS amplitude), a difference persisting in slices incubated for several hours.

Desynchronization of carbachol-induced theta-like activities by alpha-adrenergic agents in guinea pig hippocampal slices.

The effect of alpha-adrenergic agents on theta-like activity (TLA) in guinea-pig hippocampal slices was studied. TLA was induced by a cholinergic agent, carbachol. TLA had a frequency of 4.66+/-0.08 Hz (mean+/-S.E.M.) and an amplitude of 96.3+/-8.3 microV in the dentate gyrus (DG). The alpha-adrenergic agents epinephrine and clonidine increased the frequency and decreased the amplitude of TLA in a concentration-dependent manner. The agents also increased antidromic and orthodromic population spike (PS) amplitudes of the granule cells, but did not have any effect on population EPSP. Another alpha-adrenergic agent, guanabentz, had the same effect as clonidine. The adenylate cyclase inhibitor SQ22536 suppressed the increase in PS amplitude by clonidine. The results suggest that these alpha2-adrenergic agents facilitate the activity of granule cells through the activation of the alpha2-adrenoreceptor and cAMP pathway, and the facilitation causes the desynchronization of TLA.

Effects of experimental hypercapnia on hippocampal long-term potentiation in anesthetized rats

The effects of hypercapnia, which has been reported to impair consciousness, on the long-term potentiation of the population spike in the CA1 pyramidal cell of the hippocampus in anesthetized rats were studied. Experimental hypercapnemia was induced by inspired 13% CO 2 with 21% O 2. Arterial blood gas analysis after 80 min inspired 13% CO 2 showed pH 7.08±0.05, PCO 2=104.09±12.86 mmHg, PO 2=90.71±18.89 mmHg, BE −4.64±2.97 (mean±SD, n=18). Inspired 13% CO 2 reduced the amplitude of the population spike to 50% of the baseline. After delivery of tetanic stimulation (400 Hz, five bursts of eight pulses, inter-burst interval 1 s) population spike height was enhanced to pre-tetanic levels. Withdrawal of inspired CO 2 unmasked an increase in population spike amplitude. These findings suggest that acute retention of carbon dioxide, which is designated as pure hypercapnemia without hypoxemia, may suppress hippocampal synaptic transmission but not its plasticity.

Field potential recordings in dentate gyrus of anesthetized rats: stability of baseline.

Urethane is a standard anesthetic utilized for in vivo recordings in the hippocampus. In studies of long-term potentiation (LTP), the measure of interest is the response amplitude minutes to hours following train delivery. In the absence of experimental treatment, we have consistently observed upward drift in the amplitude of the population spike (PS) and EPSP slope of the dentate gyrus (DG) evoked field response in acute surgical preparations performed in the urethanized rat. The present study systematically monitored PS amplitude and EPSP slope in the DG every 30 minutes for 6 hours following optimal positioning of Teflon-coated bipolar stainless steel electrodes under urethane anesthesia. At maximal stimulus intensities, large time-dependent increases in PS amplitude (70-80%) were observed over the first 2-4 hours, an effect that was exaggerated at lower stimulus intensities. Increases in the EPSP slope were smaller in magnitude (20-30%) and stabilized within a shorter period of time (1-2 hours). Animals were warmed on a heating pad and body and brain temperature remained constant over the recording session. Reducing stimulating electrode size and recording with glass micropipettes did not alleviate the upward drift in response amplitude. Similar increases were also seen under pentobarbital anesthesia. To dissociate anesthetic from surgical effects, recordings were obtained from animals previously prepared with indwelling electrodes and injected with urethane. Although slight declines (10-15%) in EPSP slope occurred over time, no significant alterations in PS amplitude were seen in the chronic preparation at high stimulus intensities. Low stimulus intensities yielded a more variable response pattern and, in direct contrast to the acute preparation, time-dependent declines, not increases, were noted in both parameters. These data suggest that generalized surgical trauma contributes to the upward drift in response amplitude and indicate that long stabilization periods are required in acute surgical preparations for accurate field potential recordings.

Alterations in synaptic transmission and plasticity in hippocampus by a complex PCB mixture, Aroclor 1254.

Developmental exposure to polychlorinated biphenyls (PCBs) has been associated with a variety of neurological effects including cognitive dysfunction. The present study assessed the effects of acute in vitro exposure to a complex mixture of highly chlorinated PCBs, Aroclor 1254 (A1254), on synaptic transmission in the hippocampus of the rat. Increases in population spike (PS) amplitude were observed in field potentials recorded from the pyramidal cell layer of CA1 in response to 1.0-3 microg/ml of A1254. PS amplitude was increased by approximately 20% 5-10 min following the beginning of exposure to 3 microg/ml A1254, with some recovery towards baseline amplitudes occurring by 30 min, despite continuous perfusion. Longer exposures revealed that a maintained 10% increase in PS amplitude persisted beyond 90 min of exposure to 3 microg/ml A1254. A second recording electrode in the stratum radiatum revealed modest increases in EPSP slope (approximately 10%) that were transient. EPSP slope changes appeared within 5 min of exposure to A1254 (3 microg/ml), peaked at 10 min, and declined to baseline levels by 30 min, despite continued perfusion with A1254. Monitoring over a protracted period revealed relatively stable EPSP slope amplitudes following the return to baseline levels. Long-term potentiation (LTP) is a model of synaptic plasticity believed to encompass the physiological substrates of memory. Neither magnitude or persistence of PS potentiation recorded from the stratum pyramidale was affected by 3 microg/ml A1254. LTP of the EPSP slope recorded in the stratum radiatum was also induced to a comparable degree in control and A1254-treated slices. However, the augmentation in the dendritic response was not maintained in the treated slices over the 60-min posttrain recording period. Acute effects of PCBs on calcium homeostasis, protein kinase C translocation, dopaminergic function, and hormonal action may contribute to the pattern of effects seen in synaptic transmission and plasticity in the hippocampus.

The pro-convulsant actions of corticotropin-releasing hormone in the hippocampus of infant rats

Whole-cell patch-clamp and extracellular field recordings were obtained from 450- μm-thick brain slices of infant rats (10–13 days postnatal) to determine the actions of corticotropin-releasing hormone on glutamate- and GABA-mediated synaptic transmission in the hippocampus. Synthetic corticotropin-releasing hormone (0.15 μM) reversibly increased the excitability of hippocampal pyramidal cells, as determined by the increase in the amplitude of the CA1 population spikes evoked by stimulation of the Schaffer collateral pathway. This increase in population spike amplitude could be prevented by the corticotropin-releasing hormone receptor antagonist α-helical (9–41)-corticotropin-releasing hormone (10 μM). Whole-cell patch-clamp recordings revealed that, in the presence of blockers of fast excitatory and inhibitory synaptic transmission, corticotropin-releasing hormone caused only a small (1–2 mV) depolarization of the resting membrane potential in CA3 pyramidal cells, and it did not significantly alter the input resistance. However, corticotropin-releasing hormone, in addition to decreasing the slow afterhyperpolarization, caused an increase in the number of action potentials per burst evoked by depolarizing current pulses. Corticotropin-releasing hormone did not significantly change the frequency, amplitude or kinetics of miniature excitatory postsynaptic currents. However, it increased the frequency of the spontaneous excitatory postsynaptic currents in CA3 pyramidal cells, without altering their amplitude and single exponential rise and decay time constants. Corticotropin-releasing hormone did not change the amplitude of the pharmacologically isolated (i.e. recorded in the presence of GABA A receptor antagonist bicuculline) excitatory postsynaptic currents in CA3 and CA1 pyramidal cells evoked by stimulation of the mossy fibers and the Schaffer collaterals, respectively. Current-clamp recordings in bicuculline-containing medium showed that, in the presence of corticotropin-releasing hormone, mossy fiber stimulation leads to large, synchronized, polysynaptically-evoked bursts of action potentials in CA3 pyramidal cells. In addition, the peptide caused a small, reversible decrease in the amplitude of the pharmacologically isolated (i.e. recorded in the presence of glutamate receptor antagonists) evoked inhibitory postsynaptic currents in CA3 pyramidal cells, but it did not significantly alter the frequency, amplitude, rise and decay time constants of spontaneous or miniature inhibitory postsynaptic currents. These data demonstrate that corticotropin-releasing hormone, an endogenous neuropeptide whose intracerebroventricular infusion results in seizure activity in immature rats, has diverse effects in the hippocampus which may contribute to epileptogenesis. It is proposed that the net effect of corticotropin-releasing hormone is a preferential amplification of those incoming excitatory signals which are strong enough to reach firing threshold in at least a subpopulation of CA3 cells. These findings suggest that the actions of corticotropin-releasing hormone on neuronal excitability in the immature hippocampus may play a role in human developmental epilepsies.

Exposure to a conditioned aversive environment interferes with long-term potentiation induction in the fimbria–CA3 pathway

The effect of re-exposure of rats to an aversive environment on the induction of long-term potentiation was investigated in the CA3 region 3 and 12 h after contextual conditioning. Electrophysiological recordings showed that re-exposure of rats to the conditioning chamber produced a significant and long-lasting decrease in population spike amplitude at both post-conditioning delays. High-frequency stimulation of the fimbria induced a large and persistent increase in CA3 population spike amplitude (about 400% of baseline) in animals of control groups and shocked animals that were not re-exposed to the conditioning environment. However, high-frequency stimulation applied during re-exposure of shocked subjects 3 h after the initial exposure resulted in a small and transient increase in population spike amplitude (about 140% of baseline); when applied 12 h after the initial exposure, it produced a persistent depression of the response (−30% of baseline). Behavioural testing indicated that re-exposure of shocked animals to the conditioning environment elicited a qualitatively and quantitatively similar freezing behaviour at both post-conditioning delays (3 or 12 h). In contrast to the long-lasting decrease in CA3 population spike amplitude produced by re-exposure to the aversive environment, the level of freezing behaviour diminished rapidly within 10 min of exposure. These results suggest that, during exposure to a conditioned aversive environment, alterations in fimbria–CA3 neural processing may be dissociated from contextual fear-induced freezing behaviour. In addition, processes underlying long-term potentiation induction in fimbria–CA3 pathway may be opposite to those taking place during hippocampal processing of conditioned aversive contexts.

Altered synaptic plasticity in hippocampal CA1 area of apolipoprotein E deficient mice.

In mice with a homozygous or heterozygous deficiency for ApoE as well as in wild-type animals we established synaptic responsiveness in the hippocampal CA1 area following stimulation of the Schaffer/commissural fibers. The maximal population spike amplitude was significantly larger in wild-type animals than in mice lacking the ApoE gene, whereas the facilitation in population spike amplitude after paired pulse stimulation was most pronounced in homozygous mutant mice. Primed burst stimulation induced a lasting increase in population spike amplitude of all three groups. Apart from a more pronounced initial potentiation in the homozygous mutants, primed burst potentiation was comparable in all groups. Subsequent theta burst stimulation resulted in a long-term enhanced synaptic responsiveness which was impaired in heterozygous animals. The data show that both homo- and heterozygous ApoE mutant mice display altered synaptic plasticity in the hippocampal CA1 area.

Novelty-elicited, noradrenaline-dependent enhancement of excitability in the dentate gyrus.

In order to relate noradrenaline-dependent potentiation in the dentate gyrus to behavioural events, rats were made to explore an environment in which their encounters with novel stimuli could be strictly controlled and monitored. Previous experiments have shown that an encounter with novel objects in a holeboard elicits a burst response in a large population of noradrenergic neurons of the locus coeruleus. Such a burst response has been demonstrated to produce a large and transient potentiation of the population spike in the dentate gyrus. In the present series of experiments, rats were chronically implanted with stimulating electrodes in the perforant pathway and recording electrodes in the dentate gyrus. Evoked potentials were monitored in the awake rat, first while it was resting quietly in a familiar environment and then while it was exploring the holeboard containing a novel object in a specific hole. There was a tonic increase in population spike amplitude when the rat was placed in the novel holeboard environment, but this effect gradually dissipated. This increase was partly blocked by the beta-noradrenergic antagonist propranolol. In addition there was a robust phasic increase in spike amplitude when the rat encountered a novel stimulus. This phasic response lasted approximately 50-75 s and was absent in animals treated with propranolol. These results show that a behavioural encounter with a novel stimulus can transiently enhance information transmission through the hippocampus, and suggest that activation of the noradrenergic system by the novel stimulus mediates this behavior-dependent gating.