CA1 Population Spike Research Articles

A novel cholinergic induction of long-term potentiation in rat hippocampus.

1. We studied long-term cholinergic effects on synaptic transmission in submerged hippocampal slices using intra- and extracellular recording techniques. 2. Bath application of submicromolar concentrations of carbachol (CCh) produced a gradually developing, long-lasting increase in the CA1 excitatory postsynaptic potential and population spike. This potentiation was blocked by atropine and, hence, named muscarinic long-term potentiation (LTPm). Application of DL-2-amino-5-phosphonovaleric acid had no effect on LTPm, indicating that this phenomenon is N-methyl-D-aspartate receptor independent. 3. These effects of CCh were not likely to be due to the blockade of one of several K+ conductances by the drug; the time and concentration dependence of LTPm were different from those associated with cholinergic blockade of K+ conductances. 4. Removal of extracellular calcium (Cao2+) from the bath blocked synaptic transmission. CCh added in calcium-free medium induced LTPm, which was revealed upon removal of the drug by washing with normal calcium-containing medium. Neither cutting CA1-CA3 connections nor cessation of synaptic stimulation interfered with LTPm induction. 5. Application of thapsigargin or H-7 together with CCh blocked LTPm, suggesting the involvement of intracellular calcium (Cai2+) stores and protein kinases, respectively, in the LTPm mechanism. 6. Subthreshold cholinergic stimulation coupled with subthreshold tetanic stimulation caused LTP. CCh had no effect when administered after the LTP mechanism had been saturated by repeated suprathreshold tetani. Tetanic stimulation failed to cause LTP when applied after LTPm had been induced by CCh. These experiments indicate that tetanus-induced potentiation and LTPm share a common mechanism and provide a direct link between ACh and mechanisms of synaptic plasticity.

Pertussis toxin prevents neomycin-induced calcium-dependent electrophysiological effects in rat hippocampal slices

1. The influence of pertussis toxin has been studied on the effects of neomycin on CA1 field potentials in rat hippocampal slices in order to determine a role played by G protein in the modulation of synaptic transmission by the drug. 2. Neomycin (500 μM), within 30 min significantly ( P < 0.01) decreased the magnitude of the somatic CA1 excitatory postsynaptic potentials (EPSP) and population spike (PS) in control hippocampal slices. 3. Neomycin (500 μM), within 30 min failed to significantly affect the magnitude of the somatic CA1 EPSP and PS in slices obtained from animals treated intracerebroventricularly (ICV) with 1–2 μg of pertussis toxin 3 days before. 4. The results demonstrated that pertussis toxin prevents some electrophysiological effects of neomycin, suggesting a role of G protein in the modulation of the aminoglycoside antibiotic on central synaptic transmission.

Imaging cell volume changes and neuronal excitation in the hippocampal slice

Brain cell swelling is a consequence of Scizure, ischemia or excitotoxicity. Changes in light reflectance from cortical surface are now used to monitor brain activity but these intrinsic signals are poorly understood. The objectives of this study were first, to show that changes in light transmittance were correlated with cell volume and second, to image increases in light transmittance as they related to neuronal activation. Transverse hippocampal slices from the rat were used for the study. Brief exposure (4–6 min) to hypo-osmotic artificial cerebrospinal fluid (−40 mOsm) elevated light transmittance consistently and reversibly in most regions of the slice and particularly in CA1 dendritic regions. Neither zero-Ca 2+ artificial cerebrospinal fluid nor tetrodotoxin altered the transmittance increase and its subsequent reversal, suggesting that it was dependent on osmolality but independent of synaptic transmission and neuronal firing. The amplitude of the CA1 population spike evoked from Schafler collaterals increased concomitantly with the hypo-osmotic increase in light transmittance, providing evidence that the extracellular tissue resistance increased. Hyper-osmotic artificial cerebrospinal fluid (+40 mOsm) containing impermeant mannitol consistently lowered light transmittance and the amplitude of the population spike. Glycerol (+40mOsm), which is cell permeant, did not have an affect. Taken together these observations indicate that osmotic challenge alters light transmittance by inducing changes in cell volume. Transmittance increases induced by hypo-osmotic artificial cerebrospinal fluid or 10μ M kainate were small in the CA1 cell body region compared to dendritic regions. Similarly, orthodromic stimulation of axons terminating in stratum oriens or in stratum radiatum evoked transmittance increases only in their respective postsynaptic areas. In contrast, the cell body region and its adjacent proximal-apical dendrites (both sites of action potential initiation) could display dramatic increases in light transmittance upon brief exposure to 20 mM K +. The response, which may represent neuronal damage, was blocked in tetrodotoxin. Antidromic stimulation evoked a weak response in these same proximal areas. We conclude that activity-dependent increases in light transmittance across brain slices primarily reveal glial and neuronal swelling associated with excitatory synaptic input and action potential discharge. The signal can be imaged in real time to reveal neuronal activation, not only among hippocampal areas, but among neuronal regions. Cell swelling is a known consequence of excessive neuronal discharge. Therefore, the imaging of changes in light transmittance across brain slices should prove useful in monitoring epileptiform and excitotoxic states.

Stochastic versus deterministic variability in simple neuronal circuits: II. Hippocampal slice

Long time series of Schaffer collateral to CA1 pyramidal cell presynaptic volleys (stratum radiatum) and population spikes (stratum pyramidale) were evoked (driven) in rat hippocampal slices. From the driven CA1 region in normal [K+] perfusate, both population spike amplitude and an input-output function consisting of population spike amplitude divided by the presynaptic volley amplitude were analyzed. Raising [K+] in the perfusion medium to 8.5 mM, slices were induced to spontaneously burst fire in CA3 and long time series of inter-burst intervals were recorded. Three tests for determinism were applied to these series: a discrete adaptation of a local flow approach, a local dispersion approach, and nonlinear prediction. Surrogate data were generated to serve as mathematical and statistical controls. All of the population spike (6/6) and input-output (6/6) time series from the normal [K+] driven circuitry were stochastic by all three methods. Although most of the time series (5/6) from the autonomously bursting high [K+] state failed to demonstrate evidence of determinism, one (1/6) of these time series did demonstrate significant determinism. This single instance of predictability could not be accounted for by the linear correlation in these data.

The M1 antagonist pirenzepine suppresses heterosynaptic STD in the CA1 region.

The effect of the muscarinic M1 and M2 antagonists (pirenzepine and gallamine) on heterosynaptic short-term depression (HSTD) of the CA1 population spike was studied in rat hippocampal slices. HSTD was evoked by a train of 30-50 pulses at 5 Hz (theta-like stimulation; TLS) delivered to the stratum oriens. Bath-applied pirenzepine (10(-6)-3 x 10(-6) M) significantly suppressed the magnitude of HSTD in the tested radiatum input (56 +/- 26% of control, p < 0.05). In contrast, gallamine (10(-6)-10(-5) M) did not suppress HSTD (102 +/- 7%). An enhancement of HSTD during application of eserine was also antagonized by pirenzepine (71 +/- 18%, p < 0.01), but not by gallamine (152 +/- 85%). These data suggest that acetylcholine synaptically released during TLS of the stratum oriens significantly contributes to HSTD in the CA1 region by activation of the M1 muscarinic receptor subtype.

Persistent physiological effects caused by a single pentylenetetrazol induced seizure in neonatal rats

A single seizure was induced by pentylenetetrazol (PTZ; 150 mg/kg i.p.) in 1-day-old and 21-day-old rats; control littermates were given saline (i.p.) injections. In vitro recordings were made in hippocampal slices derived from adult (2-3.5-month-old) rats. The population responses in CA1, CA3 and dentate gyrus (DG) were recorded following double-pulse stimulation of Schaffer collateral (CA1 stratum radiatum, for CA1 and CA3 recordings) and perforant path (for DG recordings). Paired-pulse' stimuli at an interpulse interval ( IPI) of 10–200 ms and intensity of 1.5, 2 or 4 times the stimulus threshold were used. PTZ given on day 1 resulted in a highly significant increase in the paired-pulse facilitation (PPF) of the population EPSP, but not of the population spike, in CA1 at all stimulus intensities. In the DG, PPF of both the population EPSP and population spike was found at 1.5 x threshold intensity. PTZ given on day 21 decreased PPF of the population EPSP and spike in CA1 and had no significant effect in the DG. No significant difference was found in CA3 responses after seizures on day 1 or day 21. The slices from seized and control animals were not different in their stimulus thresholds or response to a single pulse. It is concluded that a single neonatal PTZ-induced seizure had long-lasting physiological consequences which depend on the age of seizure, It is suggested that day-1 PTZ treatment resulted in an increase in presynaptic facilitation in CA1, which was perhaps compensated by a concomitant suppression of spike excitability evoked by the second pulse, resulting in normal PPF of the population spike.

Acute effects of γ-vinyl GABA (vigabatrin) on hippocampal GABAergic inhibition in vitro

The acute effects of γ-vinyl-GABA (GVG) on GABAergic inhibition were investigated in the hippocampal slice preparation using the paired-pulse test of inhibition during extracellular recordings. Superfusion of GVG (100–500 μM) for 60 min resulted in a concentration-dependent decrease in GABAergic inhibition. Slices superfused with higher concentrations of GVG (0.5–1 mM) were hyperexcitable as demonstrated by the appearance of multiple spikes. Binding studies showed that GVG (1 mM) had no effect on the binding of [ 3H]flunitrazepam or [ 3H]TBOB and displaced no more than 15% of specific [ 3H]GABA binding, which indicates that GVG-induced disinhibition is not mediated through an action at the GABA A receptor complex. Consistent with this suggestion is the finding that GVG (500 μM) had little effect on the inhibition of the orthodromically evoked CA1 population spike produced by the GABA A receptor agonist muscimol (10 μM), whereas this inhibition was considerably attenuated by the GABA A receptor antagonist, bicuculline methiodide (5 μM). The results of this study suggest that the acute actions of GVG on the GABAergic neurotransmitter system are not involved in its anticonvulsant effect.

Modulation of hippocampal long-term potentiation and long-term depression by corticosteroid receptor activation

Long-term potentiation (LTP) and long-term depression (LTD) are lasting changes in synaptic efficacy which may underlie memory and learning processes. Hippocampal LTP has been shown to vary inversely with the degree of stress or adrenal activity, and adrenal corticosteroids (CORT) have been strongly implicated in this process. The present in vitro study was undertaken to further examine the role of glucocorticoids in LTP, and to extend this analysis to heterosynaptic LTD. Animals were injected twice daily (s.c.) for 2 days prior to sacrifice with either the corticosteroid biosynthesis inhibitor metyrapone (200 mg/kg/day) or CORT (20 mg/kg/day). Noninjected and saline-injected controls were also examined. CA1 population spike amplitudes and field EPSP slopes were assessed in response to activation of two separate stratum radiatum inputs. One input received tetanic stimulation and both inputs were monitored for 30 min following tetanization to determine long-term changes in synaptic efficacy (homosynaptic LTP of tetanized synapses; heterosynaptic LTD of nontetanized synapses). Animals exhibiting low and high serum CORT titers exhibited significantly less LTP and LTD than did animals exhibiting moderate levels of CORT. In addition, in vitro perfusion of RU-28362, a Type II glucocorticoid receptor agonist, markedly reduced both LTP and LTD. There was no correlation between serum CORT and serum glucose titers, nor was there any correlation between serum glucose and either LTP or LTD. These results are consistent with recent reports of an inverted-U function for CORT levels versus primed-burst LTP (Bennett, Diamond, Fleshner, & Rose, 1991; Diamond, Bennett, Fleshner, & Rose, 1992) and further demonstrate that manipulation of corticosterone in adrenal-intact animals affects LTP and LTD in a similar fashion.

Psychological stress repeatedly blocks hippocampal primed burst potentiation in behaving rats

Primed burst (PB) potentiation is a long-term increase in CA1 population spike amplitude produced by brief physiologically patterned electrical stimulation of the hippocampal commissure. Exposure of rats to a novel environment resulted in a blockade of short-term (Post-tetanic potentiation, PTP) and long-term (PB potentiation) plasticity in all cases ( n = 6). When the animals had extensive exposure to the environment (14 consecutive days), PTP and PB potentiation occurred. With placement of the rats in a second novel environment, once again, neither PTP nor PB potentiation was observed. Placement of rats in each of the two novel environments produced a significant increase in serum corticosterone levels, while placement in the familiar environment produced no increase in response. These findings support the hypothesis that hippocampal plasticity is repeatedly susceptible to modulation by the stress of forced exposure to a novel environment.

Effects of calcium antagonists on hypoxic and NMDA injury in rat hippocampal slices

The effects of various calcium antagonists, acting at the different neuronal calcium channels, were studied towards two models of in vitro neuronal injury in rat hippocampal slices. In particular, the influence of the drugs were tested on the electrical failure induced by treatment of hippocampal slices with hypoxia or high concentrations of the excitatory amino acid N-methyl-D-aspartate (NMDA). The L-type calcium antagonists, nifedipine (100 μM) and diltiazem (100 μM) or the T-type calcium antagonist amiloride (100 μM) failed to significantly affect the recovery from the CA1 electrical failure induced by both hypoxia or NMDA (50 μM). The N-type calcium antagonists, omega-conotoxin GVIA (0.5 μM) and neomycin (300 μM) significantly (P<0.01) increased the probability of the recovery of the CA1 population spike after hypoxia but not after NMDA (50 μM). The glutamate antagonist dizocilpine (50 μM), tested for comparison, significantly (P<0.01) increased the probability of the recovery of the CA1 population spike after hypoxia and NMDA (50 μM). The results suggest an involvement of calcium channels especially of N-type in the genesis of hypoxic but not NMDA neuronal injury.

Effects of non-opioid antitussives on hypoxia-induced electrical changes in rat hippocampal slices: A comparative study with anticonvulsant drugs

1. 1. The effects of the non-opioid antitussives caramiphen and carbetapentane and of the anticonvulsants 5,5-diphenylhydantoin and MK 801 were tested towards hypoxia-induced electrical changes in rat hippocampal slices. 2. 2. The incidence of appearance of hypoxia-induced epileptiform bursting was significantly decreased ( P < 0.05) by carbetapentane (50–100 μM), caramiphen (50–100 μM), 5,5-diphenylhydantoin (25–50 μM), and the glutamate antagonist dizocilpine (MK 801, 25–50 μM). 3. 3. The incidence of reappearance of the CA1 population spike after hypoxia was significantly increased ( P < 0.05) by carbentapentane (50–100 μM), caramiphen (50–100 μM), 5,5-diphenylhydantoin (25–50 μM), and MK 801 (25–50 μM). 4. 4. The results suggest a useful role for non-opioid antitussives and some anticonvulsants in the treatment of hypoxia-induced functional disturbances.

Protection from hypoxic and N-methyl-D-aspartate injury with azelastine, a leukotriene inhibitor

The 5-lipoxygenase metabolites, leukotrienes, increase in concentration during cerebral ischemia. Azelastine is a new anti-allergic agent which inhibits leukotriene C 4 synthesis and release. We examined the neuroprotective properties of azelastine using the hippocampal slice. Azelastine 15 μM significantly protected CA1 evoked responses from hypoxic injury, with CA1 population spike amplitude recovering to a mean 76 ± 13% in azelastine treated slices, compared to 4 ± 3% recovery in paired unmedicated slices. The EC 50 for this azelastine hypoxic protection was 9.8 μM. Azelastine additionally protected against injury induced by N-methyl-D-aspartate (NMDA), but not non-NMDA glutamate receptor agonists. No hypoxic protection was afforded by diphenhydramine 50 μM, suggesting that azelastine protection did not occur through histamine H 1 receptor blockade. The finding of protection with azelastine against hypoxic and NMDA-induced injury suggests that leukotriene production is a common pathway in these forms of neuronal injury, and that leukotriene inhibition may be a useful neuroprotective strategy.

Adenosine release is a major cause of failure of synaptic transmission during hypoglycaemia in rat hippocampal slices

Glucose-free medium (aglycaemia) caused a complete failure of CA1 population spikes (after 14.5 ± 0.8 min) and field EPSPs (after 18.1 ± 0.5 min). In the presence of the selective adenosine Al antagonist, 8-( p-sulfophenyl)theophylline (10 μM), population spikes and EPSPs were decreased by only 13.8 ± 11.9% and 32.4 ± 11.6% at the end of 17.0 ± 3.0 min and 19.8 ± 1.7 min of aglycaemia, respectively. A similar effect was produced by caffeine (0.2 mM). The ATP-sensitive K + channel blockers tolbutamide (1 mM) and glibenclamide (10 μM) had no significant effect on aglycaemic suppression of synaptic transmission. These observations indicate that endogenous adenosine, but not ATP-sensitive K + conductance, plays a major role in hypoglycaemia failure of transmission.

Neurotoxic Effects of Sodium Nitroprusside in Rat Hippocampal Slices

To investigate the possible role of nitric oxide (NO) in n -methyl-d-aspartate (NMDA)-induced neurotoxicity we examined the effects of sodium nitroprusside (SNP) in rat hippocampal slices. Incubation with 3 mM SNP for up to 2 h produced neuronal damage characterized by "nuclear ballooning" in CA3 and CA1 pyramidal neurons and interneurons. The nuclear ballooning was not blocked by lowering the external calcium concentration or coincubation with MK-801 and/or 6,7-dinitro-quinoxaline-2,3-dione. Two lines of evidence suggest that the SNP neurotoxicity is not mediated by NO. First, inactivation of SNP by UV light failed to prevent the nuclear ballooning. Second, the toxicity was not attenuated by coadministration of hemoglobin. Although cyanide can be released from SNP, potassium cyanide did not mimic the nuclear ballooning. In electrophysiological experiments, 100 μM SNP irreversibly diminished the CA1 population spike amplitude while having less effect on the field excitatory postsynaptic potential. The effect of SNP on population spikes was inhibited by hemoglobin and was not mimicked by light-inactivated SNP. These results suggest that active SNP and light-treated SNP have different effects on hippocampal neurons and that SNP induces damage that differs from that produced by NMDA or cyanide.

3-amino-2-(4-chlorophenyl)-nitropropane is a new GABA B receptor agonist, more active peripherally

The activity of the nitropropane analog of baclofen, 3-amino-2-(4-chlorophenyl)-nitropropane (N-BAC), has been examined at central and peripheral GABA B receptors. N-BAC was less potent than baclofen as a GABA B receptor agonist in depressing repetitive twitch contractions in the guinea-pig isolated ileum (IC 50s for baclofen = 4.1 ± 1.3 μM; N-BAC = 9.2 ± 0.3 μM) and vas deferens (IC 50s for baclofen = 30 μM; N-BAC = 100 μM), competitively antagonished by phaclofen, 2-hydroxysaclofen and CGP 35348 (3-aminopropyl-P-di-ethoxymethylphosphinic acid). In the ileum, the pA 2 values for CGP 35348 with baclofen (4.7 ± 0.2) and N-BAC (4.6 ± 0.3) were not significantly different (P > 0.05), indicating that both agonists activate the same receptor type. By contrast, in rat neocortical slices, N-BAC was 20 times weaker than baclofen in attenuating spontaneous discharges, sensitive to CGP 35348, whilst it was 100 times less potent than baclofen in depressing evoked CA1 population spikes in the hippocampus. This new GABA B receptor agonist, N-BAC, is thus more active at peripheral than central GABA B receptors.

Protective actions of 21-aminosteroids and MK-801 on hypoxia-induced electrophysiological changes in rat hippocampal slices

The effects of the 21-aminosteroids, U-74500A and U-78517F (drugs endowed with lipid peroxidation inhibitor properties) were tested on hypoxia-induced functional failure in rat hippocampal slices. For comparison, the effects of the non-competitive N-methyl-D-aspartate antagonist, dizocilpine (MK-801) were studied. Perfusion of slices with 50 μM of MK-801 or with 50–100 μM of U-78517F, but not with 100–200 μM of U-74500A, significantly (P<0.01) increased the incidence of reappearance of the CA1 population spikes after reoxygenation in rat hippocampal slices subjected to a 45-min hypoxic period followed by a 45-min reoxygenation period. Perfusion of slices with 12.5 μM of MK-801 plus 12.5 μM of U-78517F significantly (P<0.05) increased the incidence of reappearance of the CA1 population spikes after reoxygenation with respect to perfusion of slices with 12.5 μM of U-78517F alone or with 12.5 μM of MK-801 alone. The results show that 21-aminosteroids have protective effects against hypoxia-induced functional failure in rat hippocampal slices. In addition, the data show that, under the same experimental conditions, the NMDA receptor antagonist, MK-801, was also able to improve hypoxia-induced functional failure. On the whole, the results suggest that the hypoxia-induced functional electrical failure might depend on both release of excitatory amino acids and oxygen free-radical-mediated membrane lipid peroxidation.

Comparison of 5 alpha-pregnan-3 alpha-ol-20-one and phenobarbital on cortical synaptic activation and inhibition studied in vitro.

The effects of 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha-OH-DHP) and phenobarbital (PB) on synaptic excitation and inhibition in rat hippocampal slices in vitro were compared. Stimulations were made orthodromically and antidromically while we recorded extracellularly from the dendritic and the somatic layer of the CA1 region. Perfusion with 5 micrograms/ml of 3 alpha-OH-DHP for 30 min significantly increased the recurrent inhibition evoked by antidromic stimulation. The effect was most pronounced at short interstimulus intervals. The duration of the recurrent inhibition also was prolonged. There was no effect on the conditioned population spike after orthodromic paired-pulse stimulation. Furthermore, no effect was observed on the amplitude of the orthodromic fiber volley, the rate of increase in the field excitatory postsynaptic potential (EPSP) and the latency and amplitude of the CA1 population spike. Qualitative and quantitative similar findings were observed during perfusion with PB 0.1 mg/ml, (i.e., a concentration 20 times higher than that of 3 alpha-OH-DHP). Higher concentrations of PB also affected synaptic excitation. The findings suggest a similar effect of 3 alpha-OH-DHP and PB on recurrent GABA-ergic inhibition; however, 3 alpha-OH-DHP appears to be much more potent.

The neurotoxicity of sulfur-containing amino acids in energy-deprived rat hippocampal slices

The rat hippocampal slice preparation and its electrophysiology were used to assess the toxicity of two sulfur-containing amino acids, L-cysteate (CA) and L-cysteine (CYS). Both compounds were innocuous under normal conditions but became toxic in energy-deprived (lack of oxygen or glucose) slices. CA and CYS toxicity was apparent as both reduced the number of slices that normally recover their neuronal function (evoked CA1 population spike) after a standardized period of hypoxia or glucose deprivation (GD). The competitive N-methyl-D-aspartate (NMDA) antagonist DL-2-amino-5-phosphonovalerate blocked the toxicity of both CA and CYS in hypoxic slices, but it was effective only against CYS toxicity in glucose-deprived slices. The glycine antagonist 7-chlorokynurenate blocked CA and CYS toxicity in hypoxic slices but was unable to block their toxicity in glucose-deprived tissue. Perfusing slices with medium containing a high magnesium concentration blocked the toxicity of CA in both hypoxic and glucose-deprived slices, a treatment that was ineffective against CYS toxicity under either condition. Calcium depletion from the perfusion medium completely blocked the damaging effect of both amino acids in hypoxic slices, but it only partially blocked the toxicity of CA and did not block that of CYS in glucose-deprived slices. These results suggest that CA and CYS activate different NMDA receptor subsets and other glutamate receptor subtypes. Moreover, the results indicate a possible difference between the mechanism that lead to hypoxic neuronal damage and the one that lead to hypoglycemic neuronal damage.

Effects of calcium and paired-pulse stimulation on hypoxia-induced hippocampal electrical changes

The influence of calcium concentration changes (2 and 4 mM) and of the paired-pulse stimulation (PPS) paradigm on the effects of hypoxia has been investigated in rat hippocampal slices. Because a high calcium concentration (4 mM) facilitates paired-pulse inhibition (PPI) at a 15-ms interpulse interval, the influence of hypoxia-induced effects were tested against calcium-induced PPI. In the PPS, unconditioned response at calcium concentrations of 2 and 4 mM, and 15- or 30-ms interpulse intervals of stimulation, no significant differences were found in the latency to induce a 50% amplitude decrease of the CA1 population spikes during hypoxia. On the contrary, in the conditioned response the latency to induce a 50% amplitude decrease of CA1 population spikes was significantly increased ( p < 0.01) at 4 mM calcium, 15-ms interpulse interval with respect to experiments with 2 mM calcium, at 15- or 30-ms interpulse intervals. The data indicate that PPI is strongly affected during the early phases of hypoxia and also suggest that drugs increasing PPI could be successfully used for the treatment of brief anoxic or ischemic functional alterations.

Ontogeny of hippocampal afterdischarges in the urethane-anesthetized rat

Experimental studies have shown that seizure manifestations vary as the brain develops. This study investigated the characteristics of afterdischarges in the hippocampal circuits at various ages in the developing rat. Rats from the following post-natal periods were tested: PN 10–11, PN 14–15, PN 17–19, PN 21–23 and PN 25–27. Animals were anesthetized with urethane and recording electrodes placed in the hippocampus bilaterally. Stimulating electrodes were placed in the left CA3 region and in the angular bundle. Afterdischarges were produced in all animals using stimulus trains of 20 or 50 Hz. Rats in the PN 10–11 and 14–15 age groups had afterdischarges that consisted of population spikes in CA1 and broad positive potentials in the dentate gyrus. Between PN 17 and 19, maximal dentate activation, which consists of bursts of large amplitude population spikes in the dentate gyrus, first appeared in response to 20 Hz stimulation to CA3 or either 20 or 50 Hz stimulation to the angular bundle. Rats older than 21 days had afterdischarge patterns like those recorded in the adult. These data indicate that, in the rat, the seizure capabilities of the limbic circuits go through a major transition period around PN 17–19. The appearance of maximal dentate activation marks the ability of the developing rat brain to produce and sustain reverberatory seizure discharges.