Mechanisms of Neuronal Hyperexcitability Caused by Partial Inhibition of Na+-K+-ATPases in the Rat CA1 Hippocampal Region

2002 ◽  
Vol 88 (6) ◽  
pp. 2963-2978 ◽  
Author(s):  
Cyrille Vaillend ◽  
Susanne E. Mason ◽  
Matthew F. Cuttle ◽  
Bradley E. Alger
Keyword(s):  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Burst Firing ◽  
Membrane Properties ◽  
Initial Slope ◽  
Excitatory Postsynaptic Potential ◽  
Neuronal Hyperexcitability ◽  
Partial Inhibition ◽  
Postsynaptic Potential ◽  
Bursting Activity

Extra- and intracellular records were made from rat acute hippocampal slices to examine the effects of partial inhibition of Na+-K+-ATPases (Na+-K+pumps) on neuronal hyperexcitability. Bath application of the low-affinity cardiac glycoside, dihydroouabain (DHO), reversibly induced interictal-like epileptiform bursting activity in the CA1 region. Burst-firing was correlated with inhibition of the pumps, which was assayed by changes in [K+]ouptake rates measured with K+-ion-sensitive microelectrodes. Large increases in resting [K+]odid not occur. DHO induced a transient depolarization (5–6 mV) followed by a long-lasting hyperpolarization (∼6 mV) in CA1 pyramidal neurons, which was accompanied by a 30% decrease in resting input resistance. Block of an electrogenic pump current could explain the depolarization but not the hyperpolarization of the membrane. Increasing [K+]ofrom 3 to 5.5 mM minimized these transient shifts in passive membrane properties without preventing DHO-induced hyperexcitability. DHO decreased synaptic transmission, but increased the coupling between excitatory postsynaptic potentials and spike firing (E-S coupling). Monosynaptic inhibitory postsynaptic potential (IPSP) amplitudes declined to ∼25% of control at the peak of bursting activity; however, miniature TTX-resistant inhibitory postsynaptic current amplitudes were unaffected. DHO also reduced the initial slope of the intracellular excitatory postsynaptic potential (EPSP) to ∼40% of control. The conductances of pharmacologically isolated IPSPs and EPSPs in high-Ca/high-Mg-containing saline were also reduced by DHO by ∼50%. The extracellular fiber volley amplitude was reduced by 15–20%, suggesting that the decrease in neurotransmission was partly due to a reduction in presynaptic fiber excitability. DHO enhanced a late depolarizing potential that was superimposed on the EPSP and could obscure it. This potential was not blocked by antagonists of NMDA receptors, and blockade of NMDA, mGlu, or GABAAreceptors did not affect burst firing. The late depolarizing component enabled the pyramidal cells to reach spike threshold without changing the actual voltage threshold for firing. We conclude that reduced GABAergic potentials and enhanced E-S coupling are the primary mechanisms underlying the hyperexcitability associated with impaired Na+-K+pump activity.

Abnormal neuronal excitability in hippocampal slices from kindled rats

1985 ◽  
Vol 54 (5) ◽  
pp. 1295-1304 ◽  
Author(s):  
G. L. King ◽  
R. Dingledine ◽  
J. L. Giacchino ◽  
J. O. McNamara
Keyword(s):  
Dentate Gyrus ◽  
Hippocampal Slices ◽  
Burst Firing ◽  
Population Spike ◽  
Excitatory Postsynaptic Potential ◽  
Paired Pulse ◽  
Ca1 Region ◽  
Postsynaptic Potential ◽  
Kindled Seizures ◽  
Near Threshold

To determine if electrophysiological properties of hippocampal pathways are altered in kindled rats, extracellular recordings were made from hippocampal slices of rats kindled in the lateral entorhinal cortex and compared with those from implanted but unstimulated controls. Studies were made either 24 h or 28 days after the last kindled seizure and done in normal (3.5 mM) or elevated (7 mM) K+. The preparation of slices, data accumulation, and data analyses were done blind. One day or 28 days after the last kindled seizure, the proportion of slices with spontaneous epileptiform bursts recorded from the CA2/3 region in elevated K+ was significantly (P less than 0.001) increased in the kindled animals. The frequency of spontaneous burst firing was also increased and reached significance (P less than 0.02) at 28 days following the last kindling stimulus. One day after the last kindling stimulus, paired-pulse (GABAergic) inhibition in the CA1 region was decreased (P less than 0.001). Several measures suggested an increased synaptic inhibition in the dentate gyrus of slices from the kindled groups 1 day after kindling. Paired-pulse inhibition was increased (P less than 0.01), the current required to evoke a near-threshold population spike was increased (P less than 0.05), and the population spike amplitude was reduced for a given field excitatory postsynaptic potential (EPSP) (P less than 0.01). Twenty-eight days after the last kindling stimulus, however, paired-pulse inhibition in the dentate was slightly less in slices from kindled rats (P less than 0.005). In other respects the CA1 and dentate regions did not differ between kindled and control groups within 24 h of the last stage V seizure. Thus the maximum amplitudes of presynaptic fiber volley, population spike, and field-excitatory postsynaptic potential (EPSP) slope, and the number of population spikes evoked by a near-maximally effective afferent stimulus, were unchanged. In the CA1 region the input-output curve of field EPSP versus population spike, and the current intensity required to evoke a near-threshold population spike were also unchanged. In addition, no spontaneous bursts were recorded from CA1 in 3.5 mM K+. We conclude that either synapses or neurons intrinsic to the hippocampus are altered by kindling stimuli applied outside this brain area. The transient increase in inhibition in the dentate gyrus suggests that it may reflect a compensatory reaction to kindled seizures. In contrast, the long-lasting (at least 28 days) increase in burst firing in CA2/3 may represent a mechanism for the initiation or propagation of kindled seizures.(ABSTRACT TRUNCATED AT 400 WORDS)

Increased Pyramidal Excitability and NMDA Conductance Can Explain Posttraumatic Epileptogenesis Without Disinhibition: A Model

1999 ◽  
Vol 82 (4) ◽  
pp. 1748-1758 ◽  
Author(s):  
Paul C. Bush ◽  
David A. Prince ◽  
Kenneth D. Miller
Keyword(s):  
Experimental Data ◽  
Pyramidal Neurons ◽  
Rapid Development ◽  
Pyramidal Cells ◽  
Membrane Properties ◽  
Excitatory Postsynaptic Potential ◽  
Physiological Basis ◽  
Postsynaptic Potential ◽  
Layer V ◽  
Epileptiform Events

Partially isolated cortical islands prepared in vivo become epileptogenic within weeks of the injury. In this model of chronic epileptogenesis, recordings from cortical slices cut through the injured area and maintained in vitro often show evoked, long- and variable-latency multiphasic epileptiform field potentials that also can occur spontaneously. These events are initiated in layer V and are synchronous with polyphasic long-duration excitatory and inhibitory potentials (currents) in neurons that may last several hundred milliseconds. Stimuli that are significantly above threshold for triggering these epileptiform events evoke only a single large excitatory postsynaptic potential (EPSP) followed by an inhibitory postsynaptic potential (IPSP). We investigated the physiological basis of these events using simulations of a layer V network consisting of 500 compartmental model neurons, including 400 principal (excitatory) and 100 inhibitory cells. Epileptiform events occurred in response to a stimulus when sufficient N-methyl-d-aspartate (NMDA) conductance was activated by feedback excitatory activity among pyramidal cells. In control simulations, this activity was prevented by the rapid development of IPSPs. One manipulation that could give rise to epileptogenesis was an increase in the threshold of inhibitory interneurons. However, previous experimental data from layer V pyramidal neurons of these chronic epileptogenic lesions indicate: upregulation, rather than downregulation, of inhibition; alterations in the intrinsic properties of pyramidal cells that would tend to make them more excitable; and sprouting of their intracortical axons and increased numbers of presumed synaptic contacts, which would increase recurrent EPSPs from one cell onto another. Consistent with this, we found that increasing the excitability of pyramidal cells and the strength of NMDA conductances, in the face of either unaltered or increased inhibition, resulted in generation of epileptiform activity that had characteristics similar to those of the experimental data. Thus epileptogenesis such as occurs after chronic cortical injury can result from alterations of intrinsic membrane properties of pyramidal neurons together with enhanced NMDA synaptic conductances.

Characterization of synaptically mediated fast and slow inhibitory processes in piriform cortex in an in vitro slice preparation

1988 ◽  
Vol 59 (5) ◽  
pp. 1352-1376 ◽  
Author(s):  
G. F. Tseng ◽  
L. B. Haberly
Keyword(s):  
Membrane Potential ◽  
Piriform Cortex ◽  
Reversal Potential ◽  
Pyramidal Cells ◽  
Membrane Depolarization ◽  
Resting Membrane Potential ◽  
Excitatory Postsynaptic Potential ◽  
Pentobarbital Sodium ◽  
Postsynaptic Potential ◽  
Conductance Increase

1. Intracellular recordings were obtained from anatomically verified layer II pyramidal cells in slices from rat piriform cortex cut perpendicular to the surface. 2. Responses to afferent and association fiber stimulation at resting membrane potential consisted of a depolarizing potential followed by a late hyperpolarizing potential (LHP). Membrane polarization by current injection revealed two components in the depolarizing potential: an initial excitatory postsynaptic potential (EPSP) followed at brief latency by an inhibitory postsynaptic potential (IPSP) that inverted with membrane depolarization and truncated the duration of the EPSP. 3. The early IPSP displayed the following characteristics suggesting mediation by gamma-aminobutyric acid (GABA) receptors linked to Cl- channels: associated conductance increase, sensitivity to increases in internal Cl- concentration, blockage by picrotoxin and bicuculline, and potentiation by pentobarbital sodium. The reversal potential was in the depolarizing direction with respect to resting membrane potential so that the inhibitory effect was exclusively via current shunting. 4. The LHP had an associated conductance increase and a reversal potential of -90 mV in normal bathing medium that shifted according to Nernst predictions for a K+ potential with changes in external K+ over the range 4.5-8 mM indicating mediation by the opening of K+ channels and ruling out an electrogenic pump origin. 5. Lack of effect of bath-applied 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) or internally applied ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) on the LHP and failure of high amplitude, direct membrane depolarization to evoke a comparable potential, argue against endogenous mediation of the LHP by a Ca2+ activated K+ conductance [gK(Ca)]. However, an apparent endogenously mediated gK(Ca) with a duration much greater than the LHP was observed in a low percent of layer II pyramidal cells. Lack of effect of 8-Br-cAMP also indicates a lack of dependence of the LHP on cAMP. 6. Other characteristics of the LHP that were demonstrated include: a lack of blockage by GABAA receptor antagonists, a probable voltage sensitivity (decrease in amplitude in the depolarizing direction), and an apparent brief onset latency (less than 10 ms) when the early IPSP was blocked by picrotoxin. The LHP was unaffected by pentobarbital sodium when the early IPSP was blocked by picrotoxin. 7. Both the LHP and early IPSP were blocked by low Ca2+/high Mg2+, consistent with disynaptic mediation.(ABSTRACT TRUNCATED AT 400 WORDS)

Osmotic effects on the CA1 neuronal population in hippocampal slices with special reference to glucose

1991 ◽  
Vol 65 (5) ◽  
pp. 1055-1066 ◽  
Author(s):  
B. A. Ballyk ◽  
S. J. Quackenbush ◽  
R. D. Andrew
Keyword(s):  
Action Potential ◽  
Single Cell ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Stratum Radiatum ◽  
Resting Potential ◽  
Excitatory Postsynaptic Potential ◽  
Stratum Pyramidale ◽  
Postsynaptic Potential ◽  
Axonal Excitability

1. Lowered osmolality promotes epileptiform activity both clinically and in the hippocampal slice preparation, but it is unclear how neurons are excited. We studied the effects of altered osmolality on the electrophysiological properties of CA1 pyramidal cells in hippocampal slices by the use of field and intracellular recordings. The excitability of these neurons under various osmotic conditions was gauged by population spike (PS) amplitude, single cell properties, and evoked synaptic input. 2. The orthodromic PS recorded in stratum pyramidale and the field excitatory postsynaptic potential (EPSP) in stratum radiatum were inversely proportional in amplitude to the artificial cerebrospinal fluid (ACSF) osmolality over a range of +/- 80 milliosmoles/kgH2O (mosM). The effect was osmotic because changes occurred within the time frame expected for cellular expansion or shrinkage and because permeable substances such as dimethyl sulfoxide or glycerol were without effect. Dilutional changes in ACSF constituents were experimentally ruled out as promoting excitability. 3. To test whether the field data resulted from a change in single-cell excitability, CA1 cells were intracellularly recorded during exposure to +/- 40 mosM ACSF over 15 min. There was no consistent effect upon CA1 resting potential, cell input resistance, or action potential threshold. 4. Osmotic alteration of orthodromic and antidromic field potentials might involve a change in axonal excitability. However, the evoked afferent volley recorded in CA1 stratum pyramidale or radiatum, which represents the compound action potential (CAP) generated in presynaptic axons, remained osmotically unresponsive with regard to amplitude, duration, or latency. This was also characteristic of CAPs evoked in isolated sciatic and vagus nerve preparations exposed to +/- 80 mosM. Therefore axonal excitability and associated extracellular current flow generated periaxonally are not significantly affected by osmotic shifts. 5. The osmotic effect on field potential amplitudes appeared to be independent of synaptic transmission because the inverse relationship with osmolality held for the antidromically evoked PS. Moreover, as recorded with respect to ground, the intracellular EPSP-inhibitory postsynaptic potential (IPSP) sequence (evoked from CA3 stratum radiatum) was not altered by osmolality. 6. The PS could occasionally be recorded intracellularly as a brief negativity interrupting the evoked EPSP. In hyposmotic ACSF, the amplitude increased and action potentials arose from the trough of the negativity as expected for a field effect. This is presumably the result of enhanced intracellular channeling of current caused by the increased extracellular resistance that accompanies cellular swelling.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Intracellular and Computational Characterization of the Intracortical Inhibitory Control of Synchronized Thalamic Inputs In Vivo

1997 ◽  
Vol 78 (1) ◽  
pp. 335-350 ◽  
Author(s):  
Diego Contreras ◽  
Alain Destexhe ◽  
Mircea Steriade
Keyword(s):  
Inhibitory Control ◽  
Computational Models ◽  
Pyramidal Cells ◽  
Excitatory Postsynaptic Potential ◽  
Thalamic Stimulation ◽  
Postsynaptic Potential ◽  
Spike Wave

Contreras, Diego, Alain Destexhe, and Mircea Steriade. Intracellular and computational characterization of the intracortical inhibitory control of synchronized thalamic inputs in vivo. J. Neurophysiol. 78: 335–350, 1997. We investigated the presence and role of local inhibitory cortical control over synchronized thalamic inputs during spindle oscillations (7–14 Hz) by combining intracellular recordings of pyramidal cells in barbiturate-anesthetized cats and computational models. The recordings showed that 1) similar excitatory postsynaptic potential (EPSP)/inhibitory postsynaptic potential (IPSP) sequences occurred either during spindles or following thalamic stimulation; 2) reversed IPSPs with chloride-filled pipettes transformed spindle-related EPSP/IPSP sequences into robust bursts with spike inactivation, resembling paroxysmal depolarizing shifts during seizures; and 3) dual simultaneous impalements showed that inhibition associated with synchronized thalamic inputs is local. Computational models were based on reconstructed pyramidal cells constrained by recordings from the same cells. These models showed that the transformation of EPSP/IPSP sequences into fully developed spike bursts critically needs a relatively high density of inhibitory currents in the soma and proximal dendrites. In addition, models predict significant Ca2+ transients in dendrites due to synchronized thalamic inputs. We conclude that synchronized thalamic inputs are subject to strong inhibitory control within the cortex and propose that 1) local impairment of inhibition contributes to the transformation of spindles into spike-wave-type discharges, and 2) spindle-related inputs trigger Ca2+ events in cortical dendrites that may subserve plasticity phenomena during sleep.

Extracellular Magnesium Ion Modifies the Actions of Volatile Anesthetics in Area CA1 of Rat Hippocampus In Vitro 

2002 ◽  
Vol 96 (3) ◽  
pp. 681-687 ◽  
Author(s):  
Rika Sasaki ◽  
Koki Hirota ◽  
Sheldon H. Roth ◽  
Mitsuaki Yamazaki
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Hippocampal Slices ◽  
Volatile Anesthetics ◽  
Population Spike ◽  
Magnesium Ion ◽  
Excitatory Postsynaptic Potential ◽  
Aspartate Receptor ◽  
Postsynaptic Potential

Background Magnesium ion (Mg2+) is involved in important processes as modulation of ion channels, receptors, neurotransmitter release, and cell excitability in the central nervous system. Although extracellular Mg2+ concentration ([Mg2+]o) can be altered during general anesthesia, there has been no evidence for [Mg2+]o-dependent modification of anesthetic actions on neural excitability in central nervous system preparations. The purpose of current study was to determine whether the effects of volatile anesthetics are [Mg2+]o-dependent in mammalian central nervous system. Methods Extracellular electrophysiologic recordings from CA1 neurons in rat hippocampal slices were used to investigate the effects of [Mg2+]o and anesthetics on population spike amplitude and excitatory postsynaptic potential slope. Results The depression of population spike amplitudes and excitatory postsynaptic potential slopes by volatile anesthetics were significantly dependent on [Mg2+]o. The effects were attenuated in the presence of a constant [Mg2+]o/extracellular Ca2+ concentration ratio. However, neither N-methyl-d-aspartate receptor antagonists nor a non-N-methyl-d-aspartate receptor antagonist altered the [Mg2+]o-dependent anesthetic-induced depression of population spikes. Volatile anesthetics produced minimal effects on input-output (excitatory postsynaptic potential-population spike) relations or the threshold for population spike generation. The effects were not modified by changes in [Mg2+]o. In addition, the population spike amplitudes, elicited via antidromic (nonsynaptic) stimulation, were not influenced by [Mg2+]o in the presence of volatile anesthetics. Conclusions These results provide support that alteration of [Mg2+]o modifies the actions of volatile anesthetics on synaptic transmission and that the effects could be, at least in part, a result of presynaptic Ca2+ channel-related mechanisms.

Role of EPSPs in initiation of spontaneous synchronized burst firing in rat hippocampal neurons bathed in high potassium

1990 ◽  
Vol 64 (3) ◽  
pp. 1000-1008 ◽  
Author(s):  
N. L. Chamberlin ◽  
R. D. Traub ◽  
R. Dingledine
Keyword(s):  
Hippocampal Neurons ◽  
Pyramidal Neurons ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Burst Firing ◽  
Interictal Spikes ◽  
High Potassium ◽  
Synaptic Excitation ◽  
Ca3 Neurons

1. Spontaneous discharges that resemble interictal spikes arise in area CA3 b/c of rat hippocampal slices bathed in 8.5 mM [K+]o. Excitatory postsynaptic potentials (EPSPs) also appear at irregular intervals in these cells. The role of local synaptic excitation in burst initiation was examined with intracellular and extracellular recordings from CA3 pyramidal neurons. 2. Most (70%) EPSPs were small (less than 2 mV in amplitude), suggesting that they were the product of quantal release or were evoked by a single presynaptic action potential in another cell. It is unlikely that most EPSPs were evoked by a presynaptic burst of action potentials. Indeed, intrinsic burst firing was not prominent in CA3 b/c pyramidal cells perfused in 8.5 mM [K+]o. 3. The likelihood of occurrence and the amplitude of EPSPs were higher in the 50-ms interval just before the onset of each burst than during a similar interval 250 ms before the burst. This likely reflects increased firing probability of CA3 neurons as they emerge from the afterhyperpolarization (AHP) and conductance shunt associated with the previous burst. 4. Perfusion with 2 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a potent quisqualate receptor antagonist, decreased the frequency of EPSPs in CA3 b/c neurons from 3.6 +/- 0.9 to 0.9 +/- 0.3 (SE) Hz. Likewise, CNQX reversibly reduced the amplitude of evoked EPSPs in CA3 b/c cells. 5. Spontaneous burst firing in 8.5 mM [K+]o was abolished in 11 of 31 slices perfused with 2 microM CNQX.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuropeptide Y5 Receptors Reduce Synaptic Excitation in Proximal Subiculum, But Not Epileptiform Activity in Rat Hippocampal Slices

2000 ◽  
Vol 83 (2) ◽  
pp. 723-734 ◽  
Author(s):  
Melisa W. Y. Ho ◽  
Annette G. Beck-Sickinger ◽  
William F. Colmers
Keyword(s):  
In Vitro Model ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Membrane Properties ◽  
Stratum Radiatum ◽  
Synaptic Excitation ◽  
Vitro Model ◽  
Area Ca3

Neuropeptide Y (NPY) potently inhibits excitatory synaptic transmission in the hippocampus, acting predominantly via a presynaptic Y2 receptor. Recent reports that the Y5 receptor may mediate the anticonvulsant actions of NPY in vivo prompted us to test the hypothesis that Y5receptors inhibit synaptic excitation in the hippocampal slice and, furthermore, that they are effective in an in vitro model of anticonvulsant action. Two putative Y5 receptor–preferring agonists inhibited excitatory postsynaptic currents (EPSCs) evoked by stimulation of stratum radiatum in pyramidal cells. We recorded initially from area CA1 pyramidal cells, but subsequently switched to cells from the subiculum, where a much greater frequency of response was observed to Y5 agonist application. Bothd-Trp32NPY (1 μM) and [ahx8–20]Pro34NPY (3 μM), a centrally truncated, Y1/Y5 agonist we synthesized, inhibited stimulus-evoked EPSCs in subicular pyramidal cells by 44.0 ± 5.7% and 51.3 ± 3.5% (mean ± SE), in 37 and 58% of cells, respectively. By contrast, the less selective centrally truncated agonist, [ahx8–20] NPY (1 μM), was more potent (66.4 ± 4.1% inhibition) and more widely effective, suppressing the EPSC in 86% of subicular neurons. The site of action of all NPY agonists tested was most probably presynaptic, because agonist application caused no changes in postsynaptic membrane properties. The selective Y1 antagonist, BIBP3226 (1 μM), did not reduce the effect of either more selective agonist, indicating that they activated presynaptic Y5 receptors. Y5 receptor–mediated synaptic inhibition was more frequently observed in slices from younger animals, whereas the nonselective agonist appeared equally effective at all ages tested. Because of the similarity with the previously reported actions of Y2 receptors, we tested the ability of Y5receptor agonists to suppress stimulus train-induced bursting (STIB), an in vitro model of ictaform activity, in both area CA3 and the subiculum. Neither [ahx8–20]Pro34NPY nord-Trp32NPY were significantly effective in suppressing or shortening STIB-induced afterdischarge, with <20% of slices responding to these agonists in recordings from CA3 and none in subiculum. By contrast, 1 μM each of [ahx8–20]NPY, the Y2 agonist, [ahx5–24]NPY, and particularly NPY itself suppressed the afterdischarge in area CA3 and the subiculum, as reported earlier. We conclude that Y5receptors appear to regulate excitability to some degree in the subiculum of young rats, but their contribution is relatively small compared with those of Y2 receptors, declines with age, and is insufficient to block or significantly attenuate STIB-induced afterdischarges.

Effects of low concentrations of 4-aminopyridine on CA1 pyramidal cells of the hippocampus

1989 ◽  
Vol 61 (5) ◽  
pp. 953-970 ◽  
Author(s):  
P. Perreault ◽  
M. Avoli
Keyword(s):  
High Frequency ◽  
Hippocampal Slices ◽  
Extracellular Recording ◽  
Pyramidal Cells ◽  
Input Resistance ◽  
Peak Latency ◽  
Excitatory Postsynaptic Potential ◽  
Average Value ◽  
Bath Application

1. Intracellular and extracellular recording techniques were used to study the effects of bath application of 4-aminopyridine (4-AP) on pyramidal cells of the CA1 subfield of rat hippocampal slices maintained in vitro. The concentration of 4-AP used in most experiments was 50 microM. However, similar results were obtained with a concentration ranging from 5 to 100 microM. 2. Following 4-AP application, cells impaled with K-acetate-filled microelectrodes hyperpolarized by an average of 2.6 mV (from -68.7 to -71.3 mV, P less than or equal to 0.01). This change was accompanied by the appearance of high-frequency spontaneous hyperpolarizations. Conversely, when KCl-filled microelectrodes were used, an average depolarization of 5.8 mV [from -73.1 to -67.3 mV, not significant (NS)] associated with the occurrence of repetitive depolarizing potentials was observed. In both cases, these changes were concomitant with a small decrease in membrane input resistance, which was statistically significant only for cells impaled with K-acetate-filled microelectrodes. When synaptic transmission was blocked by tetrodotoxin (TTX), 4-AP induced in cells studied with K-acetate microelectrodes an average depolarization of 2.4 mV (from -62.8 to -60.4 mV, P less than or equal to 0.01) accompanied by a small increase in input resistance (from 32.0 to 35.8 M omega, P less than or equal to 0.05). High-frequency spontaneous potentials failed to occur under these conditions. During 4-AP application, the threshold and the latency of action potentials elicited by a depolarizing current pulse increased in 36% of the neurons studied (n = 14). 3. The amplitude of the stratum (s.) radiatum-induced excitatory postsynaptic potential (EPSP) was augmented by 4-AP. Both the early and late inhibitory postsynaptic potentials (IPSPs) evoked by orthodromic stimuli were also increased in amplitude and duration. In addition, a late (peak latency, 150-600 ms) and long-lasting (duration, 600-1,500 ms) depolarizing potential appeared between the early and the late IPSPs and progressively increased until it partially masked these hyperpolarizations. This long-lasting depolarization (LLD) could also be induced by antidromic stimulation, although in this case it was preceded by an additional, fast-rising, brief depolarization. 4. A similar brief depolarization preceded the orthodromically induced LLD in 69% of the neurons bathed in the presence of 4-AP. The average value of the peak latency of this potential was 62 +/- 27 (SD) ms for orthodromic and 110 +/- 70 ms for antidromic responses.(ABSTRACT TRUNCATED AT 400 WORDS)

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