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M Avoli

Publications and source records attributed to M Avoli.

At least 19 recordsLinked to original sources
PubMed2000

Topiramate depresses carbachol-induced plateau potentials in subicular bursting cells.

Intracellular recordings were made in an in vitro slice preparation to establish whether the antiepileptic drug topiramate reduces the depolarizing plateau potentials (PPs) induced in the rat subiculum by intracellular pulses of depolarizing current, in the presence of the cholinergic agonist carbachol (CCh, 70-100 microM). PPs lasted up to about 2 s, and disappeared during application of the muscarinic receptor antagonist atropine. Topiramate (10-100 microM, n = 22 neurons) decreased and eventually abolished in a dose-dependent manner these PPs, even when the function of excitatory amino acid and GABAA receptors was blocked. Hence, topiramate depresses muscarinic receptor-dependent PPs in the rat subiculum, thus suggesting that this form of excitation may represent a target for the mechanism of action of this antiepileptic compound.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2000

CA3-released entorhinal seizures disclose dentate gyrus epileptogenicity and unmask a temporoammonic pathway.

We have investigated the propagation of epileptiform discharges induced by 4-aminopyridine (4-AP, 50 microM) in adult mouse hippocampus-entorhinal cortex slices, before and after Schaffer collateral cut. 4-AP application induced 1) ictal epileptiform activity that disappeared over time and 2) interictal epileptiform discharges, which continued throughout the experiment. Using simultaneous field potential and [K(+)](o) recordings, we found that entorhinal and dentate ictal epileptiform discharges were accompanied by comparable elevations in [K(+)](o) (up to 12 mM from a baseline value of 3.2 mM), whereas smaller rises in [K(+)](o) (up to 6 mM) were associated with ictal activity in CA3. Cutting the Schaffer collaterals disclosed the occurrence of ictal discharges that were associated with larger rises in [K(+)](o) as compared with the intact slice. Further lesion of the perforant path blocked ictal activity and the associated [K(+)](o) increases in the dentate gyrus, indicating synaptic propagation to this area. Time delay measurements demonstrated that ictal epileptiform activity in the intact hippocampal-entorhinal cortex slice propagated via the trisynaptic path. However, after Schaffer collateral cut, ictal discharges continued to occur in CA1 and subiculum and spread to these areas directly from the entorhinal cortex. Thus our data indicate that the increased epileptogenicity of the dentate gyrus (a prominent feature of temporal lobe epilepsy as well), may depend on perforant path propagation of entorhinal ictal discharges, irrespective of mossy fiber reorganization. Moreover, hippocampal neuronal damage that is acutely mimicked in our model by Schaffer collateral cut, may contribute to "short-circuit" propagation of activity by pathways that are masked when the hippocampus is intact.

4-Aminopyridine↗
PubMed2000

Hippocampus-entorhinal cortex loop and seizure generation in the young rodent limbic system.

Application of the convulsant 4-aminopyridine (4AP, 50 microM) to adult mouse combined hippocampus-entorhinal cortex (EC) slices induces interictal and ictal discharges originating from CA3 and EC respectively. In this model of limbic seizures, ictal discharges disappear over time and are reestablished after Schaffer collateral cut, a procedure that blocks interictal propagation from CA3 to EC. Here we tested whether this form of network plasticity is operant in hippocampus-EC slices obtained from young (10-25 day-old) mice. In these experiments 4AP elicited interictal (duration = 100-250 ms; interval = 0.7 +/- 0.2 s, mean +/- SD, n = 20) and ictal (duration = 267 +/- 37 s; interval = 390 +/- 37 s, n = 20) discharges in both CA3 and EC. However, in young mouse slices the ictal events occurred throughout the experiment, whereas Schaffer collateral cut abolished CA3-driven interictal discharges in EC without influencing ictal activity (n = 10). Perforant path lesion prevented the spread of EC-driven ictal events to CA3, where interictal and short ictal discharges (duration = 32 +/- 11 s; interval = 92 +/- 9.7 s, n = 8) continued to occur. Hence, two independent forms of ictal activity were seen in CA3 and in EC after separation of these structures. In intact hippocampus-EC slices, ictal discharges were reduced by an N-methyl-D-aspartate receptor antagonist (n = 10). Under these conditions, Schaffer collateral cut abolished ictal activity in EC, not in CA3 (n = 6). Thus the young mouse hippocampus-EC loop has different properties as compared with adult tissue. These differences, which include the inability of hippocampal outputs to control ictal discharge generation in EC and the ability of the loop to sustain ictal activity, may contribute to the low-seizure threshold seen in young individuals.

4-Aminopyridine↗
PubMed1999

Epileptiform discharges in the human dysplastic neocortex: in vitro physiology and pharmacology.

Field potential and intracellular recordings were made in slices of human neocortical tissue obtained during surgery for the treatment of seizures associated with focal cortical dysplasia. Ictal-like epileptiform discharges, along with isolated field potentials, were induced by bath application of 4-aminopyridine (50-100 microM). Some of the isolated field potentials were associated with fast transients representing population spikes. Field potential profile analysis indicated that both types of synchronous activity had maximal negative values at 1,400 to 1,600 microm from the pia. The intracellular counterpart of the ictal-like discharge was a prolonged membrane depolarization capped by repetitive action potential burst firing. By contrast, the isolated field potentials were mirrored by long-lasting depolarizations with minimal action potential firing; only when population spikes occurred, the isolated field potentials were associated with epileptiform action potential bursting. Ictal-like discharges were abolished by either N-methyl-D-aspartate or non-N-methyl-D-aspartate receptor antagonists. In contrast, the isolated field potentials continued to occur synchronously during excitatory transmission blockade (although they lacked fast transients) but were abolished by the gamma-aminobutyric acid(A) receptor antagonist bicuculline methiodide (n = 2 slices). Our study demonstrates that focal cortical dysplasia tissue maintained in vitro has an intrinsic ability to generate ictal-like epileptiform events when challenged with 4-aminopyridine. These discharges depend on excitatory amino acid receptor-mediated mechanisms. Our results also show the presence in focal cortical dysplasia tissue of glutamatergic-independent synchronous potentials that are mainly contributed by gamma-aminobutyric acid(A) receptor-mediated conductances.

4-Aminopyridine↗
PubMed1999

GABA(B) receptor activation promotes seizure activity in the juvenile rat hippocampus.

We analyzed how the GABA(B) receptor agonist baclofen (10-50 microM) influences the activity induced by 4-aminopyridine (4-AP, 50 microM) in the CA3 area of hippocampal slices obtained from 12- to 25-day-old rats. Interictal and ictal discharges along with synchronous GABA-mediated potentials occurred spontaneously in the presence of 4-AP. Baclofen abolished interictal activity (n = 29 slices) and either disclosed (n = 21/29) or prolonged ictal discharges (n = 8/29), whereas GABA-mediated potentials occurred at a decreased rate. The N-methyl-D-aspartate (NMDA) receptor antagonist 3,3-(2-carboxypiperazine-4-yl)-propyl-1-phosphate (CPP, 10 microM, n = 8) did not modify the GABA-mediated potentials or the ictal events recorded in 4-AP + baclofen. In contrast ictal, activity, but not GABA-mediated potentials, was blocked by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM, n = 5). Most baclofen effects were reversed by the GABA(B) receptor antagonist CGP 35348 (1 mM; n = 4). Baseline and transient increases in [K(+)](o) associated with the 4-AP-induced synchronous activity were unaffected by baclofen. Baclofen hyperpolarized CA3 pyramids (n = 8) recorded with K-acetate-filled electrodes by 4.8 +/- 1.3 mV and made spontaneous, asynchronous hyperpolarizing and depolarizing potentials disappear along with interictal depolarizations. GABA-mediated synchronous long-lasting depolarizations (LLDs) and asynchronous depolarizations were also studied with KCl-filled electrodes in 4-AP + CPP + CNQX (n = 6); under these conditions baclofen did not reduce LLD amplitude but abolished the asynchronous events. Dentate hilus stimulation at 0. 2-0.8 Hz suppressed the ictal activity recorded in 4-AP + baclofen (n = 8). Our data indicate that GABA(B) receptor activation by baclofen decreases transmitter release leading to disappearance of interictal activity along with asynchronous excitatory and inhibitory potentials. By contrast, GABA-mediated LLDs and ictal events, which reflect intense action potential firing invading presynaptic inhibitory and excitatory terminals respectively, are not abolished. We propose that the proconvulsant action of baclofen results from 1) block of asynchronous GABA-mediated potentials causing disinhibition and 2) activity-dependent changes in hippocampal network excitability.

4-Aminopyridine↗
PubMed1999

Muscarinic receptor activation induces depolarizing plateau potentials in bursting neurons of the rat subiculum.

Acetylcholine functions as a neuromodulator in the mammalian brain by binding to specific receptors and thus bringing about profound changes in neuronal excitability. Activation of muscarinic receptors often results in an increased excitability of cortical cells. It is, however, unknown whether such an action is present in the subiculum, a limbic structure that may be involved in cognitive processes as well as in seizure propagation. Most rat subicular neurons are endowed of intrinsic membrane properties that make them fire action potential bursts. Using intracellular recordings from these bursting cells in a slice preparation, we report here that application of the cholinergic agonist carbachol (CCh, 30-100 microM) to medium containing ionotropic excitatory amino acid receptor antagonists reduces burst-afterhyperpolarizations (burst-AHPs) and discloses depolarizing plateau potentials that outlast the triggering current pulses by 140-2,800 ms. These plateau potentials appear with CCh concentrations >50 microM and are dependent on the resting membrane potential and on the intensity/duration of the triggering pulse; are recorded during application of tetrodotoxin (1 microM, n = 5 neurons); but are markedly reduced by replacing 82% of extracellular Na(+) with equimolar choline (n = 6). Plateau potentials also are abolished by Co(2+) (2 mM; n = 5) or Cd(2+) (1 mM; n = 2) application and by recording with electrodes containing the Ca(2+) chelator bis(2-aminophenoxy)ethane-N, N,N',N'-tetraacetic acid (0.2 M; n = 6). CCh-induced burst-AHP reduction and plateau potentials are reversed by the muscarinic antagonist atropine (0.5 microM, n = 7). In conclusion, our findings demonstrate a powerful muscarinic modulation of the intrinsic excitability of subicular bursting cells that is predominated by the appearance of plateau potentials. These changes in excitability may contribute to physiological processes such as learning or memory and play a role in the generation of epileptiform depolarizations. We propose that, as in other limbic structures, muscarinic plateau potentials in the subiculum are mainly due to a Ca(2+)-dependent nonselective cationic conductance.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1999

Interictal-ictal interactions and limbic seizure generation.

Interictal discharges are used in clinical practice to localize the epileptogenic focus in patients with partial epilepsy. However, the interaction between interictal and ictal discharges remains debatable. For instance, interictal events may lead to seizure onset in some models of epileptiform discharge. By contrast, in other models, disappearance of interictal activity (for example by activation of GABAB receptors) induces or potentiates ictal events. We have recently obtained new evidence for a control exerted by interictal discharges on ictal activity in rodent combined slices of hippocampus-entorhinal cortex. In this preparation continuous application of 4-aminopyridine induces: (i) interictal activity which initiates in CA3 and propagates via CA1 and subiculum to the entorhinal cortex, and return to the hippocampus through the dentate gyrus; and (ii) ictal discharges, which originate in the entorhinal cortex and propagate via the dentate gyrus to the hippocampus. Ictal discharges disappear over time, while synchronous interictal discharges continue to occur. Lesioning the Schaffer collaterals abolishes interictal discharges in CA1, entorhinal cortex and dentate gyrus and discloses entorhinal ictal discharges that propagate, via the dentate gyrus, to the CA3 subfield. Interictal activity of CA3 origin also prevents the occurrence of ictal events recorded in the entorhinal cortex in Mg(2+)-free medium. Moreover, in both models, ictal discharge generation in the entorhinal cortex after Schaffer collateral cut is prevented by mimicking CA3 activity through rhythmic electrical stimulation of CA1 hippocampal outputs. Hence, our data demonstrate that hippocampus interictal discharges control the expression of electrographic seizures in entorhinal cortex. Sectioning the Schaffer collaterals may model the epileptic condition in which cell damage in the CA3 subfield results in loss of CA3 control over the entorhinal cortex. Hence, the functional integrity of hippocampal CA3 neurons may represent a critical control point in temporal lobe epilepsy.

Animals↗
PubMed1998

Contribution of GABA(A)-mediated conductances to anoxia-induced depolarization.

CA1 pyramids were studied intracellularly in rat hippocampal slices to establish the contribution of excitatory amino acid (EAA) and GABA(A) receptors to the depolarizations induced by brief (< 10 min) anoxic episodes. An increase of the amplitude of the depolarizations evoked by successive anoxic episodes occurred with KCl (n=4 cells), not with K-acetate-filled (n=3) recording electrodes. Moreover, with K-acetate-filled electrodes the anoxic depolarization amplitude was reduced, but not abolished by EAA receptor antagonists (n=14). The residual anoxic depolarizations were blocked by a GABA(A) receptor antagonist (n=5) and decreased by the carbonic anhydrase inhibitor acetazolamide (n=4). We conclude that the anoxic depolarizations generated by CA1 pyramids are caused by the activation of EAA along with GABA(A) receptors leading to an increased membrane conductance to both Cl- and HCO3-.

Animals↗
PubMed1998

Multiple actions of the novel anticonvulsant drug topiramate in the rat subiculum in vitro.

We used an in vitro slice preparation to study whether and how the anticonvulsant drug topiramate (TPM, 50-500 microM) modulates the excitability of rat subicular neurons that generate action potential bursts mainly caused by voltage-dependent, Na+-electrogenesis. Subiculum is a gating structure for outputs originating from the hippocampus proper, and thus it may play a role in limbic seizures. In 28/45 neurons, TPM induced a steady hyperpolarization of the resting membrane potential (RMP) that ranged between -2 and -16 mV and was associated with a 24-62% decrease of the apparent membrane input resistance. TPM also depressed the ability of these cells to generate action potential bursts in response to brief (5-150 ms) depolarizing pulses; such an effect was characterized by an increase in the amount of intracellular depolarizing current required for eliciting action potential bursts, and it also occurred when the TPM-induced steady hyperpolarization was compensated by injecting steady depolarizing current. In addition TPM reduced by approx. 50% the regular action potential firing elicited by prolonged (350-1000 ms) depolarizing pulses (n=15 of 27 neurons). Recovery of the TPM-induced changes was not seen during washout for periods of 20-80 min (n=7). Both the steady hyperpolarization of the RMP and the input resistance decrease elicited by TPM were markedly reduced by the GABAA receptor antagonists bicuculline methiodide (10 microM; n=6) or picrotoxin (100 microM; n=2); such an effect was associated with a reduction, but not with blockade of the depressant action exerted by TPM on burst generation. Our findings indicate that TPM reduces subicular cell excitability, and modifies bursting ability and repetitive firing properties. These effects may be ascribed to actions on voltage-gated, Na+ electrogenesis and GABAA receptors. We propose that these changes in excitability may all contribute to the anticonvulsant action of TPM in limbic seizures that occur in temporal lobe epilepsy patients.

Action Potentials↗
PubMed1998

A comparison of the adenosine-mediated synaptic inhibition in the CA3 area of immature and adult rat hippocampus.

We compared the effects of the adenosine A1 receptor activation on the postsynaptic potentials (psps) recorded from the CA3 area of immature (postnatal days 10-20) and adult rat hippocampal neurons in vitro. The adenosine A1 receptor agonist 2-phenyl-isopropyl-adenosine (PIA, 1 microM) depressed the stimulus-induced psps less in immature and more in adult neurons. In the presence of the GABAA receptor antagonist bicuculline methiodide (BMI, 10 microM), PIA reduced the duration and number of action potentials of the stimulus-induced paroxysmal depolarizations (PDs) in immature neurons, while it blocked PDs in adult neurons. Spontaneous BMI-induced PDs, were blocked by PIA in less than half (5/12) immature and all (6/6) adult neurons. The adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 1 microM) enhanced the stimulus-induced psps in immature and adult neurons alike; this effect did not lead to stimulus-induced bursting in immature neurons. DPCPX induced spontaneous bursts (proconvulsant effect) in only 2/16 immature but in all adult (12/12) neurons. In BMI, DPCPX increased the duration and number of action potentials of the stimulus-induced PDs in immature and adult neurons alike (by about 30%), but it increased the rates of occurrence of spontaneous PDs in significantly more adult neurons. In conclusion, our results suggest that adenosine, acting via A1 receptors, is a more effective endogenous anti-epileptic in adult than in immature hippocampus, a fact which may contribute to the susceptibility of the latter to epileptogenesis.

Adenosine↗
PubMed1998

Laminar organization of epileptiform discharges in the rat entorhinal cortex in vitro.

1. Interictal and ictal epileptiform discharges induced by 4-aminopyridine (4AP, 50 microM) were studied in the rat lateral entorhinal cortex with field potential and intracellular recordings in an in vitro slice preparation. Both types of discharge disappeared in layer II, but continued to occur in layers IV-VI after a knife cut separation was made at approximately 600 micro(m) from the pia (n = 4 slices). 2. Interictal depolarizations recorded in layer IV-VI cells (amplitude, 29.4 +/- 8.6 mV; duration, 386 +/- 177.4 ms, means +/- s.d.; n = 17) were capped by action potential bursts, while smaller interictal depolarizations in layer II cells (amplitude, 11.7 +/- 5.8 mV; duration, 192.6 +/- 47.9 ms; n = 10) were associated with single action potentials and were terminated by a hyperpolarization. Ictal discharges were initiated by an interictal discharge; they were characterized by a depolarization of 31.5 +/- 6.2 mV (n = 12) in layer IV-VI and 11.6 +/- 3.5 mV (n = 7) in layer II neurones. 3. Slow, presumptive Ca2+-mediated spikes occurred in layer II (n = 4) and IV-VI (n = 6) cells loaded with the Na+ channel blocker QX-314 (50 mM). These events were synchronized with population spikes during interictal and ictal discharges, and were abolished by Ni2+ (1 mM, n = 4 cells) along with the 4AP-induced synchronous activity. 4. The N-methyl-D-aspartate (NMDA) receptor antagonist 3, 3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonate (CPP, 10 microM) abolished ictal discharges and reduced interictal depolarizations in layer IV-VI neurones (n = 4). The non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM) abolished both interictal and ictal activity (n = 4 cells). 5. These findings provide evidence for a role played by NMDA-mediated mechanisms in the generation of epileptiform discharges in the entorhinal cortex. Lack of an NMDA-mediated component along with presence of inhibition in layer II neurones results in attenuation of epileptiform activity at this site. Moreover Ca2+-mediated spikes may contribute to the appearance of epileptiform discharges in this model.

4-Aminopyridine↗
PubMed1998

Sodium channels as molecular targets for antiepileptic drugs.

Voltage-gated sodium channels mediate regenerative inward currents that are responsible for the initial depolarization of action potentials in brain neurons. Many of the most widely used antiepileptic drugs, as well as a number of promising new compounds suppress the abnormal neuronal excitability associated with seizures by means of complex voltage- and frequency-dependent inhibition of ionic currents through sodium channels. Over the past decade, advances in molecular biology have led to important new insights into the molecular structure of the sodium channel and have shed light on the relationship between channel structure and channel function. In this review, we examine how our current knowledge of sodium channel structure-function relationships contributes to our understanding of the action of anticonvulsant sodium channel blockers.

Animals↗
PubMed1998

GABA-dependent generation of ectopic action potentials in the rat hippocampus.

Intracellular recordings from CA3 pyramidal cells of rat hippocampus in a slice preparation revealed the occurrence of interictal epileptiform discharges and synchronous GABA-mediated potentials during application of 4-aminopyridine (4AP, 50 micrometer). The synchronous GABA-mediated potential consisted of a sequence of early hyperpolarization, long-lasting depolarization (LLD), and late hyperpolarization. Action potentials of variable amplitude occurred at the peak of the early hyperpolarization and during the LLD rising phase (48 of 64 cells); they were not prevented by membrane hyperpolarization and displayed inflections that were reminiscent of the initial segment-somatodendritic (IS-SD) fractionation. Interictal discharges were blocked by excitatory amino acid receptor antagonists, while both GABA-mediated potentials and action potentials of variable amplitude continued to occur (n = 10). The latter events were still recorded in the presence of the GABAB receptor antagonist CGP-35348 (0.5-1 mm, n = 4), but were abolished by the GABAA receptor antagonist bicuculline methiodide (BMI, 10 micrometer, n = 5). Localized application of BMI (20 micrometer, n = 6) or tetrodotoxin (TTX, 5 micrometer, n = 3) to the CA1 stratum radiatum blocked the variable amplitude action potentials; these effects were not seen when BMI (n = 4) or TTX (n = 4) were applied to the CA3 stratum radiatum, although both procedures made LLDs disappear. Our findings indicate that action potentials of variable amplitude recorded from CA3 pyramidal cells in the 4AP model are generated at or near the terminal region of the Schaffer collaterals and that they represent TTX-sensitive ectopic events. These action potentials are generated at this site by a BMI-sensitive (and thus GABAA-mediated) mechanism. We propose that the ectopic action potentials reflect an increased excitability of axon terminals that is presumably caused by [K+]o elevations associated with the 4AP-induced synchronous GABA-mediated potential.

4-Aminopyridine↗
PubMed1998

Participation of GABAA-mediated inhibition in ictallike discharges in the rat entorhinal cortex.

The spontaneous, synchronous activity induced by 4-aminopyridine (4AP, 50 microM) in the adult rat entorhinal cortex was analyzed with simultaneous field potential and intracellular recordings in an in vitro slice preparation. Four-AP induced isolated negative-going field potentials (interval of occurrence = 27.6 +/- 9.9 (SD) s; n = 27 slices) that corresponded to intracellular long-lasting depolarizations (LLDs), and ictallike epileptiform discharges (interval of occurrence = 10.4 +/- 5.7 min; n = 27 slices) that were initiated by the negative field potentials. LLDs recorded with K-acetate-filled microelectrodes triggered few action potentials of variable amplitude and had a duration of 1.7 +/- 0.8 s (n = 26 neurons), a peak amplitude of 11.8 +/- 5.0 mV (n = 26 neurons) and a reversal potential of -66.2 +/- 3.9 mV (n = 17 neurons). The ictal discharges studied with K-acetate microelectrodes consisted of prolonged depolarizations (duration = 72.9 +/- 44.3 s; peak amplitude = 29.2 +/- 11.4 mV; n = 25 neurons) with action-potential firing during both the tonic and the clonic phase. These depolarizations had a reversal potential of -45.3 +/- 3.8 mV (n = 4 neurons). Intracellular Cl- diffusion from KCl-filled microelectrodes made both LLDs and ictal depolarizations increase in amplitude (30.5 +/- 8.2 mV, n = 8 and 41.8 +/- 9.8 mV, n = 6 neurons, respectively). LLDs recorded with KCl and 2-(trimethyl-amino)N-(2, 6-dimethylphenyl)-acetamide (QX-314) microelectrodesreached an amplitude of 36.3 +/- 5.2 mV, lasted 12.5 +/- 6.5 s, and had a reversal potential of -31.3 +/- 2.5 mV (n = 4 neurons); under these recording procedures the ictal discharge amplitude was 41.5 +/- 5.0 mV and the reversal potential -24.0 +/- 7.0 mV (n = 4 neurons). The N-methyl-D-aspartate (NMDA) receptor antagonist 3,3-(2-carboxy-piperazine-4-yl)-pro-pyl-l-phosphonate (10 microM, n = 5 neurons) alone or concomitant with the nonNMDA receptor antagonist 6-cyano-7-nitro-quinoxaline-2,3-dione (10 microM, n = 4 neurons) abolished ictal discharges, without influencing LLDs. LLDs were blocked by the gamma-aminobutyric acid-A (GABAA) receptor antagonist bicuculline methiodide (BMI, 10 microM, n = 6 neurons) or the mu-opioid receptor agonist (-Ala2-N-Me-Phe, Gly-ol) enkephalin (DAGO, 10 microM, n = 2 neurons). Application of BMI (n = 4 neurons) or DAGO (n = 2 neurons) to control the medium abolished LLDs and ictal discharges but disclosed a novel type of epileptiform depolarization that lasted 3.5 +/- 1.2 s and occurred every 5.2 +/- 2.6 s (n = 6 neurons). Our data indicate that 4AP induces in the rat entorhinal cortex a synchronous, GABA-mediated potential that is instrumental in initiating NMDA-dependent, ictal discharges. Moreover we present evidence for an active role played by GABAA-mediated potentials in the maintenance and termination of these prolonged epileptiform events.

4-Aminopyridine↗
PubMed1998

Cortical dysplasia: an immunocytochemical study of three patients.

Human cortical dysplastic lesions are frequently associated with severe partial epilepsies. We report an immunocytochemical investigation on cortical tissue from three surgically treated patients, 20, 38, and 14 years old, with intractable epilepsy due to cortical dysplasia. The studies were performed using antibodies recognizing cytoskeletal proteins, calcium-binding proteins, and some subunits of glutamate receptors. The specimens from the three patients displayed common features: (1) focal cytoarchitectural abnormalities with an increased number of giant pyramidal neurons through all cortical layers except layer I; (2) large, round-shaped balloon cells mainly concentrated in the deepest part of the cortex and in the white matter; (3) a decrease of calcium binding protein immunopositive gamma-aminobutyric acid (GABA)ergic neurons; and (4) abnormal baskets of parvalbumin-positive terminals around the excitatory (pyramidal and large, round-shaped) neurons. These data provide evidence that the epileptogenicity in these types of cortical dysplasia is due to an increase in excitatory neurons coupled with a decrease in GABAergic interneurons.

Adolescent↗
PubMed1998

Modulation of epileptiform activity by adenosine A1 receptor-mediated mechanisms in the juvenile rat hippocampus.

The modulatory role played by purinergic mechanisms on the epileptiform discharges induced by 4-aminopyridine (4AP, 50 microM) in juvenile (10 to 25-day-old) rat hippocampal slices was studied with field potential recordings in the CA3 stratum radiatum. 4AP-induced activity consisted of interictal and ictal discharges along with isolated gamma-aminobutyric acid-mediated potentials. The adenosine analogues 2-Cl-adenosine (10-200 microM) and N-ethylcarboxamido-adenosine (5-10 microM), the A1 receptor agonist N6-(L2-phenylisopropyl)-adenosine (2-10 microM), and the adenosine uptake inhibitor dipyridamole (1-40 microM) reduced and eventually abolished interictal and ictal discharges with IC50 values that were larger for ictal discharges as compared to interictal activity. These purinergic agents did not modify the rate of occurrence of the gamma-aminobutyric acidmediated potentials recorded during application of excitatory amino acid receptor antagonists. The changes induced by 2-Cl-adenosine, N6-(L2-phenylisopropyl)-adenosine, or dypiridamole were reversed by caffeine (500 microM) or 8-cyclopentyl-1,3-dipropylxantine (100 microM). However, these adenosine receptor antagonists did not alter the epileptiform discharges induced by 4AP. The depressant effects induced by N6-(L2-phenylisopropyl)-adenosine on the epileptiform activity were maintained in the presence of barium (2 mM), which blocks adenosine postsynaptic actions. These results demonstrate that activation of adenosine A1 receptors in the juvenile rat hippocampus leads to an anticonvulsant action that can be ascribed to a decreased release of glutamate from CA3 pyramidal cell terminals. We also propose that during the first weeks of postnatal life endogenous adenosine does not activate A1 receptors to a degree to control the ability of hippocampal neurons to generate epileptiform activity in the 4AP model.

2-Chloroadenosine↗