6-cyano-7-nitroquinoxaline-2-3-dione and Epilepsy--Temporal-Lobe

It is a matter of ongoing debate whether newly generated granule cells contribute to epileptic activity in the hippocampus. To address this question, we investigated neurogenesis and epileptiform activity (EA) along the hippocampal septotemporal axis in the intrahippocampal kainate (KA) mouse model for temporal lobe epilepsy. Multisite intrahippocampal in vivo recordings and immunolabeling for c-Fos showed that the KA-induced status epilepticus (SE) extended along the septotemporal axis of both hippocampi with stronger intensity at ipsilateral temporal and contralateral sites. Accordingly, we found a position-dependent increase in proliferation (incorporation of bromodeoxyuridine) and neurogenesis (immunolabeling for doublecortin): Both were selectively increased in the ipsilateral temporal and entire contralateral subgranular zone, sparing the septal region close to the injection site. The newborn neurons were hyperexcitable and functionally integrated into the hippocampal network as revealed by patch-clamp recordings. Analysis of chronic EA also showed a differential intensity pattern along the hippocampal axis: EA was low in the septal portion with prominent sclerosis and granule cell dispersion but most pronounced in the transition zone where neurogenesis reappeared. In conclusion, SE stimulates neurogenesis in a position-dependent manner and coincidence of neurogenesis and stronger EA distal to the injection site suggests a proepileptogenic effect of increased neurogenesis.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Analysis of Variance; Animals; Bromodeoxyuridine; Cell Count; Cell Proliferation; Convulsants; Disease Models, Animal; Doublecortin Domain Proteins; Electric Stimulation; Electroencephalography; Epilepsy, Temporal Lobe; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Functional Laterality; Hippocampus; Kainic Acid; Luminescent Proteins; Lysine; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microtubule-Associated Proteins; Motor Activity; Neurogenesis; Neuropeptides; Patch-Clamp Techniques; Picrotoxin

Clinical and experimental evidence indicates that the amygdala is involved in limbic seizures observed in patients with temporal lobe epilepsy. Here, we used simultaneous field and intracellular recordings from horizontal brain slices obtained from pilocarpine-treated rats and age-matched nonepileptic controls (NECs) to shed light on the electrophysiological changes that occur within the lateral nucleus (LA) of the amygdala. No significant differences in LA neuronal intrinsic properties were observed between pilocarpine-treated and NEC tissue. However, spontaneous field activity could be recorded in the LA of 21% of pilocarpine-treated slices but never from NECs. At the intracellular level, this network activity was characterized by robust neuronal firing and was abolished by glutamatergic antagonists. In addition, we could identify in all pilocarpine-treated LA neurons: 1) large amplitude depolarizing postsynaptic potentials (PSPs) and 2) a lower incidence of spontaneous hyperpolarizing PSPs as compared with NECs. Single-shock stimulation of LA networks in the presence of glutamatergic antagonists revealed a biphasic inhibitory PSP (IPSP) in both NECs and pilocarpine-treated tissue. The reversal potential of the early GABA(A) receptor-mediated component, but not of the late GABA(B) receptor-mediated component, was significantly more depolarized in pilocarpine-treated slices. Furthermore, the peak conductance of both fast and late IPSP components had significantly lower values in pilocarpine-treated LA cells. Finally, paired-pulse stimulation protocols in the presence of glutamatergic antagonists revealed a less pronounced depression of the second IPSP in pilocarpine-treated slices compared with NECs. Altogether, these findings suggest that alterations in both pre- and postsynaptic inhibitory mechanisms contribute to synaptic hyperexcitability of LA networks in epileptic rats.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Amygdala; Animals; Disease Models, Animal; Electrophysiology; Epilepsy, Temporal Lobe; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; GABA-A Receptor Antagonists; gamma-Aminobutyric Acid; Hippocampus; Male; Matched-Pair Analysis; Nerve Net; Neural Inhibition; Neurons; Parahippocampal Gyrus; Picrotoxin; Pilocarpine; Rats; Rats, Sprague-Dawley; Receptors, GABA-A

The temporal lobe seems particularly susceptible to seizure activity. Mesial temporal lobe structures, including the hippocampus, have the lowest seizure thresholds in the brain. Conversely, thresholds in the frontal neocortex are significantly higher. The development of intact, isolated preparations of hippocampus and neocortex in vitro allows for study into mechanisms governing seizure threshold.. Epileptiform discharges in isolated mouse neocortical blocks were compared with the contralateral intact hippocampus, isolated from the same brain, by using the low-Mg2+, 4 aminopyridine (4-AP), and low-Ca2+ in vitro seizure models. The pharmacology of low Mg(2+)-induced ictal-like events (ILEs) generated in the hippocampus and neocortex was then compared by using glutamatergic antagonists DL-2-amino-5-phosphonovaleric acid (APV) and 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), and the Ca2+ channel antagonist, nifedipine.. Neocortical blocks generated both recurrent, spontaneous ILEs and interictal-like events under low-Mg2+ artificial CSF (aCSF) perfusion, distinct from those generated in the hippocampus. ILEs from the hippocampus displayed lower thresholds and longer durations as compared with isolated neocortical blocks. Similar results were obtained during 4-AP perfusion. Perfusion with low-Ca2+ ACSF did not produce stereotypical ILEs in the neocortical block, producing instead recurrent, slow depolarizations. Both ILEs and recurrent, slow depolarizations were produced in the hippocampus. Application of APV and nifedipine exacerbated low Mg(2+)-induced ILEs in the hippocampus but not the neocortex, indicating a distinct pharmacology for partial seizures of different brain regions.. The developing mouse hippocampus demonstrates increased ictogenesis compared with the developing neocortex in vitro, consistent with clinical observations and in vivo experimental models.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Calcium Channel Blockers; Convulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy, Temporal Lobe; Evoked Potentials; Excitatory Amino Acid Antagonists; Frontal Lobe; Functional Laterality; Hippocampus; Hypocalcemia; In Vitro Techniques; Magnesium Deficiency; Mice; Mice, Inbred C57BL; Neocortex; Nifedipine; Seizures; Synaptic Transmission

We sought to identify the inhibitory interneurons of the rat hippocampal CA1 region selectively vulnerable in the kainic acid (KA) model of temporal lobe epilepsy and to determine whether their selective vulnerability could be due to differential short-term KA effects.. We quantified vulnerable interneurons in stratum oriens-alveus (O/A) by using immunohistochemistry for glutamic acid decarboxylase (GAD), parvalbumin (PV), and somatostatin (SS) after KA injections in rats, and then compared in normal slices the effects of KA on interneurons either in O/A (vulnerable to KA) or in strata radiatum and lacunosum-moleculare (R/LM) (resistant to KA) by using whole-cell recording and calcium imaging.. GAD-, PV- and SS-positive cells in O/A were decreased after KA treatment in P20 and P30 rats. Both short (1-min) and long (10-min) applications of KA produced similar tetrodotoxin (TTX)-insensitive membrane depolarization and decrease in input resistance in O/A and R/LM interneurons. KA responses were antagonized by CNQX and GYKI52466, suggesting AMPA receptor activation. KA also generated a similar increase in intracellular Ca2+ in O/A and R/LM interneurons, which was antagonized by CNQX and GYKI52466.. The selective vulnerability of GAD-, PV-, and SS-immunopositive O/A interneurons in the KA model may not arise from cell-specific short-term membrane effects or calcium responses induced by KA, but from other glutamate receptor-mediated excitotoxic processes.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Calcium; Disease Models, Animal; Epilepsy, Temporal Lobe; Excitatory Amino Acid Agonists; Glutamate Decarboxylase; Hippocampus; Immunohistochemistry; In Vitro Techniques; Interneurons; Kainic Acid; Male; Neural Inhibition; Parvalbumins; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Glutamate; Somatostatin; Tetrodotoxin

Poly(A(+)) RNA was extracted from the temporal lobe (TL) of medically intractable epileptic patients which underwent surgical TL resection. Injection of this mRNA into Xenopus oocytes led to the expression of ionotropic receptors for gamma-aminobutyric acid (GABA), kainate (KAI) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Membrane currents elicited by GABA inverted polarity at -15 mV, close to the oocyte's chloride equilibrium potential, were inhibited by bicuculline, and were potentiated by pentobarbital and flunitrazepam. These basic characteristics were also displayed by GABA currents elicited in oocytes injected with mRNAs isolated from human TL glioma (TLG) or from mouse TL. However, the GABA receptors expressed by the epileptic TL mRNA exhibited some unusual properties, consisting in a rapid current run-down after repetitive GABA applications and a large EC(50) (125 microM). AMPA alone evoked very small or nil currents, whereas KAI induced larger currents. Nevertheless, upon cyclothiazide treatment, AMPA elicited substantial currents that, like the KAI currents, were inhibited by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Furthermore, the glutamate receptor 5 (GluR5) agonist, ATPA, failed to evoke an obvious current although both RT-PCR and Western blot analyses showed GluR5 expression in the epileptic TL. Oocytes injected with mouse TL or human TLG mRNAs generated KAI and AMPA currents similar to those evoked in oocytes injected with epileptic TL mRNA but, in contrast to these, the mouse TL and human TLG oocytes were also responsive to ATPA. Our findings are in accord with the concept that both a depression of GABA inhibition and a dysfunction of the KAI-receptor system maintain a high neuronal excitability that results in epileptic seizures.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Adolescent; Adult; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Bicuculline; Epilepsy, Temporal Lobe; Female; gamma-Aminobutyric Acid; Humans; Male; Membrane Potentials; Oocytes; Receptors, Neurotransmitter; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Temporal Lobe; Xenopus

Chronically epileptic rats, produced by prior injection of pilocarpine, were used to investigate whether changes in intrinsic neuronal excitability may contribute to the epileptogenicity of the hippocampus in experimental temporal lobe epilepsy (TLE). Paired extra-/intracellular electrophysiological recordings were made in the CA1 pyramidal layer in acute hippocampal slices prepared from control and epileptic rats and perfused with artificial cerebrospinal fluid (ACSF). Whereas orthodromic activation of CA1 neurons evoked only a single, stimulus-graded population spike in control slices, it produced an all-or-none burst of population spikes in epileptic slices. The intrinsic firing patterns of CA1 pyramidal cells were determined by intrasomatic positive current injection. In control slices, the vast majority (97%) of the neurons were regular firing cells. In epileptic slices, only 53% the pyramidal cells fired in a regular mode. The remaining 47% of the pyramidal cells were intrinsic bursters. These neurons generated high-frequency bursts of three to six spikes in response to threshold depolarizations. A subgroup of these neurons (10.1% of all cells) also burst fired spontaneously even after suppression of synaptic activity. In epileptic slices, burst firing in most cases (ca 70%) was completely blocked by adding the Ca2+ channel blocker Ni2+ (1 mM) to, or removing Ca2+ from, the ACSF, but not by intracellular application of the Ca2+ chelater 1,2-bis(o-aminophenoxy)ethane-N,N,N ',N '-tetra-acetic acid (BAPTA), suggesting it was driven by a Ca2+ current. Spontaneously recurring population bursts were observed in a subset of epileptic slices. They were abolished by adding 2 M 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) to the ACSF, indicating that synaptic excitation is critical for the generation of these events. All sampled pyramidal cells fired repetitively during each population burst. The firing of spontaneously active bursters anteceded the population discharge, whereas most other pyramidal cells began to fire conjointly with the first population spike. Thus, spontaneous bursters are likely to be the initiators of spontaneous population bursts in epileptic slices. The dramatic up-regulation of intrinsic bursting in CA1 pyramidal cells, particularly the de novo appearance of Ca2+-dependent bursting, may contribute to the epileptogenicity of the hippocampus in the pilocarpine model of TLE. These findings have important implications for the pharmacologi

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Animals; Calcium; Calcium Channel Blockers; Calcium Channels; Chelating Agents; Disease Models, Animal; Egtazic Acid; Electric Stimulation; Electrophysiology; Epilepsy, Temporal Lobe; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Hippocampus; Humans; In Vitro Techniques; Male; Nickel; Pilocarpine; Pyramidal Cells; Rats

Glutamate receptor-mediated changes in light transmittance were imaged in the dentate gyri of the epileptic hippocampi, taken from patients with temporal lobe epilepsy and the rat pilocarpine model, to investigate epilepsy-associated alterations in activity-induced cell swelling. A static pattern of light transmittance corresponded to the layered structure of dentate gyrus and reflected epilepsy-associated alterations. Hypoosmotic stress produced more than 35% of dynamic changes in the increase of light transmittance as a reflection of osmotic swelling in the epileptic dentate gyri. This degree of increase was not different from the increase observed in control dentate gyri, suggesting that the capability of osmotically regulating cell volume was preserved in the epileptic dentate gyri. In contrast, alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) induced activity-dependent swelling and an increase in light transmittance by 60.5% in the control dentate gyri, whereas the degree of increase in the epileptic dentate gyri remained 17.9% in response to AMPA. Selective attenuation of light transmittance in response to AMPA in the epileptic but not control dentate gyri suggested a possible alteration in the swelling properties of the epileptic dentate gyri that are linked to the AMPA receptor activation. Surviving cells in the epileptic hippocampus may have a mechanism of downregulating neuronal activity-dependent swelling to maintain optimal cell volume during repeated network hyperexcitation in epilepsy.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Adult; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Brain Edema; Dentate Gyrus; Epilepsy, Temporal Lobe; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Humans; Light; Male; Membrane Potentials; Neurons; Optics and Photonics; Organ Culture Techniques; Osmotic Pressure; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Tetrodotoxin

Alterations in synaptic inhibition are associated with epileptiform activity in several acute animal models; however, it is not clear if there are changes in inhibition in chronically epileptic tissue. We have used intracellular recordings from granule cells of patients with temporal lobe epilepsy to determine whether synaptic inhibition is compromised. Two groups of patients with medial temporal lobe epilepsy were used, those with medial temporal lobe sclerosis (MTLE), and those with extrahippocampal masses (MaTLE) where the cell loss and synaptic reorganization that characterize MTLE are not seen. Although the level of tonic inhibition at the somata was not significantly different in the two patient groups, there was a reduction in the conductance of polysynaptic perforant path-evoked fast and slow inhibitory postsynaptic potentials (IPSPs) (53% and 66%, respectively). We found that there was a comparable decrease in the monosynaptic IPSP conductances examined in the presence of glutamatergic antagonists as that seen for the polysynaptically evoked IPSPs. These data suggest that the decrease in inhibition seen in normal artificial cerebrospinal fluid in MTLE granule cells cannot be solely explained by a decrease in excitatory input onto inhibitory interneurons and may reflect changes at the interneuron-granule cells synapse or in the number of specific inhibitory interneurons.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Dentate Gyrus; Electric Conductivity; Epilepsy, Temporal Lobe; Evoked Potentials; Excitatory Amino Acid Antagonists; Humans; In Vitro Techniques; Membrane Potentials; Neural Inhibition; Neurons; Sclerosis; Synapses

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.

Topics: 4-Aminopyridine; 6-Cyano-7-nitroquinoxaline-2,3-dione; Adolescent; Adult; Anticonvulsants; Cerebral Cortex; Child; Electroencephalography; Epilepsies, Partial; Epilepsy, Frontal Lobe; Epilepsy, Temporal Lobe; Evoked Potentials; Female; Humans; In Vitro Techniques; Magnetic Resonance Imaging; Male; Membrane Potentials; Piperazines

Intracellular recording techniques were used to examine GABA(A) receptor-mediated synaptic inhibition in pyramidal cells of the CA1 region of the rat hippocampus in the post-self sustaining limbic status epilepticus model of temporal lobe epilepsy. Orthodromically evoked, monosynaptic inhibitory postsynaptic potentials were recorded in vitro following pharmacological blockade of ionotropic glutamate and GABA(B) receptors. Inhibitory postsynaptic potentials from epileptic tissue were kinetically altered relative to controls; both the 10-90% rise-time and width (measured at half-maximum amplitude) were reduced by approximately 50% resulting in significant shortening of duration. The degree of pyramidal cell hyperexcitability, assessed before pharmacological treatment as the number of action potentials evoked by maximum intensity afferent stimulation, correlated significantly with the magnitude of synaptic potential duration reduction determined following blockade of glutamatergic neurotransmission. Bath application of the benzodiazepine type 1 receptor agonist zolpidem reduced post-self sustaining limbic status epilepticus CA1 pyramidal cell hyperexcitability substantially (but not completely) via a marked increase in inhibitory postsynaptic potential area. Post-self-sustaining limbic status epilepticus inhibitory postsynaptic potentials which exhibited the most pronounced shortening were augmented by zolpidem to a greater degree than longer duration synaptic potentials. In contrast, zolpidem-induced augmentation of control inhibitor, postsynaptic potential area was much less robust. It is suggested that a deficiency in post-self-sustaining limbic status epilepticus GABA(A) receptor-mediated synaptic inhibition contributes to a state of partial disinhibition which is a major factor in enhanced CA1 excitability in chronic limbic epilepsy. Possible mechanisms underlying post-self-sustaining limbic status epilepticus kinetic abnormalities are discussed.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Animals; Disease Models, Animal; Electric Stimulation; Epilepsy, Temporal Lobe; Evoked Potentials; GABA Antagonists; GABA-A Receptor Antagonists; GABA-B Receptor Antagonists; Hippocampus; Hypnotics and Sedatives; Male; Phosphinic Acids; Propanolamines; Pyramidal Cells; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, GABA-B; Regression Analysis; Synapses; Zolpidem

The effect of partial hippocampal kindling, a model of temporal lobe seizure, on monosynaptic inhibition mediated by GABA was studied. Kindled rats were given 15 nonconvulsive hippocampal afterdischarges, and control rats were given low frequency or no stimulations. At 1-2 d after kindling, paired-pulse depression (PPD) of the IPSCs recorded in CA1 neurons in vitro was significantly smaller in kindled as compared with control rats. The difference in PPD persisted for at least 21 d after kindling. The decrease in PPD of the IPSCs after partial hippocampal kindling was likely caused by a reduced GABA autoinhibition after downregulation of presynaptic GABAB receptors. The GABAB antagonist CGP35348 (1 mM) suppressed PPD of the IPSCs more strongly in control than in kindled rats. Direct activation of the presynaptic GABAB receptors by baclofen suppressed the monosynaptic IPSCs significantly more in control than in kindled rats. The decay rate of a single-pulse IPSC was faster in kindled than in control rats on day 1 or day 21 after partial kindling. The difference in IPSC decay between kindled and control rats was found with or without a GABAB receptor antagonist. The low efficacy of the presynaptic GABAB receptors in kindled rats may provide compensatory stabilization of the postsynaptic membrane against further seizures or plasticity.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Animals; Epilepsy, Temporal Lobe; GABA Antagonists; Hippocampus; Kindling, Neurologic; Long-Term Potentiation; Male; Rats; Receptors, GABA-B

In the kindling model of temporal lobe epilepsy, several physiological indicators of inhibition by gamma-aminobutyric acid (GABA) in the hippocampal dentate gyrus are consistent with an augmented, rather than a diminished, inhibition. In brain slices obtained from epileptic (kindled) rats, the excitatory drive onto inhibitory interneurons was increased and was paralleled by a reduction in the presynaptic autoinhibition of GABA release. This augmented inhibition was sensitive to zinc most likely after a molecular reorganization of GABAA receptor subunits. Consequently, during seizures, inhibition by GABA may be diminished by the zinc released from aberrantly sprouted mossy fiber terminals of granule cells, which are found in many experimental models of epilepsy and in human temporal lobe epilepsy.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Chlorides; Dentate Gyrus; Epilepsy, Temporal Lobe; Excitatory Amino Acid Antagonists; GABA-A Receptor Antagonists; gamma-Aminobutyric Acid; Humans; In Vitro Techniques; Interneurons; Kindling, Neurologic; Male; Neural Inhibition; Pyridines; Rats; Rats, Wistar; Receptors, GABA-A; Receptors, GABA-B; Synaptic Transmission; Zinc; Zinc Compounds; Zolpidem

This study investigates the plasticity of the excitatory synapses in an experimental model of epilepsy, the kainic acid-lesioned rat hippocampus. Stimulation of afferents in the CA1 area of lesioned hippocampi produced an epileptiform burst of action potentials, with an underlying synaptic potential composed of mixed alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA; 80%) and N-methyl-D-aspartate (NMDA; 20%) receptor-mediated components. Tetanic stimulation yielded a long-term potentiation (LTP) of the mixed AMPA/NMDA receptor-mediated population excitatory postsynaptic potentials. However, the same type of tetanus resulted in a long-term depression (LTD) of pharmacologically isolated NMDA receptor-mediated responses. This LTD occurred independently of the antagonism of AMPA receptors. This suggests that tetanic stimulation produced LTP of AMPA and LTD of NMDA receptor-mediated responses simultaneously. Finally, both LTP and LTD were shown to be NMDA dependent. This property has profound functional implications for the control of excitatory networks in temporal lobe epilepsy.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Animals; Electric Stimulation; Epilepsy, Temporal Lobe; Excitatory Amino Acid Antagonists; Hippocampus; Kainic Acid; Long-Term Potentiation; Male; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Synapses; Synaptic Transmission

The number of orthodromically evoked population spikes was used to classify brain slice tissue from the dentate gyrus of temporal lobe epileptic patients as "more excitable" (multiple population spikes) or "less excitable" (a single population spike). During orthodromic stimulation, "more excitable" tissue exhibited less paired-pulse depression in comparison to "less excitable" tissue. During antidromic stimulation, both multiple population spikes and paired-pulse depression were observed in "more excitable" tissue. "Less excitable" tissue exhibited a single antidromic spike and often no antidromically evoked paired-pulse depression. The strength of antidromic paired-pulse depression was correlated positively with the number of antidromic spikes and was correlated negatively with orthodromic paired-pulse depression. Although orthodromic and antidromic paired-pulse depression were correlated to the number of orthodromically evoked population spikes, this correlation was not as strong as that between orthodromic paired-pulse depression, antidromic paired-pulse depression, and number of antidromically evoked population spikes. The antidromic paired-pulse depression observed in tissue exhibiting antidromically evoked multiple population spikes was enhanced rather than blocked by bicuculline. In addition, the blockade of the antidromic paired-pulse depression by CNQX indicated that this inhibition is mediated by an AMPA-type glutamatergic synapse. We suggest that alterations in circuitry occur in the dentate gyrus of some temporal lobe epileptic patients and were manifested by both a loss of inhibitory input as well as an increase of inhibition, which was dependent on the pathway of stimulation. The results of pairing antidromic and orthodromic stimuli were consistent with these conclusions.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Adult; Bicuculline; Electric Stimulation; Epilepsy, Temporal Lobe; Female; Hippocampus; Humans; Male; Receptors, GABA-A; Synaptic Transmission

In humans temporal lobe epilepsy (TLE) is characterized by recurrent seizures, neuronal hyperexcitability, and selective loss of certain neuronal populations in the hippocampus. Animal models of the condition indicate that a diminution of inhibition mediated by gamma-aminobutyric acid (GABA) accounts for the altered function, and it has been hypothesized that the diminution arises because GABAergic basket interneurons are "dormant" as a result of their being disconnected from excitatory inputs. In hippocampal slices, inhibitory postsynaptic potentials (IPSPs) were elicited in CA1 pyramidal cells by activation of basket cells; responses from an animal model of TLE were compared to those from control tissue. IPSPs evoked indirectly by activation of terminals that then excited basket cells were reduced in the epileptic tissue, whereas IPSPs evoked by direct activation of basket cells, when excitatory neurotransmission was blocked, were not different from controls. These results provide support for the "dormant basket cell" hypothesis and have implications for the pathophysiology and treatment of human TLE.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Animals; Baclofen; Electric Stimulation; Epilepsy, Temporal Lobe; Evoked Potentials; Hippocampus; In Vitro Techniques; Interneurons; Male; Membrane Potentials; Picrotoxin; Pyramidal Tracts; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Status Epilepticus