| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
REPORT
1Section of Neurology, Neuroscience Center at Dartmouth, Dartmouth Medical School, Lebanon, New Hampshire; 2Institut de NeuroBiologie de la Méditerraneé, Institut National de la Santé et de la Recherche Médicale U29, Marseille, France
Submitted 8 February 2005; accepted in final form 29 June 2005
 |
ABSTRACT |
|---|
|
30% of cases. Co-infusion of the GABAA receptor agonist isoguvacine or the GABAA-positive allosteric modulator diazepam completely prevented high-K+/low Mg2+-induced seizures. In in vitro studies using hippocampal slices, we also found that high-K+/low Mg2+ produced ictal activity that was exacerbated by bicuculline and gabazine and reduced by isoguvacine. Thus in the model of high-K+/low Mg2+-induced seizures both in in vivo and in vitro conditions, GABA, acting via GABAA receptors, has an anticonvulsant effect during the critical developmental period of enhanced excitability. |
|
INTRODUCTION |
|---|
|
; Holmes et al. 2002). These clinical findings are paralleled by laboratory observations in lower animals. A critical period of seizure susceptibility—the second postnatal week in the rat—has been documented with various epileptogenic agents and conditions including kainic acid (Albala et al. 1984; Tremblay et al. 1984), electrical stimulation (Moshe et al. 1981), hypoxia (Jensen et al. 1991), penicillin (Swann and Brady 1984), picrotoxin (Gomez-Di Cesare et al. 1997), fever (Baram et al. 1997; Holtzman et al. 1981), GABAB receptor antagonists (McLean et al. 1996), and increased extracellular potassium (Dzhala and Staley 2003; Khazipov et al. 2004). Although several hypothesis have been put forward to explain the increased excitability during this period of life (for reviews, see (Baram and Hatalski 1998; Holmes and Ben-Ari 1998; Swann and Hablitz 2000), the underlying mechanisms are not completely understood. Recently it has been demonstrated that the critical period of enhanced excitability lays within the time window when GABA exerts paradoxical excitatory action, raising a hypothesis that enhanced excitability is due to the inversed—excitatory instead of inhibitory—actions of GABA (Dzhala and Staley 2003; Khazipov et al. 2004).
GABA is the principal inhibitory neurotransmitter in the adult brain. However, at early developmental stages, GABA acting via GABAA receptors may exert excitatory effects (Ben-Ari et al. 1989, 1997, Ben-Ari 2002). The excitatory effects of GABA are due to elevated intracellular concentration of chloride ions because of delayed expression of the chloride extruder KCC2 resulting in a depolarized value of GABAA-mediated conductance (Rivera et al. 1999). In addition to the excitatory effects, depolarizing GABA may also exert inhibitory actions on immature neurons via a shunting mechanism (Chen et al. 1996; Khalilov et al. 1999; Lamsa et al. 2000; Lu and Trussell 2001; Wells et al. 2000). Thus GABA in the immature brain plays both an excitatory and inhibitory roles. Hence the complexity in the GABAergic contributions to neuronal network phenomena including paroxysmal discharges. While mainly antiepileptic effects of GABA have been documented thus far in the immature brain (Kubova and Mares 1991; Kubova et al. 1999; Smythe et al. 1988; Velisek et al. 1995), recent studies using a high-potassium model of ictogenesis in the hippocampal slices from neonatal rats suggested that excitatory GABA may be causally linked to ictal activity in the early developmental window (Dzhala and Staley 2003). The GABAA antagonists bicuculline and gabazine completely suppressed high-potassium-induced ictal-like events, whereas GABAA agonists muscimol and isoguvacine significantly increased the frequency and duration of the ictal events (Dzhala and Staley 2003). In another study using a similar model (Khazipov et al. 2004), blockade of GABAA receptors resulted either in a blockade or reduction in frequency of high-potassium-induced ictal events, in confirmation of the Dzhala and Staley (2003) result, and further suggesting a proconvulsant role for GABA; however, GABAA antagonist also caused a significant increase in the amplitude of population spikes, suggesting a coexisting anticonvulsant role for GABA during the critical development period.
Although slices can provide valuable information, extrapolation of the results obtained in vitro to the in vivo situation may often be difficult in particular when it comes to complex network phenomena (Steriade 2001). Therefore in the present study, we studied the effects of the GABAA acting drugs on epileptiform activity induced by high-K+/low Mg2+ in the hippocampus of postnatal rats in vivo and hippocampal slices in vitro. We found that blockade of GABAA receptors significantly facilitates seizures induced by intrahippocampal injection of high-K+/low Mg2+ solution, whereas the GABAA-promoting drugs—the agonist isoguvacine and positive allosteric modulator diazepam—completely prevents the epileptiform activity. Similar proconvulsive actions of the GABAA antagonists and anticonvulsive actions of the GABAA-promoting drugs were also found in the hippocampal slices in vitro. It appears that in the high-K+/low-Mg2+ model of ictogenesis, GABA acting via GABAA receptors has an anticonvulsant role during the critical developmental period of enhanced excitability.
|
|
METHODS |
|---|
|
Sprague-Dawley rat pups (n = 36) of postnatal days [P] 8–12 and six rat pups at P4–P6 were used for in vivo part of the study and were treated in accordance with the guidelines set by the National Institutes of Health and Dartmouth Medical School for the humane treatment of animals as described in details previously (Khazipov et al. 2004). In brief, animals were anesthetized with isoflurane (induction 4%, maintenance 2%) in an O2 carrier using an agent-specific vaporizer (Isotec 3, Ohmeda Medical System). For general analgesia, 0.01–0.02 mg/kg buprenorphine hydrochloride (Buprenex) was administered subcutaneously. Skin, subcutaneous fat, and periosteum were removed from the skull, which then was covered with a thin layer of dental acrylic except for an area of 2 mm in diameter above the hippocampus and small area above the cerebellum for placement of recording and reference electrodes. Two anchor bars were attached to the frontal and the occipital bones of the skull with dental acrylic. Rats were placed in the cotton nest with the head restrained in the stereotaxic apparatus by the skull bars. The body temperature was maintained constant at 35°C using a heater (Warner Instrumental).
A burr hole of 0.5 mm in diameter was drilled in the skull above the hippocampus. The dura was cut and removed. A wire electrode (50 µm in diameter; California Fine Wire, Grover Beach, CA) for extracellular field potential recordings was inserted into the application cannula (0.2 mm diam, Plastic One. Roanoke, VA). The tip of the recording electrode was extended for 100 µm from the cannula ending. The application cannula with recording electrode was positioned into the CA3 pyramidal cell layer of the hippocampus under stereotaxic and electrophysiological guidance (2.0–2.5 mm caudal to bregma; 2.0–2.5 mm from midline; depth: 2,700–3,100 µm). Reference and ground electrodes were implanted into the cerebellum. After surgery, the isoflurane anesthesia was stopped, and the pups were left to recover from anesthesia for 10–15 min, and then electrophysiological data were recorded uninterrupted for 60–120 min.
Electrical signals were amplified (1,000 times) with filter settings of 0.1–5,000 Hz using a differential amplifier (A-M Systems, Carlsborg, WA) and digitized at 10 kHz using an A/D converter (Digidata 1322A; Axon Instruments). Off-line analysis of the hippocampal electrogram was performed using Clampfit (Axon Instruments) and Origin 5.0 (Microcal Software, Northampton, MA). Group data are expressed as means ± SE; error bars also indicate SE.
Interictal-like activity was defined as brief (80–200 ms) high-amplitude spikes in the electroencephalograph (EEG) that occurred in isolation on a background of otherwise normal activity. Ictal-like activity consisted of rhythmic spikes. Tonic was arbitrary used to describe sustained rhythmic spikes, whereas clonic was defined as bursts of rhythmic spikes interspersed with lower-amplitude, nonrhythmic activity (McCormick and Contreras 2001). The tonic and clonic rhythms refer to the EEG correlates to the tonic and clonic behaviors observed during seizures. In this study, we used these terms arbitrarily to describe the EEG patterns that typically occur in conjunction with behavioral seizures. The term epileptiform discharges was used to describe either ictal or interictal activity.
After the recordings, the rat was anesthetized, and the brain was removed. Sagittal 300-µm slices were cut using a vibroslicer Leica VT 1000S (Leica Microsystems, Nussloch GmbH). Electrode position verification was performed under light microscopic evaluation.
Slice preparation
Sprague-Dawley rat pups (n = 6) of P8–P12 were prepared as described (Khazipov et al. 2004). In brief, rats were deeply anesthetized using isoflurane and decapitated. The brain was removed and placed into ice-cold "solution" of the following composition (in mM): 250 sucrose, 2 KCl, 0.5 CaCl2, 7 MgCl2, 26 NaHCO3, 1.2 NaH2PO4, and 11 glucose (pH = 7.4). Transverse hippocampal slices were cut using the Leica 1000S vibroslicer (Leica Microsystems, Nussloch GmbH). After dissection, slices were kept in an oxygenated (95% O2–5% CO2) artificial cerebrospinal fluid (ACSF) solution of the following composition (in mM): 126 NaCl, 3.5 KCl, 2.0 CaCl2, 1.3 MgCl2, 25 NaHCO3, 1.2 NaH2PO4, and 11 glucose (pH 7.3) at 30–32°C for 
1.5 h before use.
Electrophysiological recordings
For recordings, slices were transferred to a submersion-type thermostatic chamber (Warner Instrument, Hamden, CT) and superfused at 30–32°C at a rate of 1–3 ml/min with the oxygenated ACSF. Extracellular recordings were made from CA3 pyramidal cell layer using borosilicate glass pipettes. The patch electrodes were made from borosilicate glass capillaries (GC150F-15, Clark Electromedical Instruments) and filled with extracellular solution. Pipette resistances ranged from 5 to 7 M
. The recordings were performed using an Axopatch 200A amplifier (Axon Instruments) and digitized (10 kHz) on-line with an A/D converter Digidata 1322A (Axon Instruments).
Administration of drugs
For the in vivo experiments, drugs were applied locally through the stainless-steel cannula (100 µm ID) using microsyringes. Drugs were dissolved in the ACSF. In the experiments with high potassium and low magnesium, 10 mM KCl was substituted for equivalent concentrations of NaCl. MgCl2 was omitted from the ACSF. Application was made by repetitive injection of 5 µl-volumes (duration: 10–15 s; interval: 5 min; number: 
10 times). Repetitive microinjections were chosen instead of single continuous injection to avoid displacement of the recording electrode.
In the in vitro experiments, high K+/low Mg2+ was applied directly to the perfusion solution. When assessing the role of GABAA-acting drugs on seizure induction, the slices were incubated with isoguvacine, bicuculline, gabazine or diazepam for 10 min prior to application of high K+/ low Mg2+.We varied the sequence of drugs application to avoid use-dependent effects.
Chemicals
6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX), D-(–)-2-amino-5-phosphonopentanoic acid (D-APV), isoguvacine, bicuculline, and SR 95531 hydrobromide (gabazine) were obtained from Tocris (Ellisville, MO). All other chemicals were purchased from Sigma (St. Louis, MO).
|
|
RESULTS |
|---|
|
100 µm; Fig. 1A). Seizures occurred after the fifth to ninth microinjection (6.8 ± 1.6; n = 5 rats; Fig. 1D). Electrographic seizures had typical ictal morphology with an initial phase of initial bursting discharge followed by the tonic- (4–10 Hz) and clonic-like discharges (Fig. 1, B and C). Once induced, seizures were generated in response to each additional microinjection. The duration of the interictal and ictal discharges did not change significantly with the serial injections of high-K+/low-Mg2+ solution. Injection of the high-K+ (10 mM)/low-Mg2+ ACSF in young rat pups (P4–P6; n = 6) did not lead to electrographic seizures (not shown).
|
|
|
In the next series of experiments, we studied the effects of GABAA-acting drugs on the high-K+/low-Mg2+-induced epileptiform activity in the P8-12 hippocampal slices in vitro (Fig. 4). Using extracellular field potential recordings form CA3 pyramidal cell layer we found that brief application of the high-K+/low-Mg2+ ACSF readily induces ictal-like tonic-clonic discharges in all slices studied (n = 11; Fig. 4A). Maximal amplitude and frequency of the population spikes were 1.2 ± 0.2 mV and 9.2 ± 1.1 Hz during the epileptiform discharges. In the presence of 10 µM isoguvacine, application of high-K+/ low-Mg2+ solution also caused epileptiform activity in P8 slices but both the maximal amplitude and frequency of population spikes during the discharges were significantly reduced by 25 ± 3 and 42 ± 3%, respectively (n = 6; Fig. 4C). In P12 slices, isoguvacine (10 µM) completely prevented the generation of epileptiform discharges in response to high-K+/low-Mg2+ solution (n = 4). Bicuculline (15 µM) (n = 6) and gabazine (n = 5) (10 µM) increased the maximal amplitude of the population spikes by 26 ± 3% as well as the maximal frequency of the population spikes by 53 ± 4% (for bicuculline, n = 3 at P8 and n = 3 at P12; for gabazine, n = 3 at P8 and n = 2 at P12 slices; Fig. 4B). Application of diazepam 10 µM did not significantly change the amplitude or frequency of discharges evoked by application of 10 mM K+/low Mg2+ solution (n = 4; n = 2 at P8 and n = 2 at P12).
|
|
|
DISCUSSION |
|---|
|
We found that blockade of GABAA receptors with bicuculline and gabazine facilitated high-K+/low-Mg2+-induced seizures, and bicuculline also induced seizures in 30% of cases in vivo. We also found that isoguvacine, which activates GABAA receptors directly, as well as diazepam, which enhances GABAA-mediated responses evoked by endogenous GABA, efficiently inhibit seizures induced by high-K+/low-Mg2+ solution in vivo. Similar proconvulsive effects of the GABAA blockers and anticonvulsive effects of the GABAA agonist were observed in the model of high-K+/low-Mg2+-induced ictogenesis in the hippocampal slices at P8–P12 rats in vitro. The present results are consistent with an anticonvulsant role of GABA during early brain development.
The role of GABA in ictogenesis during the first weeks of life has been previously studied in different in vitro and in vivo models, but the conclusions differ. It has been demonstrated that blockade of GABAA receptors induces interictal- and ictal-like activities (Gomez-Di Cesare et al. 1997; Khalilov et al. 1997, 1999; Lamsa et al. 2000; Quilichini et al. 2002, 2003; Swann and Brady 1984; Wells et al. 2000) and aggravates seizure-like activity induced by other epileptogenic agents and conditions in various hippocampal and neocortical preparations from birth onwards. GABAA agonists and positive modulators also typically suppress epileptiform activity in the immature cortex (Quilichini et al. 2002, 2003). Yet in several models of ictogenesis, including the acute high-potassium model in hippocampal slices (Dzhala and Staley 2003; Khazipov et al. 2004) and mirror focus in the intact hippocampus in vitro model (Khalilov et al. 2003), blockade of GABAA receptors reduces the frequency or even completely suppresses ictal-like events, whereas GABAA agonists increases the frequency and duration of the ictal-like events (Dzhala and Staley 2003). Interestingly, the "proepileptic" actions of GABA have been also observed in several in vitro models of ictogenesis in adults. It has been shown that during seizure-like activity in slices from adult animals, a dynamic switch occurs in the action of GABA from inhibitory to excitatory as a result of massive release of GABA (Avoli et al. 1996; Lopantsev and Avoli 1998) and that GABAA-mediated excitation contributes substantially to neuronal synchronization during seizure-like events in the low-magnesium model (Kohling et al. 2000). Exposure of a rat hippocampal slice to GABAB receptor antagonists in the absence of ionotropic glutamatergic transmission leads to a progressive synchronization of spontaneous interneuronal activity (Uusisaari et al. 2002). Fujiwara-Tsukamato et al. (2003) have shown that GABAergic excitation participates in the expression of seizure-like rhythmic synchronization (afterdischarge) in the mature hippocampal CA1 region. Involvement of depolarizing GABA in the generation of interictal activity has been also shown in slices from patients with temporal lobe epilepsy (Cohen et al. 2002). On the other hand, in intact adult animals in vivo, GABAA receptor agonists and modulators, which enhance GABAA action typically exert anticonvulsive actions (Sankar and Holmes 2004).
Diversity in the roles for GABA in different models of ictogenesis may partly reflect dualism in the actions of depolarizing GABA. Even though GABA has a depolarizing and excitatory effect, GABA may also exert inhibitory function due to a shunting mechanism (Chen et al. 1996; Khalilov et al. 1999; Lamsa et al. 2000; Lu and Trussell 2001; Wells et al. 2000). The net effect of GABA depends on several factors including the reversal potential for GABAA-mediated responses. Indeed, the depolarizing effect of GABA in the immature brain is demonstrated by particular physiological patterns of activity such as giant depolarizing potentials in vitro (Ben-Ari et al. 1989; Khazipov et al. 2004). Yet despite these depolarizing effects of GABA, seizures do not spontaneously occur. A more positive shift in the reversal of GABAA-mediated signals results in seizures sensitive to GABAA antagonists (Khalilov et al. 2003).
Thus GABAergic control of epileptiform activity in the immature brain appears to be extremely complex with a net effect depending on variety of factors contributing to ictogenesis. Further studies are needed to determine the role of GABA in various animal models of ictogenesis and in children with epilepsy of various etiologies.
|
|
GRANTS |
|---|
|
|
|
FOOTNOTES |
|---|
Address for reprint requests and other correspondence: G. L. Holmes, Section of Neurology, Dartmouth Medical School, Dartmouth-Hitchcock Medical School, One Medical Center Dr., Lebanon, NH 03756 (E-mail: Gregory.L.Holmes{at}Dartmouth.Edu)
|
|
REFERENCES |
|---|
|
Avoli M, Barbarosie M, Lucke A, Nagao T, Lopantsev V, and Kohling R, Synchronous GABA-mediated potentials and epileptiform discharges in the rat limbic system in vitro. J Neurosci 16: C3912–3924, 1996.
Baram TZ, Gerth A, and Schultz L. Febrile seizures: an appropriate-aged model suitable for long-term studies. Brain Res Devel Brain Res 98: C265–270, 1997.
Baram TZ and Hatalski CG. Neuropeptide-mediated excitability: a key triggering mechanism for seizure generation in the developing brain. Trends Neurosci 21: C471–476, 1998.
Ben-Ari Y. Excitatory actions of GABA during development: the nature of the nurture. Nat Rev Neurosci 3: C728–739, 2002.
Ben-Ari Y, Cherubini E, Corradetti R, and Gaiarsa JL. Giant synaptic potentials in immature rat CA3 hippocampal neurones. J Physiol 416: C303–325, 1989.
Ben-Ari Y, Khazipov R, Leinekugel X, Caillard O, and Gaiarsa JL. GABAA, NMDA and AMPA receptors: a developmentally regulated "menage a trois." Trends Neurosci 20: C523–529, 1997.
Chen G, Trombley PQ, and van den Pol AN. Excitatory actions of GABA in developing rat hypothalamic neurons. J Physiol 494: C451–464, 1996.
Cohen I, Navarro V, Clemenceau S, Baulac M, and Miles R. On the origin of interictal activity in human temporal lobe epilepsy in vitro. Science 298: C1418–1421, 2002.
Dzhala VI and Staley KJ. Excitatory actions of endogenously released GABA contribute to initiation of ictal epileptiform activity in the developing hippocampus. J Neurosci 23: C1840–1846, 2003.
Fujiwara-Tsukamoto Y, Isomura Y, Nambu A, and Takada M. Excitatory GABA input directly drives seizure-like rhythmic synchronization in mature hippocampal CA1 pyramidal cells. Neuroscience 119: C265–275, 2003.
Gomez-Di Cesare CM, Smith KL, Rice FL, and Swann JW. Axonal remodeling during postnatal maturation of CA3 hippocampal pyramidal neurons. J Comp Neurol 384: C165–180, 1997.
Holmes GL. Neonatal seizures. Semin Pediatr Neurol 1: C72–82, 1994.
Holmes GL and Ben-Ari Y. Seizures in the developing brain: perhaps not so benign after all. Neuron 21: C1231–1234, 1998.
Holmes GL, Khazipov R, and Ben Ari Y. New concepts in neonatal seizures. Neuroreport 13: C3–8, 2002.
Holtzman D, Obana K, and Olson J. Hyperthermia-induced seizures in the rat pup: a model for febrile convulsions in children. Science 213: C1034–1036, 1981.
Jensen FE, Applegate CD, Holtzman D, Belin TR, and Burchfiel JL. Epileptogenic effect of hypoxia in the immature rodent brain. Ann Neurol 29: C629–637, 1991.
Khalilov I, Dzhala V, Ben-Ari Y, and Khazipov R. Dual role of GABA in the neonatal rat hippocampus. Dev Neurosci 21: C310–319, 1999.
Khalilov I, Holmes GL, and Ben Ari Y. In vitro formation of a secondary epileptogenic mirror focus by interhippocampal propagation of seizures. Nat Neurosci 6: C1079–1085, 2003.
Khalilov I, Khazipov R, Esclapez M, and Ben-Ari Y. Bicuculline induces ictal seizures in the intact hippocampus recorded in vitro. Eur J Pharmacol 319: C5–6, 1997.
Khazipov R, Khalilov I, Tyzio R, Morozova E, Ben Ari Y, and Holmes GL. Developmental changes in GABAergic actions and seizure susceptibility in the rat hippocampus. Eur J Neurosci 19: C590–600, 2004a.
Kohling R, Vreugdenhil M, Bracci E, and Jefferys JG. Ictal epileptiform activity is facilitated by hippocampal GABAA receptor-mediated oscillations. J Neurosci 20: C6820–6829, 2000.
Kubova H and Mares P. Anticonvulsant effects of phenobarbital and primidone during ontogenesis in rats. Epilepsy Res 10: C148–155, 1991.[CrossRef]
Kubova H, Mikulecka A, Haugvicova R, and Mares P. The benzodiazepine receptor partial agonist Ro-198022 suppresses generalized seizures without impairing motor functions in developing rats. Naunyn Schmiedebergs Arch Pharmacol 360: C 565–574, 1999.
Lamsa K, Palva JM, Ruusuvuori E, Kaila K, and Taira T. Synaptic GABA(A) activation inhibits AMPA-kainate receptor-mediated bursting in the newborn (P0-P2) rat hippocampus. J Neurophysiol 83: C359–366, 2000.
Leinekugel X, Khazipov R, Cannon RC, Hirase H, Ben Ari Y, and Buzsaki G. Correlated bursts of activity in the neonatal hippocampus in vivo. Science 296: 2049–2052, 2002.
Lopantsev V and Avoli M. Participation of GABAA-mediated inhibition in ictallike discharges in the rat entorhinal cortex. J Neurophysiol 79: C352–360, 1998.
Lu T and Trussell LO. Mixed excitatory and inhibitory GABA-mediated transmission in chick cochlear nucleus. J Physiol 535: C125–131, 2001.
McCormick DA and Contreras D. On the cellular and network bases of epileptic seizures. Annu Rev Physiol 63: C815–846, 2001.[CrossRef]
McLean HA, Caillard O, Khazipov R, Ben-Ari Y, and Gaiarsa JL. Spontaneous release of GABA activates GABAB receptors and controls network activity in the neonatal rat hippocampus. J Neurophysiol 76: C1036–1046, 1996.
Moshe SL, Sharpless NS, and Kaplan J. Kindling in developing rats: variability of afterdischarge thresholds with age. Brain Res 211: C190–195, 1981.[CrossRef]
Quilichini PP, Diabira D, Chiron C, Ben Ari Y, and Gozlan H. Persistent epileptiform activity induced by low Mg2+ in intact immature brain structures. Eurn J Neurosci 16: C850–860, 2002.
Quilichini PP, Diabira D, Chiron C, Milh M, Ben Ari Y, and Gozlan H. Effects of antiepileptic drugs on refractory seizures in the intact immature corticohippocampal formation in vitro. Epilepsia 44: C1365–1374, 2003.[CrossRef]
Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, Pirvola U, Saarma M, and Kaila K. The K+/Cl– co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397: C251–255, 1999.
Sankar R and Holmes GL. Mechanisms of action for the commonly used antiepileptic drugs: relevance to antiepileptic drug-associated neurobehavioral adverse effects. J Child Neurol 19, Suppl 1: C6–14, 2004.
Smythe JW, Ryan CL, and Pappas BA. A behavioral and electrocorticographic comparison of diazepam and pentylenetetrazol in rat pups. Pharmacol Biochem Behav 30: C479–482, 1988.[CrossRef]
Steriade M. Impact of network activities on neuronal properties in corticothalamic systems. J Neurophysiol 86: C1–39, 2001.
Swann JW and Brady RJ. Penicillin-induced epileptogenesis in immature rat CA3 hippocampal pyramidal cells. Brain Res 314: C243–254, 1984.
Swann JW and Hablitz JJ. Cellular abnormalities and synaptic plasticity in seizure disorders of the immature nervous system. Ment Retard Dev Disabil Res Rev 6: C258–267, 2000.
Tremblay E, Nitecka L, Berger ML, and Ben-Ari Y. Maturation of kainic acid seizure-brain damage syndrome in the rat. I. Clinical, electrographic and metabolic observations. Neuroscience 13: C1051–1072, 1984.
Uusisaari M, Smirnov S, Voipio J, and Kaila K. Spontaneous epileptiform activity mediated by GABA(A) receptors and gap junctions in the rat hippocampal slice following long-term exposure to GABA(B) antagonists. Neuropharmacology 43: C563–572, 2002.
Velisek L, Veliskova J, Ptachewich Y, Ortiz J, Shinnar S, and Moshe SL. Age-dependent effects of gamma-aminobutyric acid agents on flurothyl seizures. Epilepsia 36: C 636–643, 1995.[Medline]
Wells JE, Porter JT, and Agmon A. GABAergic inhibition suppresses paroxysmal network activity in the neonatal rodent hippocampus and neocortex. J Neurosci 20: C8822–8830, 2000.
This article has been cited by other articles:
|
|
 |
|
  F. Frohlich, M. Bazhenov, V. Iragui-Madoz, and T. J. Sejnowski Potassium Dynamics in the Epileptic Cortex: New Insights on an Old Topic Neuroscientist, October 1, 2008; 14(5): 422 - 433. [Abstract] [PDF]
|
|
|
|
 |
|
 D. Isaev, E. Isaeva, T. Shatskih, Q. Zhao, N. C. Smits, N. W. Shworak, R. Khazipov, and G. L. Holmes Role of Extracellular Sialic Acid in Regulation of Neuronal and Network Excitability in the Rat Hippocampus J. Neurosci., October 24, 2007; 27(43): 11587 - 11594. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ben-Ari, J.-L. Gaiarsa, R. Tyzio, and R. Khazipov GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations Physiol Rev, October 1, 2007; 87(4): 1215 - 1284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Ziburkus, J. R. Cressman, E. Barreto, and S. J. Schiff Interneuron and Pyramidal Cell Interplay During In Vitro Seizure-Like Events J Neurophysiol, June 1, 2006; 95(6): 3948 - 3954. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
TOP
ABSTRACT
INTRODUCTION
), recorded in CA3 pyramidal cell layer. Note that seizure-like events are generated in response to 2nd application. B and C: example of the ictal-like event on expanded time scale and its phases. D: average plot of seizure probability obtained from 5 animals.