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Research paper thumbnail of Matrix metalloproteinase-9 activity increased by two different types of epileptic seizures that do not induce neuronal death: A possible role in homeostatic synaptic plasticity

Matrix metalloproteases (MMPs) degrade or modify extracellular matrix or membrane-bound proteins ... more Matrix metalloproteases (MMPs) degrade or modify extracellular matrix or membrane-bound proteins in the brain. MMP-2 and MMP-9 are activated by treatments that result in a sustained neuronal depolarization and are thought to contribute to neuronal death and structural remodeling. At the synapse, MMP actions on extracellular proteins contribute to changes in synaptic efficacy during learning paradigms. They are also activated during epileptic seizures, and MMP-9 has been associated with the establishment of aberrant synaptic connections after neuronal death induced by kainate treatment. It remains unclear whether MMPs are activated by epileptic activities that do not induce cell death. Here we examine this point in two animal models of epilepsy that do not involve extensive cell damage. We detected an elevation of MMP-9 enzymatic activity in cortical regions of secondary generalization after focal seizures induced by 4-aminopyridine (4-AP) application in rats. Pro-MMP-9 levels were also higher in Wistar Glaxo Rijswijk (WAG/Rij) rats, a genetic model of generalized absence epilepsy, than they were in Sprague-Dawley rats, and this elevation was correlated with diurnally occurring spike-wave-discharges in WAG/Rij rats. The increased enzymatic activity of MMP-9 in these two different epilepsy models is associated with synchronized neuronal activity that does not induce widespread cell death. In these epilepsy models MMP-9 induction may therefore be associated with functions such as homeostatic synaptic plasticity rather than neuronal death. ß

Research paper thumbnail of Generalization of seizures parallels the formation of “dark” neurons in the hippocampus and pontine reticular formation after focal–cortical application of 4-aminopyridine (4-AP) in the rat

Distribution and time course of the occurrence of "dark" neurons were compared with the EEG activ... more Distribution and time course of the occurrence of "dark" neurons were compared with the EEG activity and behavior of rats during 4-aminopyridine (4-AP) induced epileptic seizures.

Research paper thumbnail of Temporal changes of intracellular signal elements and examination of neuronal cell viability in a 4-aminopyridine induced focal epileptic model in the rat brain

Research paper thumbnail of Correlation between seizure spreading and spatio-temporal induction of matrix metalloproteinase-9 in a 4-aminopyridine induced focal epilepsy model

Research paper thumbnail of Can the Pontine Reticular Formation be the (6Hz) theta generator?

Research paper thumbnail of Seizure related expression of matrix metalliproteinases in pharmacological and genetic models without tissue damage

Research paper thumbnail of Increased functional connectivity in the limbic network of isoflurane-anaesthetized rats during electrical stimulation of the nucleus pontis oralis

Research paper thumbnail of The mode of death of epilepsy-induced “dark” neurons is neither necrosis nor apoptosis: an electron-microscopic study

Morphological aspects of the formation and fate of neurons that underwent dramatic ultrastructura... more Morphological aspects of the formation and fate of neurons that underwent dramatic ultrastructural compaction ("dark" neurons) induced by 4-aminopyridine epilepsy were compared in an excitotoxic and a neighboring normal-looking area of the rat brain cortex. In the excitotoxic area, the later the ultrastructural compaction began after the outset of epilepsy, the higher the degree of mitochondrial swelling and ribosomal sequestration were; a low proportion of the affected neurons recovered in 1 day; the others were removed from the tissue through a necrotic-like sequence of ultrastructural changes (swelling of the cell, gradual disintegration of the intracellular organelles and dispersion of their remnants into the surroundings through large gaps in the plasma and nuclear membranes). In the normallooking area, the ultrastructural elements in the freshly-formed "dark" neurons were apparently normal; most of them recovered in 1 day; the others were removed from the tissue through an apoptotic-like sequence of ultrastructural changes (the formation of membrane-bound, electrondense, compact cytoplasmic protrusions, and their braking up into membrane-bound, electrondense, compact fragments, which were swallowed by phagocytotic cells). Since these ultrastructural features differ fundamentally from those characteristic of necrosis, it seems logical that, in stark contrast with the prevailing conception, the cause of death of the epilepsy-induced "dark" neurons in the normallooking cortical area cannot be necrosis. An apoptotic origin can also be precluded by virtue of the absence of its characteristics. As regards the excitotoxic environment, it is assumed that pathobiochemical processes in it superimpose a necrotic-like removal process on already dead "dark" neurons.

Research paper thumbnail of Res. Center for Natural Sci., Budapest, Hungary

Research paper thumbnail of Propagation of spike and wave activity to the medial prefrontal cortex and dorsal raphe nucleus of WAG/Rij rats

Physiology & Behavior, 2007

Although there is pharmacological evidence for the involvement of the serotonergic system in the ... more Although there is pharmacological evidence for the involvement of the serotonergic system in the expression of spike and wave discharges (SWDs) in experimental absence epilepsy, no direct investigation of this paroxysm in the dorsal raphe nucleus (DRN), one of the main serotonergic nuclei, has been carried out. We have now recorded the EEG simultaneously with local field potentials and unit

Research paper thumbnail of Brainstem Stimulation Increases Functional Connectivity of Basal Forebrain-Paralimbic Network in Isoflurane-Anesthetized Rats

Brain Connectivity, 2014

Brain states and cognitive-behavioral functions are precisely controlled by subcortical neuromodu... more Brain states and cognitive-behavioral functions are precisely controlled by subcortical neuromodulatory networks. Manipulating key components of the ascending arousal system (AAS), via deep-brain stimulation, may help facilitate global arousal in anesthetized animals. Here we test the hypothesis that electrical stimulation of the oral part of the pontine reticular nucleus (PnO) under light isoflurane anesthesia, associated with loss of consciousness, leads to cortical desynchronization and specific changes in blood-oxygenation-level-dependent (BOLD) functional connectivity (FC) of the brain. BOLD signals were acquired simultaneously with frontal epidural electroencephalogram before and after PnO stimulation. Whole-brain FC was mapped using correlation analysis with seeds in major centers of the AAS. PnO stimulation produced cortical desynchronization, a decrease in dand h-band power, and an increase in approximate entropy. Significant increases in FC after PnO stimulation occurred between the left nucleus Basalis of Meynert (NBM) as seed and numerous regions of the paralimbic network. Smaller increases in FC were present between the central medial thalamic nucleus and retrosplenium seeds and the left caudate putamen and NBM. The results suggest that, during light anesthesia, PnO stimulation preferentially modulates basal forebrain-paralimbic networks. We speculate that this may be a reflection of disconnected awareness.

Research paper thumbnail of Deep-brain silicon multielectrodes with surface-modified Pt recording sites

2012 IEEE Sensors, 2012

Extreme-long (up to 70 mm) Si neural multielectrodes are presented for the first time. Probes wit... more Extreme-long (up to 70 mm) Si neural multielectrodes are presented for the first time. Probes with different shaft lengths (15-70 mm) were formed by deep reactive ion etching and have been equipped with Pt recording sites of various configurations. In vivo measurements on rodents indicated good mechanical stability, robust implantation and targeting capability, and high quality signals from different locations of the cerebrum have been recorded. The accompanied tissue damage was characterized by histology. With platinum electroplating, electrical impedance reduction was achieved, the improved charge transfer capability was characterized by cyclic voltammetry.

Research paper thumbnail of Matrix metalloproteinase-9 activity increased by two different types of epileptic seizures that do not induce neuronal death: A possible role in homeostatic synaptic plasticity

Neurochemistry International, 2010

Matrix metalloproteases (MMPs) degrade or modify extracellular matrix or membrane-bound proteins ... more Matrix metalloproteases (MMPs) degrade or modify extracellular matrix or membrane-bound proteins in the brain. MMP-2 and MMP-9 are activated by treatments that result in a sustained neuronal depolarization and are thought to contribute to neuronal death and structural remodeling. At the synapse, MMP actions on extracellular proteins contribute to changes in synaptic efficacy during learning paradigms. They are also activated during epileptic seizures, and MMP-9 has been associated with the establishment of aberrant synaptic connections after neuronal death induced by kainate treatment. It remains unclear whether MMPs are activated by epileptic activities that do not induce cell death. Here we examine this point in two animal models of epilepsy that do not involve extensive cell damage. We detected an elevation of MMP-9 enzymatic activity in cortical regions of secondary generalization after focal seizures induced by 4-aminopyridine (4-AP) application in rats. Pro-MMP-9 levels were also higher in Wistar Glaxo Rijswijk (WAG/Rij) rats, a genetic model of generalized absence epilepsy, than they were in Sprague-Dawley rats, and this elevation was correlated with diurnally occurring spike-wave-discharges in WAG/Rij rats. The increased enzymatic activity of MMP-9 in these two different epilepsy models is associated with synchronized neuronal activity that does not induce widespread cell death. In these epilepsy models MMP-9 induction may therefore be associated with functions such as homeostatic synaptic plasticity rather than neuronal death. ß

Research paper thumbnail of Doxycycline could aggravate the absence-like epileptic seizures of WAG/Rij rats via matrix metalloproteinase inhibition

Neurochemistry International, 2011

Matrix metalloproteinases (MMPs) are known to be activated in the brain by epileptic seizures and... more Matrix metalloproteinases (MMPs) are known to be activated in the brain by epileptic seizures and elevated MMP-9 activity has been found in a genetic model of generalized absence epilepsy (Wistar Albino Glaxo Rijswijk/WAG/Rij rats). In this study we posed the question, whether MMP inhibitory dose of doxycycline (20 mg/kg) could affect the spike-wave-discharges (SWDs) of the WAG/Rij rat. We found that intraperitoneal (i.p.) administration of 20 mg/kg doxycycline significantly increased the incidence and duration of SWDs for 4 h. As doxycycline has both MMP inhibitory and anti-inflammatory effects we also tested a lower dose of doxycycline (10 mg/kg, i.p.) and a selective broad-spectrum MMP inhibitor GM6001 (N-[2(R)-2-(hydroxamido carbonylmethyl)-4-methylpentanoyl]-L-tryptophane methylamide) intracerebroventricularly (i.c.v., 10 ng/rat). While 10 mg/kg doxycycline significantly increased the SWD number for 1 h, GM6001 significantly increased the SWD number during the whole 4-h recording period. Our results could indicate that the induction of MMPs in the epileptic brain, besides contributing to structural remodeling, would also be associated with such functions as homeostatic synaptic plasticity which might counteract epileptic seizures.

Research paper thumbnail of In Vivo Measurements With Robust Silicon-Based Multielectrode Arrays With Extreme Shaft Lengths

IEEE Sensors Journal, 2000

In this paper, manufacturing and in vivo testing of extreme-long Si-based neural microelectrode a... more In this paper, manufacturing and in vivo testing of extreme-long Si-based neural microelectrode arrays are presented. Probes with different shaft lengths (15-70 mm) are formed by deep reactive ion etching and have been equipped with platinum electrodes of various configurations. In vivo measurements on rats indicate good mechanical stability, robust implantation, and targeting capability. High-quality signals have been recorded from different locations of the cerebrum of the rodents. The accompanied tissue damage is characterized by histology.

Research paper thumbnail of Special Issue on Sensors and Sensing Systems for Neurophysiology

IEEE Sensors Journal, 2000

Research paper thumbnail of Seizure related expression of matrix metalliproteinases in pharmacological and genetic models without tissue damage

Frontiers in Systems Neuroscience, 2009

Research paper thumbnail of Can the Pontine Reticular Formation be the (6Hz) theta generator?

Frontiers in Systems Neuroscience, 2009

Research paper thumbnail of Abstracts presented at the 8th International Symposium on Memory and Awareness in Anesthesia (MAA8): Milwaukee, WI, USA, June 2-5, 2011

British Journal of Anaesthesia, 2012

Anaesthesia offers an important tool for the scientific study of consciousness. Recent works will... more Anaesthesia offers an important tool for the scientific study of consciousness. Recent works will be discussed with an aim towards answering basic questions regarding the nature of consciousness and how it is removed by anaesthesia. What brain areas and systems must ...

Research paper thumbnail of Generalization of seizures parallels the formation of “dark” neurons in the hippocampus and pontine reticular formation after focal–cortical application of 4-aminopyridine (4-AP) in the rat

Brain Research, 2008

Distribution and time course of the occurrence of "dark" neurons were compared with the EEG activ... more Distribution and time course of the occurrence of "dark" neurons were compared with the EEG activity and behavior of rats during 4-aminopyridine (4-AP) induced epileptic seizures.

Research paper thumbnail of Matrix metalloproteinase-9 activity increased by two different types of epileptic seizures that do not induce neuronal death: A possible role in homeostatic synaptic plasticity

Matrix metalloproteases (MMPs) degrade or modify extracellular matrix or membrane-bound proteins ... more Matrix metalloproteases (MMPs) degrade or modify extracellular matrix or membrane-bound proteins in the brain. MMP-2 and MMP-9 are activated by treatments that result in a sustained neuronal depolarization and are thought to contribute to neuronal death and structural remodeling. At the synapse, MMP actions on extracellular proteins contribute to changes in synaptic efficacy during learning paradigms. They are also activated during epileptic seizures, and MMP-9 has been associated with the establishment of aberrant synaptic connections after neuronal death induced by kainate treatment. It remains unclear whether MMPs are activated by epileptic activities that do not induce cell death. Here we examine this point in two animal models of epilepsy that do not involve extensive cell damage. We detected an elevation of MMP-9 enzymatic activity in cortical regions of secondary generalization after focal seizures induced by 4-aminopyridine (4-AP) application in rats. Pro-MMP-9 levels were also higher in Wistar Glaxo Rijswijk (WAG/Rij) rats, a genetic model of generalized absence epilepsy, than they were in Sprague-Dawley rats, and this elevation was correlated with diurnally occurring spike-wave-discharges in WAG/Rij rats. The increased enzymatic activity of MMP-9 in these two different epilepsy models is associated with synchronized neuronal activity that does not induce widespread cell death. In these epilepsy models MMP-9 induction may therefore be associated with functions such as homeostatic synaptic plasticity rather than neuronal death. ß

Research paper thumbnail of Generalization of seizures parallels the formation of “dark” neurons in the hippocampus and pontine reticular formation after focal–cortical application of 4-aminopyridine (4-AP) in the rat

Distribution and time course of the occurrence of "dark" neurons were compared with the EEG activ... more Distribution and time course of the occurrence of "dark" neurons were compared with the EEG activity and behavior of rats during 4-aminopyridine (4-AP) induced epileptic seizures.

Research paper thumbnail of Temporal changes of intracellular signal elements and examination of neuronal cell viability in a 4-aminopyridine induced focal epileptic model in the rat brain

Research paper thumbnail of Correlation between seizure spreading and spatio-temporal induction of matrix metalloproteinase-9 in a 4-aminopyridine induced focal epilepsy model

Research paper thumbnail of Can the Pontine Reticular Formation be the (6Hz) theta generator?

Research paper thumbnail of Seizure related expression of matrix metalliproteinases in pharmacological and genetic models without tissue damage

Research paper thumbnail of Increased functional connectivity in the limbic network of isoflurane-anaesthetized rats during electrical stimulation of the nucleus pontis oralis

Research paper thumbnail of The mode of death of epilepsy-induced “dark” neurons is neither necrosis nor apoptosis: an electron-microscopic study

Morphological aspects of the formation and fate of neurons that underwent dramatic ultrastructura... more Morphological aspects of the formation and fate of neurons that underwent dramatic ultrastructural compaction ("dark" neurons) induced by 4-aminopyridine epilepsy were compared in an excitotoxic and a neighboring normal-looking area of the rat brain cortex. In the excitotoxic area, the later the ultrastructural compaction began after the outset of epilepsy, the higher the degree of mitochondrial swelling and ribosomal sequestration were; a low proportion of the affected neurons recovered in 1 day; the others were removed from the tissue through a necrotic-like sequence of ultrastructural changes (swelling of the cell, gradual disintegration of the intracellular organelles and dispersion of their remnants into the surroundings through large gaps in the plasma and nuclear membranes). In the normallooking area, the ultrastructural elements in the freshly-formed "dark" neurons were apparently normal; most of them recovered in 1 day; the others were removed from the tissue through an apoptotic-like sequence of ultrastructural changes (the formation of membrane-bound, electrondense, compact cytoplasmic protrusions, and their braking up into membrane-bound, electrondense, compact fragments, which were swallowed by phagocytotic cells). Since these ultrastructural features differ fundamentally from those characteristic of necrosis, it seems logical that, in stark contrast with the prevailing conception, the cause of death of the epilepsy-induced "dark" neurons in the normallooking cortical area cannot be necrosis. An apoptotic origin can also be precluded by virtue of the absence of its characteristics. As regards the excitotoxic environment, it is assumed that pathobiochemical processes in it superimpose a necrotic-like removal process on already dead "dark" neurons.

Research paper thumbnail of Res. Center for Natural Sci., Budapest, Hungary

Research paper thumbnail of Propagation of spike and wave activity to the medial prefrontal cortex and dorsal raphe nucleus of WAG/Rij rats

Physiology & Behavior, 2007

Although there is pharmacological evidence for the involvement of the serotonergic system in the ... more Although there is pharmacological evidence for the involvement of the serotonergic system in the expression of spike and wave discharges (SWDs) in experimental absence epilepsy, no direct investigation of this paroxysm in the dorsal raphe nucleus (DRN), one of the main serotonergic nuclei, has been carried out. We have now recorded the EEG simultaneously with local field potentials and unit

Research paper thumbnail of Brainstem Stimulation Increases Functional Connectivity of Basal Forebrain-Paralimbic Network in Isoflurane-Anesthetized Rats

Brain Connectivity, 2014

Brain states and cognitive-behavioral functions are precisely controlled by subcortical neuromodu... more Brain states and cognitive-behavioral functions are precisely controlled by subcortical neuromodulatory networks. Manipulating key components of the ascending arousal system (AAS), via deep-brain stimulation, may help facilitate global arousal in anesthetized animals. Here we test the hypothesis that electrical stimulation of the oral part of the pontine reticular nucleus (PnO) under light isoflurane anesthesia, associated with loss of consciousness, leads to cortical desynchronization and specific changes in blood-oxygenation-level-dependent (BOLD) functional connectivity (FC) of the brain. BOLD signals were acquired simultaneously with frontal epidural electroencephalogram before and after PnO stimulation. Whole-brain FC was mapped using correlation analysis with seeds in major centers of the AAS. PnO stimulation produced cortical desynchronization, a decrease in dand h-band power, and an increase in approximate entropy. Significant increases in FC after PnO stimulation occurred between the left nucleus Basalis of Meynert (NBM) as seed and numerous regions of the paralimbic network. Smaller increases in FC were present between the central medial thalamic nucleus and retrosplenium seeds and the left caudate putamen and NBM. The results suggest that, during light anesthesia, PnO stimulation preferentially modulates basal forebrain-paralimbic networks. We speculate that this may be a reflection of disconnected awareness.

Research paper thumbnail of Deep-brain silicon multielectrodes with surface-modified Pt recording sites

2012 IEEE Sensors, 2012

Extreme-long (up to 70 mm) Si neural multielectrodes are presented for the first time. Probes wit... more Extreme-long (up to 70 mm) Si neural multielectrodes are presented for the first time. Probes with different shaft lengths (15-70 mm) were formed by deep reactive ion etching and have been equipped with Pt recording sites of various configurations. In vivo measurements on rodents indicated good mechanical stability, robust implantation and targeting capability, and high quality signals from different locations of the cerebrum have been recorded. The accompanied tissue damage was characterized by histology. With platinum electroplating, electrical impedance reduction was achieved, the improved charge transfer capability was characterized by cyclic voltammetry.

Research paper thumbnail of Matrix metalloproteinase-9 activity increased by two different types of epileptic seizures that do not induce neuronal death: A possible role in homeostatic synaptic plasticity

Neurochemistry International, 2010

Matrix metalloproteases (MMPs) degrade or modify extracellular matrix or membrane-bound proteins ... more Matrix metalloproteases (MMPs) degrade or modify extracellular matrix or membrane-bound proteins in the brain. MMP-2 and MMP-9 are activated by treatments that result in a sustained neuronal depolarization and are thought to contribute to neuronal death and structural remodeling. At the synapse, MMP actions on extracellular proteins contribute to changes in synaptic efficacy during learning paradigms. They are also activated during epileptic seizures, and MMP-9 has been associated with the establishment of aberrant synaptic connections after neuronal death induced by kainate treatment. It remains unclear whether MMPs are activated by epileptic activities that do not induce cell death. Here we examine this point in two animal models of epilepsy that do not involve extensive cell damage. We detected an elevation of MMP-9 enzymatic activity in cortical regions of secondary generalization after focal seizures induced by 4-aminopyridine (4-AP) application in rats. Pro-MMP-9 levels were also higher in Wistar Glaxo Rijswijk (WAG/Rij) rats, a genetic model of generalized absence epilepsy, than they were in Sprague-Dawley rats, and this elevation was correlated with diurnally occurring spike-wave-discharges in WAG/Rij rats. The increased enzymatic activity of MMP-9 in these two different epilepsy models is associated with synchronized neuronal activity that does not induce widespread cell death. In these epilepsy models MMP-9 induction may therefore be associated with functions such as homeostatic synaptic plasticity rather than neuronal death. ß

Research paper thumbnail of Doxycycline could aggravate the absence-like epileptic seizures of WAG/Rij rats via matrix metalloproteinase inhibition

Neurochemistry International, 2011

Matrix metalloproteinases (MMPs) are known to be activated in the brain by epileptic seizures and... more Matrix metalloproteinases (MMPs) are known to be activated in the brain by epileptic seizures and elevated MMP-9 activity has been found in a genetic model of generalized absence epilepsy (Wistar Albino Glaxo Rijswijk/WAG/Rij rats). In this study we posed the question, whether MMP inhibitory dose of doxycycline (20 mg/kg) could affect the spike-wave-discharges (SWDs) of the WAG/Rij rat. We found that intraperitoneal (i.p.) administration of 20 mg/kg doxycycline significantly increased the incidence and duration of SWDs for 4 h. As doxycycline has both MMP inhibitory and anti-inflammatory effects we also tested a lower dose of doxycycline (10 mg/kg, i.p.) and a selective broad-spectrum MMP inhibitor GM6001 (N-[2(R)-2-(hydroxamido carbonylmethyl)-4-methylpentanoyl]-L-tryptophane methylamide) intracerebroventricularly (i.c.v., 10 ng/rat). While 10 mg/kg doxycycline significantly increased the SWD number for 1 h, GM6001 significantly increased the SWD number during the whole 4-h recording period. Our results could indicate that the induction of MMPs in the epileptic brain, besides contributing to structural remodeling, would also be associated with such functions as homeostatic synaptic plasticity which might counteract epileptic seizures.

Research paper thumbnail of In Vivo Measurements With Robust Silicon-Based Multielectrode Arrays With Extreme Shaft Lengths

IEEE Sensors Journal, 2000

In this paper, manufacturing and in vivo testing of extreme-long Si-based neural microelectrode a... more In this paper, manufacturing and in vivo testing of extreme-long Si-based neural microelectrode arrays are presented. Probes with different shaft lengths (15-70 mm) are formed by deep reactive ion etching and have been equipped with platinum electrodes of various configurations. In vivo measurements on rats indicate good mechanical stability, robust implantation, and targeting capability. High-quality signals have been recorded from different locations of the cerebrum of the rodents. The accompanied tissue damage is characterized by histology.

Research paper thumbnail of Special Issue on Sensors and Sensing Systems for Neurophysiology

IEEE Sensors Journal, 2000

Research paper thumbnail of Seizure related expression of matrix metalliproteinases in pharmacological and genetic models without tissue damage

Frontiers in Systems Neuroscience, 2009

Research paper thumbnail of Can the Pontine Reticular Formation be the (6Hz) theta generator?

Frontiers in Systems Neuroscience, 2009

Research paper thumbnail of Abstracts presented at the 8th International Symposium on Memory and Awareness in Anesthesia (MAA8): Milwaukee, WI, USA, June 2-5, 2011

British Journal of Anaesthesia, 2012

Anaesthesia offers an important tool for the scientific study of consciousness. Recent works will... more Anaesthesia offers an important tool for the scientific study of consciousness. Recent works will be discussed with an aim towards answering basic questions regarding the nature of consciousness and how it is removed by anaesthesia. What brain areas and systems must ...

Research paper thumbnail of Generalization of seizures parallels the formation of “dark” neurons in the hippocampus and pontine reticular formation after focal–cortical application of 4-aminopyridine (4-AP) in the rat

Brain Research, 2008

Distribution and time course of the occurrence of "dark" neurons were compared with the EEG activ... more Distribution and time course of the occurrence of "dark" neurons were compared with the EEG activity and behavior of rats during 4-aminopyridine (4-AP) induced epileptic seizures.