Person: GÜLHAN, REZZAN
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GÜLHAN
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Publication Metadata only The relationship between age-related development of spike-and-wave discharges and the resistance to amygdaloid kindling in rats with genetic absence epilepsy(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2008) ONAT, FİLİZ; Carcak, Nihan; Aker, Rezzan Guelhan; Oezdemir, Osman; Demiralp, Tamer; Onat, Filiz YilmazGenetic Absence Epilepsy Rats from Strasbourg (GAERS) are resistant to amygdaloid kindling. Since in GAERS the characteristics of spike-and-wave discharges (SWDs) change with age, we have studied the relation between SWD maturation and the development of kindling resistance. Non-epileptic Wistar rats and GAERS were stimulated in basolateral amygdala with 400 mu A at 20 min intervals until they reached stage 5 seizures or for a maximum of 36 stimulations. All of the Wistar rats, the postnatal (PN) day 20 GAERS and the (kindling-prone) subgroups of GAERS at PN30 and PN60 reached stage 5 seizures; at PN20, PN30 and PN60 kindling rates were significantly slower in GAERS compared to Wistar rats. At PN30 and PN60, 41% and 69% of GAERS, respectively, showed no stage 3, 4 or 5 seizures after 36 stimulations (kindling-resistant subgroups). The SWD maturation involves changes in spectral patterns and correlate with age-related increases in kindling resistance in GAERS. (C) 2008 Elsevier Inc. All rights reserved.Publication Open Access Amygdala kindling in the WAG/Rij rat model of absence epilepsy(WILEY, 2006-01) ONAT, FİLİZ; Aker, RG; Yananli, HR; Gurbanova, AA; Ozkaynakci, AE; Ates, N; van Luijtelaar, G; Onat, FYPurpose: The kindling model in rats with genetic absence epilepsy is suitable for studying mechanisms involved in the propagation and generalization of seizure activity in the convulsive and nonconvulsive components of epilepsy. In the present study, we compared the amygdala kindling rate and afterdischarge characteristics of the nonepileptic Wistar control rat with a well-validated model of absence epilepsy, the WAG/Rij rat, and demonstrated the effect of amygdala kindling on spike-and-wave discharges (SWDs) in the WAG/Rij group. Methods: Electrodes were stereotaxically implanted into the basolateral amygdala of rats for stimulation and recording and into the cortex for recording. After a recovery period, the animals were stimulated at their afterdischarge thresholds. EEG was recorded to analyze SWDs and afterdischarge durations. The seizure severity was evaluated by using Racine's 5-stage scale. Results: All nonepileptic control and four of seven WAG/Rij animals reached a stage 5 seizure state, whereas three animals failed to reach stage 3, 4, or 5 and stayed at stage 2 after application of 30 stimulations. Interestingly, WAG/Rij rats, resistant to kindling, demonstrated a significantly longer duration of SWDs on the first day of the experiment before kindling stimulation than did the kindled WAG/Rij animals. Additionally, the cumulative total duration and the number of SWDs after the kindling stimulation were statistically increased compared with SWDs before kindling stimulation. Conclusions: The results of our study demonstrate that the progress of amygdala kindling is changed in rats with genetic absence epilepsy, perhaps as a consequence of the hundreds of daily SWDs.Publication Metadata only GABA(A) receptor mediated transmission in the thalamic reticular nucleus of rats with genetic absence epilepsy shows regional differences: Functional implications(ELSEVIER SCIENCE BV, 2006) ONAT, FİLİZ; Aker, Rezzan Gulhan; Ozyurt, Hazan B.; Yananli, Hasan R.; Cakmak, Yusuf Ozgur; Ozkaynakci, Aydan E.; Sehirli, Umit; Saka, Erdinc; Cavdar, Safiye; Onat, Filiz YimazThe aim of the present study was to investigate the effect of local injections of the GABA(A) receptor antagonist, bicuculline, into the rostral and caudal parts of the thalamic reticular nucleus (TRN), on the generation of spike-and-wave discharges in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Spike-and-wave discharges are important in the pathophysiology of absence epilepsy and generated by the cortico-thalamo-cortical pathway, where GABA has a significant role, particularly in the TRN. Artificial cerebrospinal fluid or bicuculline was administered to rostral or caudal parts of TRN of GAERS through a stereotaxically placed guide cannula. Administration of bicuculline produced opposite effects according to the injection site. Administration into the caudal TRN produced statistically significant increases in the duration of spike-and-wave discharges, whereas injections into the rostral TRN produced significant decreases. Correspondingly, distinct patterns of afferent connections have been demonstrated with the wheat-germ-agglutinin horseradish peroxidase (WGA-HRP) retrograde tracing method in control non-epileptic rats and GAERS for the rostral and caudal parts of the TRN. Injection of WGA-HRP tracer showed no detectable difference regarding the rostral and caudal connections between GAERS and Wistar animals. Rostral parts of TRN have thalamic and cortical connections that are primarily motor and limbic whereas for the caudal parts these connections are primarily sensory. Further, the rostral parts receive inputs from the substantia nigra pars reticularis and the ventral pallidum that the caudal part lacks. The extent to which these connectional differences may be responsible for the functional differences demonstrated by the bicucculine injections remains to be explored. (c) 2006 Elsevier B.V. All rights reserved.Publication Metadata only Changes in intracellular protein expression in cortex., thalamus and hippocampus in a genetic rat model of absence epilepsy(PERGAMON-ELSEVIER SCIENCE LTD, 2011) OGAN, AYŞE; Danis, Ozkan; Demir, Serap; Gunel, Aslihan; Aker, Rezzan Gulhan; Gulcebi, Medine; Onat, Filiz; Ogan, AyseEpilepsy is a chronic disorder characterized by repeated seizures resulting from abnormal activation of neurons in the brain. Although mutations in genes related to Na+, K+, Ca2+ channels have been defined, few studies show intracellular protein changes. We have used proteomics to investigate the expression of soluble proteins in a genetic rat model of absence epilepsy Genetic Absence Epilepsy Rats from Strasbourg (GAERS). The advantage of this technique is its high throughput quantitative and qualitative detection of all proteins with their post-translational modifications at a given time. The parietal cortex and thalamus, which are the regions responsible for the generation of absence seizures, and the hippocampus, which is not involved in this activity, were dissected from GAERS and from non-epileptic control rat brains. Proteins from each tissue sample were isolated and separated by two-dimensional gel electrophoresis. Spots that showed significantly different levels of expression between controls and GAERS were identified by nano LC-ESI-MS/MS. Identified proteins were: ATP synthase subunit delta and the 14-3-3 zeta isoform in parietal cortex; myelin basic protein and macrophage migration inhibitory factor in thalamus; and macrophage migration inhibitory factor and 0-beta 2 globulin in hippocampus. All protein expressions were up-regulated in GAERS except 0-beta globulin. These soluble proteins are related to energy generation, signal transduction, inflammatory processes and membrane conductance. These results indicate that not only membrane proteins but also cytoplasmic proteins may take place in the pathophysiology and can be therapeutic targets in absence epilepsy. (C) 2011 Elsevier Inc. All rights reserved.Publication Metadata only Perirhinal cortical kindling in rats with genetic absence epilepsy(ELSEVIER IRELAND LTD, 2010) ONAT, FİLİZ; Akman, Ozlem; Karson, Ayse; Aker, Rezzan Gulhan; Ates, Nurbay; Onat, Filiz YilmazTwo genetic models of absence epilepsy, GAERS and WAG/Rij rat strains, are resistant to progression of partial seizures induced by amygdaloid or hippocampal kindling. Perirhinal cortex is one of the crucial areas for the secondary generalization of partial seizures. Therefore we focused on perirhinal cortical kindling in both epileptic rat strains and examined whether the resistance to limbic epilepsy is restricted to the amygdala and hippocampus or whether it can also occur with perirhinal cortical kindling. The mean afterdischarge (AD) thresholds were significantly higher in WAG/Rij and GAERS compared to the Wistar rats. Analysis of the rate of perirhinal cortical kindling for the 3 strains indicated highly significant differences. The mean number of stimulations for the development of the first stage 2, 3, 4 or 5 seizures was significantly higher in WAG/Rij and GAERS groups than in Wistar rats. Further, the cumulative total duration and number of SWDs increased during the first epoch of the post-stimulation period at the first stage 2 and 4/5 seizures in the WAG/Rij and GAERS rats compared to the pre-stimulation period. The higher AD threshold and delays to all stages of kindling in WAG/Rij and GAERS indicate that the perirhinal cortex is a part of the circuits involved in the kindling resistance in genetic models of absence epilepsy. (C) 2010 Elsevier Ireland Ltd. All rights reserved.Publication Metadata only Ultrastructural GABA immunocytochemistry in the mossy fiber terminals of Wistar and genetic absence epileptic rats receiving amygdaloid kindling stimulations(ELSEVIER, 2011) AKAKIN, DİLEK; Akakin, Dilek; Sirvanci, Serap; Gurbanova, Ayten; Aker, Rezzan; Onat, Filiz; San, TangulThe existence of absence epilepsy and temporal lobe epilepsy in the same patient is not common in clinical practice. The reason why both types of seizures are rarely seen in the same patient is not well understood. Therefore, we aimed to investigate kindling in a well known model of human absence epilepsy, genetic absence epilepsy rats from Strasbourg (GAERS). In the present study, we analyzed whether the GABA content of GAERS that received kindling stimulations was altered in the hippocampal mossy fiber terminals compared to non-epileptic control (NEC) Wistar rats. For this purpose, we used an immunocytochemical technique at the ultrastructural level. Ultrathin sections were immunolabeled with anti-GABA antibody and transmission electron microscopy was used for the ultrastructural examination. The number of gold particles per nerve terminal was counted and the area of the nerve terminal was determined using NIH image analysis program. The GABA density was found to be higher in sham-operated GAERS than sham-operated Wistar rats. The density was increased in kindling Wistar group compared to sham-operated Wistar and kindling GAERS groups. No statistical difference was observed between sham-operated GAERS and kindling GAERS groups. The increase in GABA levels in stimulated Wistar rats may be a result of a protective mechanism. Furthermore, there may be strain differences between Wistar rats and GAERS and our findings addressing different epileptogenesis mechanisms in these strains might be a basis for future experimental studies. (C) 2010 Elsevier B.V. All rights reserved.Publication Metadata only Hippocampal kindling in rats with absence epilepsy resembles amygdaloid kindling(ELSEVIER, 2008) ONAT, FİLİZ; Akman, Ozlem; Karson, Ayse; Aker, Rezzan Gulhan; Ates, Nurbay; Onat, Filiz YilmazPurpose: WAG/Rij and GAERS rats show delays or resistance to secondary generalization of limbic seizures during amygdaloid kindling. In this study, we aimed to evaluate the kindling from a different limbic site, hippocampus, and to compare its effects on spike-and-wave discharges (SWDs) with that of amygdaloid kindling. Methods: Recording electrodes were implanted epidurally and a stimulation/recording electrode was implanted into the ventral hippocampus in the WAG/Rij, GAERS and Wistar rats. Animals received kindling stimulation twice daily at their afterdischarge thresholds until they reached stage 5 seizures, or the maximum number of stimulations (50) had been delivered. The EEG was recorded to analyze SWDs and afterdischarge durations. Results: All Wistar rats reached stage 5 by the 34th stimulation. 4 of 8 WAG/Rij rats and 3 of 6 GAERS rats displayed stage 4/5 seizures (kindling-prone rats); the rest stayed at stage 2 seizures (kindling-resistant rats) even after 50th stimulations. The cumulative duration and number of SWDs decreased in the post-stimulation period after the first stage 2 seizures, whereas these parameters increased after the first stage 3 seizures in the kindling-prone WAG/Rij and GAERS. The peak frequency of SWDs and its harmonics decreased significantly only in the GAERS group after stage 4 seizures. Conclusion: Hippocampal kindling resembles amygdaloid kindling in showing a delay of or resistance to secondary seizure generalization, which supported the interaction of thalamo-cortical and limbic circuitry in GAERS and WAG/Rij. (C) 2008 Elsevier B.V. All rights reserved.Publication Metadata only Resistance to propagation of amygdaloid kindling seizures in rats with genetic absence epilepsy(BLACKWELL PUBLISHING INC, 2002) ONAT, FİLİZ; Eskazan, E; Onat, FY; Aker, R; Oner, GPurpose: The existence of absence epilepsy and temporal partial seizure pattern in the same patient is an uncommon state. In the present study, we aimed to evaluate whether the process of kindling as a model of complex partial seizures with secondary generalization is altered in rats with genetic absence epilepsy. Methods: Six- to 12-month-old nonepileptic control Wistar rats and genetic absence epileptic rats from Strasbourg (GAERS) were used in the experiments. One week before the experiments, bilateral stimulation and recording electrodes were implanted stereotaxically into the basolateral amygdala and cortex, respectively. Animals were stimulated at their afterdischarge threshold current twice daily for the process of kindling and accepted as fully kindled after the occurrence of five grade 5 seizures. Bilateral EEGs from amygdala and cortex were recorded continuously during 20 min before and 40 min after each stimulus. Results: All control Wistar rats were fully kindled after stimulus 12 to 15. Although the maximal number of stimulations had been applied, GAERS remained at stage 2, and no motor seizures were observed. The afterdischarge duration in bilateral amygdala and the cortex after the kindling stimulus was shorter in GAERS when compared with control rats. Conclusions: Occurrence of only grade 2 seizures and no observation of grade 3-5 seizures in GAERS with the maximal number of stimulations would suggest that the generalized absence seizures may be the reason of the resistance in the secondary generalization of limbic seizures during amygdala kindling.Publication Metadata only Increased inhibitory synaptic activity in the hippocampus (CA1) of genetic absence epilepsy rats: Relevance of kindling resistance(ELSEVIER, 2016) ONAT, FİLİZ; Carcak, Nihan; Dilekoz, Ergin; Gulhan, Rezzan; Onur, Rustu; Onat, Filiz Yilmaz; Sara, YildirimPurpose: Genetic absence epilepsy rats from Strasbourg (GAERS), a well-validated genetic rat model for typical absence epilepsy, are known to manifest a resistance to secondary generalization of abnormal focal electrical activity evoked by kindling. The mechanism of this resistance is still unclear. In order to understand the possible mechanism of kindling resistance, we investigated for the first time, the differences of short-term synaptic plasticity by using a paired-pulse paradigm as an indicator of GABAergic activity in CM region of hippocampus in GAERS and non-epileptic Wistar rats in-vivo. Methods: Rats were subjected to kindling process, basolateral amygdala was stimulated twice a day, with a supra-threshold current, until they displayed limbic or convulsive seizures. One hour after the last kindling stimulation, evoked field potentials from CA1 pyramidal layer of hippocampus were recorded in-vivo under urethane anesthesia. Results: In response to supra-threshold kindling stimulations GAERS showed a significantly delayed kindling progression and displayed a significant increase in hippocampal excitability at early stages of kindling that is the critical for the development of convulsive seizures. In control rats that were not received kindling stimulation, paired-pulse depression (PPD) was significantly pronounced in GAERS with respect to the Wistar group. During the kindling course, PPD was gradually reduced in the Wistar rats as kindling progression was advanced. However in GAERS, PPD ratios were not significantly changed at early stages of kindling. When GAERS reached convulsive stage, their PPD ratios became similar to that of Wistar rats. Discussion: The increased inhibition in paired-pulse responses at early stages of kindling in GAERS suggests the role of augmented GABAergic activity as one of the underlying mechanisms of kindling resistance observed in genetic rat models of absence epilepsy. (C) 2016 Published by Elsevier B.V.Publication Open Access The effect of generalized absence seizures on the progression of kindling in the rat(BLACKWELL PUBLISHING, 2007-09) ONAT, FİLİZ; Onat, Filiz Yilmaz; Aker, Rezzan Guelhan; Gurbanova, Ayten Azizova; Ates, Nurbay; van Luijtelaar, GillesThe involvement of the thalamus in limbic epileptogenesis has recently drawn attention to the connectivity between the nuclei of the thalamus and limbic structures. Thalamo-limbic circuits are thought to regulate limbic seizure activity whereas thalamocortical circuits are involved in the expression and generation of spike-and-wave discharges (SWDs) in the absence epilepsy models. Genetic Absence Epilepsy Rats From Strasbourg (GAERS) and WAG/Rij (Wistar Albino Glaxo from Rijswijk) are well-defined genetic animal models of absence epilepsy. We aimed to examine the duration of behavioral changes in the kindling process and the relation of SWD activity to the kindling progress in the GAERS and WAG/Rij animals. Electrodes were stereotaxically implanted into the basolateral amygdala and the cortex of rats for stimulation and recording. The animals were stimulated at the threshold for producing afterdischarges. EEG was recorded to analyze SWDs and afterdischarge durations. The seizure severity was evaluated using Racine's 5-stage scale. None of the GAERS animals reached stage 3, 4, or 5 after application of 30 stimulations. The WAG/Rij animals showed different rate of kindling, therefore they were further categorized into the kindling-resistant, slow-kindled, and rapid-kindled groups. The kindling-resistant animals demonstrated a significantly longer duration of SWDs on the first day of the experiment before kindling stimulation and shorter duration of afterdischarge than did the kindled WAG/Rij animals. Behavioral durations at stage 2 were longer in kindled Wistar and WAG/Rij animals compared to kindling-resistant WAG/Rij and GAERS. These results suggest that mechanisms involved in the generation of SWDs act as a counterbalance to the excitability induced by kindling.