Person: ONAT, FİLİZ
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ONAT
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FİLİZ
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Publication Open Access Animal models of absence epilepsies: What do they model and do sex and sex hormones matter?(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2014-12) ONAT, FİLİZ; van Luijtelaar, Gilles; Onat, Filiz Yilmaz; Gallagher, Martin J.While epidemiological data suggest a female prevalence in human childhood- and adolescence-onset typical absence epilepsy syndromes, the sex difference is less clear in adult-onset syndromes. In addition, although there are more females than males diagnosed with typical absence epilepsy syndromes, there is a paucity of studies on sex differences in seizure frequency and semiology in patients diagnosed with any absence epilepsy syndrome. Moreover, it is unknown if there are sex differences in the prevalence or expression of atypical absence epilepsy syndromes. Surprisingly, most studies of animal models of absence epilepsy either did not investigate sex differences, or failed to find sex-dependent effects. However, various rodent models for atypical syndromes such as the AY9944 model (prepubertal females show a higher incidence than prepubertal males), BN model (also with a higher prevalence in males) and the Gabral deletion mouse in the C57BL/6J strain offer unique possibilities for the investigation of the mechanisms involved in sex differences. Although the mechanistic bases for the sex differences in humans or these three models are not yet known, studies of the effects of sex hormones on seizures have offered some possibilities. The sex hormones progesterone, estradiol and testosterone exert diametrically opposite effects in genetic absence epilepsy and pharmacologically-evoked convulsive types of epilepsy models. In addition, acute pharmacological effects of progesterone on absence seizures during proestrus are opposite to those seen during pregnancy. 17 beta-Estradiol has anti-absence seizure effects, but it is only active in atypical absence models. It is speculated that the pro-absence action of progesterone, and perhaps also the delayed pro-absence action of testosterone, are mediated through the neurosteroid allopregnanolone and its structural and functional homolog, androstanediol. These two steroids increase extrasynaptic thalamic tonic GABAergic inhibition by selectively targeting neurosteroid-selective subunits of GABA(A) receptors (GABA(A)Rs). Neurosteroids also modulate the expression of GABA(A)R containing the gamma 2, alpha 4, and delta subunits. It is hypothesized that differences in subunit expression during pregnancy and ovarian cycle contribute to the opposite effects of progesterone in these two hormonal states. (C) 2014 Elsevier Inc All rights reserved.Publication Open Access The effects of partial bilateral lesioning of substantia nigra in a genetic absence epilepsy rat model(2002-04-01) GÜLHAN, REZZAN; ONAT, FİLİZ; GÖREN, MEHMET ZAFER; GÖREN M. Z., GÜLHAN R., ONAT F., Ergün A.Objective: \"Genetic Absence Epilepsy Rats from Strasbourg\" (GAERS), an inbred Wistar strain, serve as an experimental venue. These rats generate spontaneous spike-and-wave discharges (SWD) and have increased γ-aminobutyric acid (GABA) levels in the ventrolateral thalamus (VLT). Recently, substantia nigra pars reticulata (SNpr) was reported to act as an endogeneous inhibitory mechanism in the generation, onset and maintenance of various types of seizures. The presence of tonic control exerted by SNpr in absence seizures should also be tested in GAERS. Methods: In this current study, GABA and L-glutamic acid release in VLT of GAERS with partial bilateral electrolytic lesions of SNpr was evaluated by using microdialysis technique with fluorescent detection. Results: GABA levels in VLT were 0.12±0.04 μM and 0.24±0.08 μM in sham-lesioned and SNpr-lesioned GAERS, respectively. L-glutamic acid level was found to be 0.41 5±0.150 μM in sham-lesioned group and 0.324±0.094 μM in SNpr-lesioned GAERS. Statistical analysis revealed no significant difference between sham-lesioned and SNpr-lesioned rats. The number and the duration of SWD were also similar in two groups. Conclusion: These findings show that SNpr does not exert a tonic control in GAERS and we assume that intact SNpr acts as a site that may exert an inhibition on target structures when activated in GAERS.Publication Open Access The Role of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in the Pathophysiology of Absence Epilepsy(KARE PUBL, 2018) ONAT, FİLİZ; Yavuz, Melis; Onat, FilizHyperpolarization-activated cyclic nucleotide-gated (HCN) channels participate in pacemaker currents, modulating the funny current (I[f]) in cardiac cells and the hyperpolarization-activated current (I[h]) in neurons. Depending on the neuronal and synaptic localization, HCN channels regulate synaptic integration, long-term potentiation, synaptic transmission, and resting membrane potential. In summary, it contributes to the electrical activity between the excitatory and inhibitory stimuli through its shunting effect. Several second messengers modulate I(h) currents in the synapses by changing voltage-dependent activation kinetics. I(h) currents are being investigated in numerous central nervous system disorders, including epilepsy. On one hand, it is well known that I(h) currents lead to synchronized oscillations in the rhythmic burst mode in thalamocortical neurons underlying the pathophysiology of absence epilepsy. However, much of the evidence is contradictory. Therefore, it is important to understand the dynamic relationship of HCN channels within the oscillatory networks to determine the regional queerness of I(h), and we need further investigation to determine if upregulation or downregulation of I(h) is needed in order to suppress seizure activity.Publication Open Access The Role of Rho/Rho-Kinase Pathway in the Pathophysiology of Absence Epilepsy(KARE PUBL, 2018) ONAT, FİLİZ; Carcak, Nihan; Yavuz, Melis; Eryigit, Tugba; Kurt, Akif Hakan; Urhan Kucuk, Meral; Onat, Filiz; Buyukafsar, KansuObjectives: Rho/Rho-kinase (ROCK) signaling has been shown to contribute to neuroinflammation, epileptogenesis, and seizures in convulsive-type epilepsy models. However, this pathway has not been investigated in the pathophysiology of absence epilepsy. The aim of this study was to investigate ROCK activity in brain regions involved in spike-and-wave discharge (SWD) generation and the effects of the Rho-kinase inhibitor, Y-27632, on ROCK activity in genetic absence epilepsy rats from Strasburg (GAERS). Methods: ROCK activity in the somatosensorial cortex, hippocampus, and thalamus was measured using an enzyme-linked immunosorbent assay (ELISA). An intracerebroventricular (i.c.v.) injection of Y-27632 was administered at a dose of 20 nmol/5 mu l and changes in ROCK activity were assessed. To evaluate the effect of Y-27632 on SWDs, i.c.v. 20 nmol and 60 nmol doses of Y-27632 were administered to the GAERS subjects and electroencephalography was performed. Results: ROCK activity was elevated in the somatosensory cortex in the GAERS study subjects, and the Rho-kinase enzyme inhibitor, Y-27632, suppressed this increase. In addition, Y-27632 significantly reduced the total and mean duration of SWDs compared with the control group. Conclusion: The findings indicate that the Rho-kinase pathway may play a role in the generation of absence seizures, and that the suppressive effect of Y-27632 on SWDs may be a potential therapeutic target for this anti-absent effect.Publication Open Access The effect of amygdala kindling on neuronal firing patterns in the lateral thalamus in the GAERS model of absence epilepsy(WILEY, 2014-05) ONAT, FİLİZ; Carcak, Nihan; Zheng, Thomas; Ali, Idrish; Abdullah, Ahmad; French, Chris; Powell, Kim L.; Jones, Nigel C.; van Raay, Leena; Rind, Gil; Onat, Filiz; O'Brien, Terence J.ObjectiveThe co-occurrence of absence and mesial temporal lobe epilepsy is rare in both humans and animal models. Consistent with this, rat models of absence epilepsy, including genetic absence epilepsy rats from Strasbourg (GAERS), are resistant to experimental temporal lobe epileptogenesis, in particular by amygdala kindling. Structures within the cortical-thalamocortical system are critically involved in the generation and maintenance of the electrographic spike-and-wave discharges (SWDs) that characterize absence seizures. Using in vivo electrophysiologic recordings, this study investigated the role of thalamocortical circuitry in the generalization of amygdala-kindling induced seizures in the GAERS and the nonepileptic control (NEC) strain of Wistar rats. MethodsGAERS and NEC rats were implanted with a stimulating electrode in amygdala and stimulated at afterdischarge threshold twice daily to a maximum number of 30 stimulations. Thereafter extracellular single neuron recordings were performed in vivo under neuroleptanesthesia in the thalamocortical network. ResultsIn NEC rats, amygdala kindling induced convulsive class V seizures and altered characteristics of neuronal activity in the thalamic reticular nucleus (TRN), in particular decreased firing rates and increased burst firing patterns. Less marked changes were seen in other regions examined: the ventroposteromedial nucleus of thalamus (VPM), the CA3 region of the hippocampus, and the deep layers (V/VI) of the cortex. GAERS did not progress beyond class II seizures, with a matched number of kindling stimulations, and the thalamic neuronal firing alterations observed in NEC rats were not seen. SignificanceThese data suggest that the TRN plays an important role in kindling resistance in GAERS and is central to the control of secondary generalization of limbic seizures. A PowerPoint slide summarizing this article is available for download in the Supporting Information section .