| 1. |
- Nanobashvili, Z, et al.
(author)
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Suppression of limbic motor seizures by electrical stimulation in thalamic reticular nucleus
- 2003
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In: Experimental Neurology. - 0014-4886. ; 181:2, s. 224-230
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Journal article (peer-reviewed)abstract
- Kindling is a model of temporal lobe epilepsy in which repeated electrical stimulations in limbic areas lead to progressive increase of seizure susceptibility, culminating in generalized convulsions and the establishment of a permanent epileptic syndrome. We studied here the effect of stimulations in the thalamic reticular nucleus (TRN) on. the development of seizures and hippocampal hyperexcitability in kindling elicited from the ventral hippocampus in rats. Animals given 12 kindling stimulations per day with 30-min intervals for 4 consecutive days developed generalized convulsions on day 4. Stimulations in TRN delivered simultaneously with those in the hippocampus induced marked suppression of seizure generalization. Similarly, the number of generalized seizures and the duration of behavioral convulsions were reduced when rats subjected to 40 kindling stimulations with 5-min intervals during about 3 h were costimulated in the TRN. The anticonvulsant effect of TRN costimulation was detected also when rats were test-stimulated in the hippocampus at 24 h and 2 and 4 weeks after the initial 40 hippocampal stimulations. Our data provide the first evidence that TRN stimulations can act to suppress limbic motor seizures in hippocampal kindling and suggest a new approach for seizure control in temporal lobe epilepsy. (C) 2003 Elsevier Science (USA). All rights reserved.
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| 2. |
- Bengzon, Johan, et al.
(author)
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Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures
- 1997
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In: Proceedings of the National Academy of Sciences. - 1091-6490. ; 94:19, s. 10432-10437
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Journal article (peer-reviewed)abstract
- Neuronal apoptosis was observed in the rat dentate gyrus in two experimental models of human limbic epilepsy. Five hours after one hippocampal kindling stimulation, a marked increase of in situ terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) of fragmented DNA was observed in nuclei located within and on the hilar border of the granule cell layer and in the polymorphic region. Forty kindling stimulations with 5-min interval produced higher numbers of labeled nuclei compared with one stimulation. The increase of TUNEL-positive nuclei was prevented by the protein synthesis inhibitor cycloheximide but not affected by the N-methyl-D-aspartate receptor antagonist MK-801. Kainic acid-induced seizures lead to a pattern of labeling in the hippocampal formation identical to that evoked by kindling. A large proportion of cells displaying TUNEL-positive nuclei was double-labeled by the neuron-specific antigen NeuN, demonstrating the neuronal identity of apoptotic cells. Either 1 or 40 kindling stimulations also gave rise to a marked increase of the number of cells double-labeled with the mitotic marker bromodeoxyuridine and NeuN in the subgranular zone and on the hilar border of the dentate granule cell layer. The present data show that single and intermittent, brief seizures induce both apoptotic death and proliferation of dentate gyrus neurons. We hypothesize that these processes, occurring early during epileptogenesis, are primary events in the development of hippocampal pathology in animals and possibly also in patients suffering from temporal lobe epilepsy.
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| 3. |
- Ferencz, Istvan, et al.
(author)
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Septal cholinergic neurons suppress seizure development in hippocampal kindling in rats: comparison with noradrenergic neurons
- 2001
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In: Neuroscience. - 1873-7544. ; 102:4, s. 819-832
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Journal article (peer-reviewed)abstract
- Widespread lesions of forebrain cholinergic or noradrenergic projections by intraventricular administration of 192 IgG-saporin or 6-hydroxydopamine, respectively, accelerate kindling epileptogenesis. Here we demonstrate both quantitative and qualitative differences between the two lesions in their effects on hippocampal kindling in rats. Epileptogenesis was significantly faster after noradrenergic as compared to cholinergic denervation, and when both lesions were combined, kindling development resembled that in animals with 6-hydroxydopamine lesion alone. Furthermore, whereas the 192 IgG-saporin lesion promoted the development only of the early stages of kindling, administration of 6-hydroxydopamine or both neurotoxins accelerated the late stages also. To investigate the contribution of different subparts of the basal forebrain cholinergic system to its seizure-suppressant action in hippocampal kindling, 192 IgG-saporin was injected into medial septum/vertical limb of the diagonal band of Broca or nucleus basalis magnocellularis, leading to selective hippocampal or cortical cholinergic deafferentation, respectively. The denervation of the hippocampus facilitated kindling similar to the extensive lesion caused by intraventricular 192 IgG-saporin, whereas the cortical lesion had no effect. These results indicate that although both noradrenergic and cholinergic projections to the forebrain exert powerful inhibitory effects on hippocampal kindling epileptogenesis, the action of the cholinergic system is less pronounced and occurs specifically prior to seizure generalization. In contrast, noradrenergic neurons inhibit the development of both focal and generalized seizures. The septo-hippocampal neurons are responsible for the antiepileptogenic effect of the cholinergic system in hippocampal kindling, whereas the cortical projection is not significantly involved. Conversely, we have previously shown [Ferencz I. et al. (2000) Eur. J. Neurosci., 12, 2107-2116] that seizure-suppression in amygdala kindling is exerted through the cortical and not the hippocampal cholinergic projection. This shows that, depending on the location of the primary epileptic focus, i.e. the site of stimulation, basal forebrain cholinergic neurons operate through different subsystems to counteract seizure development in kindling.
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| 4. |
- Jakubs, Katherine, et al.
(author)
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Environment Matters: Synaptic Properties of Neurons Born in the Epileptic Adult Brain Develop to Reduce Excitability.
- 2006
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In: Neuron. - : Elsevier BV. - 0896-6273. ; 52:6, s. 1047-1059
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Journal article (peer-reviewed)abstract
- Neural progenitors in the adult dentate gyrus continuously produce new functional granule cells. Here we used whole-cell patch-clamp recordings to explore whether a pathological environment influences synaptic properties of new granule cells labeled with a GFP-retroviral vector. Rats were exposed to a physiological stimulus, i.e., running, or a brain insult, i.e., status epilepticus, which gave rise to neuronal death, inflammation, and chronic seizures. Granule cells formed after these stimuli exhibited similar intrinsic membrane properties. However, the new neurons born into the pathological environment differed with respect to synaptic drive and short-term plasticity of both excitatory and inhibitory afferents. The new granule cells formed in the epileptic brain exhibited functional connectivity consistent with reduced excitability. We demonstrate a high degree of plasticity in synaptic inputs to adult-born new neurons, which could act to mitigate pathological brain function.
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| 5. |
- Kokaia, Merab, et al.
(author)
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Suppressed kindling epileptogenesis in mice with ectopic overexpression of galanin
- 2001
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 98:24, s. 14006-14011
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Journal article (peer-reviewed)abstract
- The neuropeptide galanin has been shown to suppress epileptic seizures. In cortical and hippocampal areas, galanin is normally mainly expressed in noradrenergic afferents. We have generated a mouse overexpressing galanin in neurons under the platelet-derived growth factor B promoter. RIA and HPLC analysis revealed up to 8-fold higher levels of galanin in transgenic as compared with wild-type mice. Ectopic galanin overexpression was detected especially in dentate granule cells and hippocampal and cortical pyramidal neurons. Galanin-overexpressing mice showed retardation of seizure generalization during hippocampal kindling, a model for human complex partial epilepsy. The high levels of galanin in mossy fibers found in the transgenic mice were further increased after seizures. Frequency facilitation of field excitatory postsynaptic potentials, a form of short-term synaptic plasticity assessed in hippocampal slices, was reduced in mossy fiber-CA3 cell synapses of galanin-overexpressing mice, indicating suppressed glutamate release. This effect was reversed by application of the putative galanin receptor antagonist M35. These data provide evidence that ectopically overexpressed galanin can be released and dampen the development of epilepsy by means of receptor-mediated action, at least partly by reducing glutamate release from mossy fibers.
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| 6. |
- Melin, Esbjörn, et al.
(author)
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Disease Modification by Combinatorial Single Vector Gene Therapy : A Preclinical Translational Study in Epilepsy
- 2019
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In: Molecular Therapy - Methods and Clinical Development. - : Elsevier BV. - 2329-0501. ; 15, s. 179-193
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Journal article (peer-reviewed)abstract
- Gene therapy has been suggested as a plausible novel approach to achieve seizure control in patients with focal epilepsy that do not adequately respond to pharmacological treatment. We investigated the seizure-suppressant potential of combinatorial neuropeptide Y and Y2 receptor single vector gene therapy based on adeno-associated virus serotype 1 (AAV1) in rats. First, a dose-response study in the systemic kainate-induced acute seizure model was performed, whereby the 1012 genomic particles (gp)/mL titer of the vector was selected as an optimal concentration. Second, an efficacy study was performed in the intrahippocampal kainate chronic model of spontaneous recurrent seizures (SRSs), designed to reflect a likely clinical scenario, with magnetic resonance image (MRI)-guided focal unilateral administration of the vector in the hippocampus during the chronic stage of the disease. The efficacy study demonstrated a favorable outcome of the gene therapy, with a 31% responder rate (more than 50% reduction in SRS frequency) and 13% seizure-freedom rate, whereas no such effects were observed in the control animals. The inter-SRS and SRS cluster intervals were also significantly prolonged in the treated group compared to controls. In addition, the SRS duration was significantly reduced in the treated group but not in the controls. This study establishes the SRS-suppressant ability of the single vector combinatorial neuropeptide Y/Y2 receptor gene therapy in a clinically relevant chronic model of epilepsy.
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| 7. |
- Nanobashvili, Avtandil, et al.
(author)
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Chronic BDNF deficiency permanently modifies excitatory synapses in the piriform cortex.
- 2005
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In: Journal of Neuroscience Research. - : Wiley. - 1097-4547 .- 0360-4012. ; 81:5, s. 696-705
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Journal article (peer-reviewed)abstract
- Brain-derived neurotrophic factor (BDNF), aside from its classic neurotrophic role in development and survival of neurons, has been shown to be involved in modification and plasticity of central synapses. In mice with BDNF gene deletion (BDNF+/-), deficits in synaptic transmission are often observed but are reversed readily by administration of BDNF, suggesting its acute effect. In support, blockade of BDNF signaling in wild-type hippocampal slices by TrkB-IgG closely reproduces synaptic alterations observed in BDNF+/- mice. We demonstrate that in BDNF+/- mice, lateral olfactory tract (LOT) synapses exhibit decreased release probability of glutamate, suggested by increased paired-pulse facilitation (PPF) of field excitatory postsynaptic potentials (fEPSPs), as well as by slower blocking rate of N-methyl-D-aspartate (NMIDA) receptor-mediated excitatory postsynaptic currents (EPSCs) by MK-801 in the pyramidal neurons of the piriform cortex. The changes in PPF were not mimicked in wild-type mice by acute blockade of BDNF signaling by TkrB-IgG. These data imply that BDNF deficit during development might lead to chronic changes of excitatory transmission in LOT synapses. Modification of the LOT synapses in BDNF+/- mice was associated with altered inhibitory drive onto the mitral cells from the granule and glomerular neurons, which in turn exhibited decreased renewal rate compared to that in wild-type mice. Taken together, these data suggest that BDNF deficiency can have both acute and more permanent effects on synaptic function, particularly when BDNF signaling is compromised during the early stages of brain development. In the latter case, altered synaptic properties in BDNF+/- mice could be secondary to other complex changes in the brain, e.g., cell survival/proliferation.
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| 8. |
- Nanobashvili, Avtandil, et al.
(author)
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Generalization of rapidly recurring seizures is suppressed in mice lacking glial cell line-derived neurotrophic factor family receptor alpha2.
- 2003
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In: Neuroscience. - 1873-7544. ; 118:3, s. 845-852
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Journal article (peer-reviewed)abstract
- Recent experimental evidence indicates that neurotrophic factors play a role in the pathophysiology of epilepsy. The objective of this study was to explore whether signaling through one of the glial cell line-derived neurotrophic factor family receptors, GFRα2, influences the severity of kindling-evoked, rapidly recurring seizures and the subsequent development of permanent hyperexcitability. We applied the rapid kindling model to adult mice, using 40 threshold stimulations delivered with 5-min interval in the ventral hippocampus. Generalized seizures were fewer and developed later in response to kindling stimulations in mice lacking GFRα2. However, GFRα2 gene deletion did not influence the acquisition of the permanent abnormal excitability as assessed 4 weeks later. In situ hybridization revealed marked and dynamic changes of GFRα2 mRNA levels in several forebrain areas following the stimulus-evoked seizures. Our findings provide evidence that signaling through the GFRα2 receptor contributes to seizure generalization in rapid kindling.
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| 9. |
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| 10. |
- Nanobashvili, Avtandil
(author)
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Role of Neuropeptides and Neurotrophic Factors in Seizure Modulation
- 2003
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Doctoral thesis (other academic/artistic)abstract
- The presented thesis explores role of glial cell line derived neurotrophic factor family receptor a2 (GFRa2), as well as neuropeptide Y (NPY) and galanin and their receptors in modulation of seizure activity. We demonstrate that mice lacking the GFRa2 gene (GFRa2-/-) exhibit suppressed seizure generalization in traditional and rapid kindling models. We suggest that impaired basal excitatory transmission at medial perforant path granule cell synapses, detected in these animals might partly account for the observed deficit in the kindling development. Moreover, GFRa2-/- mice exhibit impaired persistence of kindling epilepsy following traditional kindling, which is associated with the lack of seizure-induced downregulation of NPY immunoreactivity in hilar interneurons. It is conceivable that alterations in NPY signaling in GFRa2-/- mice could lead to the above-mentioned impaired maintenance of abnormal excitability. We also demonstrate that rapidly recurring seizures evoke cell- and region-specific, differential regulation of genes for NPY and its receptors (Y1, Y2 and Y5) in widespread areas of the rat limbic system. Moreover, using recently developed highly selective Y5 receptor agonist and antagonist, we show that activation of this receptor dampens spontaneous (interictaform) bursting in the CA3 region of rat hippocampal slices. Our studies demonstrating that NPY exerts inhibitory effect on spontaneous epileptiform activity in the entorhinal cortex further strengthen the concept of NPY as a widespread regulator of epileptic activity in the brain. Using galanin overexpressing mice, we show that ectopically expressed galanin in cortical and hippocampal neurons is regulated by seizures, is released during high frequency neuronal activity, and suppresses kindling epileptogenesis by interacting with presynaptic galanin receptors and decreasing glutamate release.
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