SwePub - search: WFRF:(Kokaia Zaal)

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1.	Ahlenius, Henrik, et al. (author) Neural stem and progenitor cells retain their potential for proliferation and differentiation into functional neurons despite lower number in aged brain. 2009 In: The Journal of Neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 29:14, s. 4408-4419 Journal article (peer-reviewed)abstract Neurogenesis in the subventricular zone (SVZ), which gives rise to new neurons in the olfactory bulb, continues throughout life but declines with increasing age. Little is known about how aging affects the intrinsic properties of the neural stem and progenitor cells (NSCs) in SVZ and the functional characteristics of their neuronal progeny. Here, we have compared the properties of NSCs isolated from embryonic lateral ganglionic eminence and adult and aged SVZ in mice using in vivo and in vitro systems, analyzed their gene expression profile, and studied their electrophysiological characteristics before and after differentiation into neurons. We show a loss of NSCs in SVZ from aged mice accompanied by reduced expression of genes for NSC markers, developmentally important transcription factors, and neurogenic factors. However, when isolated in vitro, the NSCs from SVZ of aged animals have capacity for proliferation and multilineage differentiation, including production of functional neurons, similar to that of NSCs in adult mice, albeit with lower efficacy. These properties are of major importance when considering therapeutic applications of neuronal replacement from endogenous NSCs in the injured, aged brain.
2.	Bengzon, Johan, et al. (author) Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures 1997 In: Proceedings of the National Academy of Sciences. - 1091-6490. ; 94:19, s. 10432-10437 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.
3.	Elmer, Eskil, et al. (author) Delayed kindling development after rapidly recurring seizures: relation to mossy fiber sprouting and neurotrophin, GAP-43 and dynorphin gene expression 1996 In: Brain Research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 712:1, s. 19-34 Journal article (peer-reviewed)abstract Development of kindling and mossy fiber sprouting, and changes of gene expression were studied after 40 seizures produced during about 3 h by electrical stimulation every 5 min in the ventral hippocampus. As assessed by 5 test stimulations, enhanced responsiveness was present already after 6-24 h but from 1 week post-seizure increased gradually up to 4 weeks without additional stimuli. Sprouting of mossy fibers in the dentate gyrus was demonstrated only at 4 weeks with Timm's staining. In situ hybridization showed a transient increase (maximum at 2 h) of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), TrkB and TrkC mRNA levels and reduction (maximum at 12-24 h) of neurotrophin-3 (NT-3) mRNA expression in dentate granule cells after the seizures. In addition, BDNF mRNA levels were elevated in CA1 and CA3 regions, amygdala and piriform cortex. Marked increases of mRNA for growth-associated protein (GAP-43), with maximum expression at 12-24 h, were observed in dentate granule cells and in amygdala-piriform cortex. Dynorphin mRNA levels showed biphasic changes in dentate granule cells with an increase at 2 h followed by a decrease at 24 h. No long-term alterations of gene expression were observed. These findings indicate that increased responsiveness develops rapidly after recurring seizures but that the kindled state is reached gradually in about 4 weeks. Mossy fiber sprouting occurs in parallel to epileptogenesis and may play a causative role. Short-term changes of neurotrophin and Trk, GAP-43 and dynorphin mRNA levels and the assumed alterations of the corresponding proteins could trigger structural rearrangements underlying kindling but might also contribute to the initial increase of seizure susceptibility.
4.	Elmer, Eskil, et al. (author) Dynamic changes of brain-derived neurotrophic factor protein levels in the rat forebrain after single and recurring kindling-induced seizures 1998 In: Neuroscience. - 1873-7544. ; 83:2, s. 351-362 Journal article (peer-reviewed)abstract Regional levels of brain-derived neurotrophic factor protein were measured in the rat brain using enzyme immunoassay following seizures evoked by hippocampal kindling stimulations. One stimulation, which induced a brief, single episode of epileptiform activity in hippocampus and piriform cortex but not in parietal cortex or striatum, gave rise to a transient increase of brain-derived neurotrophic factor levels in dentate gyrus and CA3 region and a decrease in piriform cortex. After 40 rapidly recurring seizures, with epileptiform activity also involving parietal cortex and striatum, increases were observed in dentate gyrus, CA3 and CA1 regions, piriform cortex and striatum. Maximum levels were reached at 2-24 h and brain-derived neurotrophic factor then returned to baseline except in dentate gyrus, where elevated protein content was sustained for four days. The differential regulation of brain-derived neurotrophic factor protein levels in various forebrain structures, which only partly correlates to messenger RNA changes, could indicate regional differences in protein release, antero- or retrograde transport, or brain-derived neurotrophic factor promotor activation. The dynamic changes of brain-derived neurotrophic factor levels in regions involved in the generation and spread of seizure activity may regulate excitability and trigger plastic responses in the post-seizure period.
5.	Elmer, Eskil, et al. (author) Epileptogenesis induced by rapidly recurring seizures in genetically fast- but not slow-kindling rats 1998 In: Brain Research. - 1872-6240. ; 789:1, s. 111-117 Journal article (peer-reviewed)abstract A brief period of rapidly recurring hippocampal seizures can lead to the progressive development of a permanent increase of seizure susceptibility over several weeks, so-called 'delayed kindling'. We have analyzed seizure parameters critical for the induction of delayed kindling in two strains of rats characterized by fast and slow rates of traditional kindling, respectively. Forty seizures were produced during about 3 h by electrical kindling stimulations every 5 min in the ventral hippocampus. The fast rats displayed several generalized convulsions and had long periods of epileptiform activity, whereas the slow animals only exhibited brief, focal seizures. Changes in excitability were determined after 4 weeks using five test stimulations, and 2 weeks later by subjecting all animals to traditional hippocampal kindling. The fast rats showed clearly enhanced responsiveness at these time points, whereas no evidence of permanently increased seizure susceptibility was obtained in the slow rats. Our data indicate that the long-lasting stimulus-evoked seizures are mainly responsible for inducing delayed kindling, whereas the number of seizure events or generalized convulsions, and the total duration of epileptiform activity are less important. We hypothesize that long seizure episodes may be necessary to trigger the cascade of gene changes regulating the development of epilepsy.
6.	Elmer, Eskil, et al. (author) Mossy fibre sprouting: evidence against a facilitatory role in epileptogenesis 1997 In: NeuroReport. - 1473-558X. ; 8:5, s. 1193-1196 Journal article (peer-reviewed)abstract Sprouting of mossy fibres from dentate granule cells occurs in several animal models of epilepsy and in epileptic humans. Mossy fibre sprouting might contribute to epileptogenesis but also could be a compensatory, inhibitory response. We analysed mossy fibre sprouting in the supragranular zone of the dentate gyrus using Timm's histochemical method in genetically fast and slow kindling rats. Before the start of amygdala kindling, the slow rats showed higher Timm's staining scores than did the fast kindlers. No increase of mossy fibre density was observed when the animals were stimulated until either the fast or the slow rats had reached the fully kindled state. Our data argue against the hypothesis that mossy fibre sprouting facilitates epileptogenesis.
7.	Elmer, Eskil, et al. (author) Regulation of neuronal nitric oxide synthase mRNA levels in rat brain by seizure activity 1996 In: NeuroReport. - 1473-558X. ; 7:7, s. 1335-1335 Journal article (peer-reviewed)abstract The regulation of neuronal nitric oxide synthase (NOS) mRNA levels during kindling epileptogenesis in the rat brain was investigated using in situ hybridization. Following 40 rapidly recurring seizures evoked by hippocampal stimulations, NOS mRNA expression decreased by 56% in the dentate granule cell layer (maximum at 2 h) and increased by 420,105 and 1260% in the CA1 and CA3 pyramidal layers and piriform cortex, respectively (maximum at 12-24 h). Gene expression had returned to control levels after one week. The presumed alterations of nitric oxide production, following the changes in NOS mRNA shown here, may modulate synaptic function during kindling development, and could influence neuronal vulnerability after epileptic insults.
8.	Elmer, Eskil, et al. (author) Suppressed kindling epileptogenesis and perturbed BDNF and TrkB gene regulation in NT-3 mutant mice 1997 In: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 145:1, s. 93-103 Journal article (peer-reviewed)abstract In the kindling model of epilepsy, repeated electrical stimulations lead to progressive and permanent intensification of seizure activity. We find that the development of amygdala kindling is markedly retarded in mice heterozygous for a deletion of the neurotrophin-3 (NT-3) gene (NT-3+/- mice). These mice did not reach the fully kindled state (3rd grade 5 seizure) until after 28 +/- 4 days of stimulation compared to 17 +/- 2 days in the wild-type animals. The deficit in the NT-3+/- mice reflected dampening of the progression from focal to generalized seizures. The number of stimulations required to evoke focal (grade 1 and 2) seizures did not differ between the groups, but the NT-3 mutants spent a considerably longer period of time (13 +/- 3 days) than wild-type mice (2 +/- 1 days) in grade 2 seizures. As assessed by test stimulation 4-12 weeks after the 10th grade 5 seizure, kindling was maintained in the NT-3 mutants. In situ hybridization showed 30% reduction of basal NT-3 mRNA levels and lack of upregulation of TrkC mRNA expression at 2 h after a generalized seizure in dentate granule cells of the NT-3+/- mice, whereas the seizure-evoked increase in brain-derived neurotrophic factor (BDNF) and TrkB mRNA levels was enhanced. These results indicate that endogenous NT-3 levels can influence the rate of epileptogenesis, and suggest a link between NT-3 and BDNF gene regulation in dentate granule cells.
9.	Ferencz, Istvan, et al. (author) Effects of cholinergic denervation on seizure development and neurotrophin messenger RNA regulation in rapid hippocampal kindling 1997 In: Neuroscience. - 1873-7544. ; 80:2, s. 389-399 Journal article (peer-reviewed)abstract Intraventricular 192 IgG-saporin was used to induce a selective lesion of basal forebrain cholinergic neurons in rats. When subjected to 40 rapid hippocampal kindling stimulations with 5-min intervals, these animals exhibited increased number of generalized seizures and a higher mean seizure grade in response to the first five stimulations, and required fewer stimuli to develop focal behavioural seizures, as compared to non-lesioned rats. In contrast, both groups showed similarly enhanced responsiveness when test stimulated four weeks later. Using in situ hybridization, cholinergic denervation was found to cause a significant decrease of basal brain-derived neurotrophic factor messenger RNA levels in the hippocampal formation and piriform cortex, whereas gene expression for nerve growth factor, neurotrophin-3, and TrkB and TrkC was unchanged. Four weeks after rapid kindling stimulations, basal levels of brain-derived neurotrophic factor messenger RNA in the dentate granule cells were restored to normal in the lesioned rats, whereas neurotrophin-3 messenger RNA levels were decreased. No differences in the seizure-evoked levels of neurotrophin and Trk messenger RNAs were detected, except in the dentate granule cell layer, which had significantly higher brain-derived neurotrophic factor messenger RNA expression in the lesioned animals at 2 h. In conclusion, the basal forebrain cholinergic system (i) dampens the severity of recurring seizures induced by rapid hippocampal kindling stimulations, but has no effect on the subsequent delayed phase of epileptogenesis; and (ii) exerts a tonic stimulation of basal brain-derived neurotrophic factor messenger RNA levels in the hippocampal formation and piriform cortex. The findings also indicate that the cholinergic lesion does not affect neurotrophin and Trk gene expression after recurring seizures, and that the kindling process leads to long-term changes in basal brain-derived neurotrophic factor and neurotrophin-3 messenger RNA levels in the denervated animals.
10.	Ferencz, Istvan, et al. (author) Septal cholinergic neurons suppress seizure development in hippocampal kindling in rats: comparison with noradrenergic neurons 2001 In: Neuroscience. - 1873-7544. ; 102:4, s. 819-832 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.
11.	Ferencz, Istvan, et al. (author) Suppression of kindling epileptogenesis in rats by intrahippocampal cholinergic grafts 1998 In: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 10:1, s. 213-220 Journal article (peer-reviewed)abstract Selective immunolesioning of the basal forebrain cholinergic system by 192 IgG-saporin, which leads to a dramatic loss of the cholinergic innervation in cortical and hippocampal regions, facilitates the development of hippocampal kindling in rats. The aim of the present study was to explore whether grafted cholinergic neurones are able to reverse the lesion-induced increase of seizure susceptibility. Intraventricular 192 IgG-saporin was administered to rats which 3 weeks later were implanted with rat embryonic, acetylcholine-rich septal-diagonal band tissue ('cholinergic grafts') or cortical tissue/vehicle ('sham grafts') bilaterally into the hippocampal formation. After 3 months, the grafted animals as well as non-lesioned control rats were subjected to daily hippocampal kindling stimulations. In the animals with cholinergic grafts, which had reinnervated the hippocampus and dentate gyrus bilaterally, there was a marked suppression of the development of seizures as compared with the hyperexcitable, sham-grafted rats. This effect was significantly correlated to the density of the graft-derived cholinergic innervation of the host hippocampal formation. The kindling rate in the rats with cholinergic grafts was similar to that in non-lesioned controls. These results provide further evidence that the intrinsic basal forebrain cholinergic system dampens kindling epileptogenesis and demonstrate that this function can be exerted also by grafted cholinergic neurones.
12.	Gloveli, T, et al. (author) Kindling alters entorhinal cortex-hippocampal interaction by increased efficacy of presynaptic GABA(B) autoreceptors in layer III of the entorhinal cortex 2003 In: Neurobiology of Disease. - 0969-9961. ; 13:3, s. 203-212 Journal article (peer-reviewed)abstract We studied the effect of kindling, a model of temporal lobe epilepsy, on the frequency-dependent information transfer from the entorhinal cortex to the hippocampus in vitro. In control rats repetitive synaptic activation of layer III projection cells resulted in a frequency dependent depression of the synaptic transfer of action potentials to the hippocampus. One-to-two-days after kindling this effect was strongly reduced. Although no substantial change in synaptic inhibition upon single electrical stimulation was detected in kindled rats, there was a significant depression in the prolonged inhibition following high frequency stimulation. In kindled animals, paired-pulse depression (PPD) of stimulus-evoked IPSCs in layer III neurons was significantly stronger than in control rats. The increase of PPD is most likely caused by an increased presynaptic GABA(B) receptor-mediated autoinhibition. In kindled animals activation of presynaptic GABA(B) receptors by baclofen (10 muM) suppressed monosynaptic IPSCs significantly more than in control rats. In contrast, activation of postsynaptic GABA(B) receptors by baclofen was accompanied by comparable changes of the membrane conductance in both animal groups. Thus, in kindled animals activation of the layer III-CA1 pathway is facilitated by an increased GABA(B) receptor-mediated autoinhibition leading to an enhanced activation of the monosynaptic EC-CA1 pathway. (C) 2003 Elsevier Science (USA). All rights reserved.
13.	Gonzalez-Ramos, Ana, et al. (author) Human stem cell-derived GABAergic neurons functionally integrate into human neuronal networks 2021 In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1 Journal article (peer-reviewed)abstract Gamma-aminobutyric acid (GABA)-releasing interneurons modulate neuronal network activity in the brain by inhibiting other neurons. The alteration or absence of these cells disrupts the balance between excitatory and inhibitory processes, leading to neurological disorders such as epilepsy. In this regard, cell-based therapy may be an alternative therapeutic approach. We generated light-sensitive human embryonic stem cell (hESC)-derived GABAergic interneurons (hdIN) and tested their functionality. After 35 days in vitro (DIV), hdINs showed electrophysiological properties and spontaneous synaptic currents comparable to mature neurons. In co-culture with human cortical neurons and after transplantation (AT) into human brain tissue resected from patients with drug-resistant epilepsy, light-activated channelrhodopsin-2 (ChR2) expressing hdINs induced postsynaptic currents in human neurons, strongly suggesting functional efferent synapse formation. These results provide a proof-of-concept that hESC-derived neurons can integrate and modulate the activity of a human host neuronal network. Therefore, this study supports the possibility of precise temporal control of network excitability by transplantation of light-sensitive interneurons.
14.	Jakubs, Katherine, et al. (author) Environment Matters: Synaptic Properties of Neurons Born in the Epileptic Adult Brain Develop to Reduce Excitability. 2006 In: Neuron. - : Elsevier BV. - 0896-6273. ; 52:6, s. 1047-1059 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.
15.	Jakubs, Katherine, et al. (author) Inflammation regulates functional integration of neurons born in adult brain. 2008 In: The Journal of Neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 28:47, s. 12477-12488 Journal article (peer-reviewed)abstract Inflammation influences several steps of adult neurogenesis, but whether it regulates the functional integration of the new neurons is unknown. Here, we explored, using confocal microscopy and whole-cell patch-clamp recordings, whether a chronic inflammatory environment affects the morphological and electrophysiological properties of new dentate gyrus granule cells, labeled with a retroviral vector encoding green fluorescent protein. Rats were exposed to intrahippocampal injection of lipopolysaccharide, which gave rise to long-lasting microglia activation. Inflammation caused no changes in intrinsic membrane properties, location, dendritic arborization, or spine density and morphology of the new cells. Excitatory synaptic drive increased to the same extent in new and mature cells in the inflammatory environment, suggesting increased network activity in hippocampal neural circuitries of lipopolysaccharide-treated animals. In contrast, inhibitory synaptic drive was more enhanced by inflammation in the new cells. Also, larger clusters of the postsynaptic GABA(A) receptor scaffolding protein gephyrin were found on dendrites of new cells born in the inflammatory environment. We demonstrate for the first time that inflammation influences the functional integration of adult-born hippocampal neurons. Our data indicate a high degree of synaptic plasticity of the new neurons in the inflammatory environment, which enables them to respond to the increase in excitatory input with a compensatory upregulation of activity and efficacy at their afferent inhibitory synapses.
16.	Kokaia, Merab, et al. (author) Biphasic differential changes of GABAA receptor subunit mRNA levels in dentate gyrus granule cells following recurrent kindling-induced seizures 1994 In: Brain Research. Molecular Brain Research. - 0169-328X. ; 23:4, s. 323-332 Journal article (peer-reviewed)abstract GABAA receptor alpha 1, beta 3 and gamma 2 subunit mRNA levels have been measured in hippocampus using in situ hybridization, following 1, 10 and 40 seizures produced by rapid kindling stimulations. Major alterations of gene expression were largely confined to the dentate gyrus. One stimulus-induced seizure reduced gamma 2 mRNA levels in the dentate gyrus by 30%. In contrast, mRNA expression increased for alpha 1 in CA1 and CA3 and for beta 3 in CA1 to around 30% above control values. Ten stimulations reduced beta 3 (by 19%) and gamma 2 (by 37%) mRNA expression in the dentate gyrus. No changes were observed in other hippocampal subregions. Forty kindling-induced seizures led to biphasic alterations of subunit mRNA levels in dentate gyrus with only minor changes in CA1-CA3. Up to 4 h after the last seizure mRNA expression for alpha 1 was slightly decreased in dentate gyrus, whereas marked reductions were observed for beta 3 and gamma 2 (by 41% and 48%, respectively). Between 12 and 48 h there were major increases of alpha 1 (by 59%) and gamma 2 (by 35%) mRNA levels but no significant changes of beta 3 mRNA expression. Subunit mRNA levels had returned to control values after 5 days, which argues against a direct involvement of GABAA receptor in kindling-evoked hyperexcitability. The rapid and transient, biphasic changes of GABAA receptor subunits following recurrent seizures could play an important role in stabilizing granule cell excitability, thereby reducing seizure susceptibility. The differential regulation of subunit mRNA levels following seizures suggests a novel mechanism for changing the physiological properties of dentate granule cells through possible GABAA receptor complexes with different subunit composition.
17.	Kokaia, Merab, et al. (author) Immunolesioning of basal forebrain cholinergic neurons facilitates hippocampal kindling and perturbs neurotrophin messenger RNA regulation 1996 In: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 70:2, s. 313-327 Journal article (peer-reviewed)abstract The immunotoxin 192 IgG-saporin induces an efficient and specific lesion of low-affinity nerve growth factor receptor-bearing cholinergic neurons in the basal forebrain. Intraventricular injection of 192 IgG-saporin, which caused a complete loss of cholinergic afferents to the hippocampus and neocortex and a partial denervation of amygdala and piriform cortex, was found to markedly facilitate the initial stages of seizure development in hippocampal kindling. In contrast, the progression of kindling process from focal to generalized seizures was not affected. In situ hybridization demonstrated that basal levels of brain-derived neutrotrophic factor messenger RNA in the hippocampal formation and piriform cortex were significantly decreased by the lesion, which also attenuated the seizure-induced increase of brain-derived neurotrophic factor messenger RNA expression in the hippocampus and frontal cortex. In the dentate gyrus, the 192 IgG-saporin lesion selectively reduced the upregulation of messenger RNAs for brain-derived neurotrophic factor exons I and III after a generalized seizure, whereas the increase of exon II messenger RNA was unchanged. The lesion abolished the seizure-evoked increase of nerve growth factor and TrkC messenger RNA levels and decrease of neutrophin-3 messenger RNA expression in dentate granule cells, while TrkB messenger RNA levels were not affected. We conclude that the basal forebrain cholinergic system (1) suppresses kindling epileptogenesis in the hippocampus, and (2) enhances both basal and seizure-evoked brain-derived neurotrophic factor synthesis in the hippocampal formation and some cortical areas through a specific pattern of activation of promoters within the brain-derived neurotrophic factor gene.
18.	Kokaia, Merab, et al. (author) Seizure development and noradrenaline release in kindling epilepsy after noradrenergic reinnervation of the subcortically deafferented hippocampus by superior cervical ganglion or fetal locus coeruleus grafts 1994 In: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 130:2, s. 351-361 Journal article (peer-reviewed)abstract Solid pieces of fetal locus coeruleus (LC) or superior cervical ganglion (SCG) were placed into a fimbria-fornix lesion cavity in 6-hydroxydopamine-treated, noradrenaline (NA)-denervated rats. Six to 8 months later, all animals were subjected to electrical kindling stimulations in the hippocampus until they had reached the fully kindled state. Nongrafted lesioned animals showed markedly increased kindling rate which was partly attenuated by LC but not SCG grafts. In both LC- and SCG-grafted animals, dopamine beta-hydroxylase immunocytochemistry demonstrated a high density of graft-derived noradrenergic fibers in the dorsal hippocampus, whereas reinnervation of the ventral hippocampus was much more sparse. Subregional distribution of these fibers within the hippocampus was different in the two grafted groups. Both grafts partly restored basal extracellular NA levels in the hippocampus and reacted to generalized seizures by a significant (two- to threefold) increase of NA release, as measured by intracerebral microdialysis. Our data indicate (i) that seizure activity can regulate transmitter release from noradrenergic neurons in both LC and SCG grafts, (ii) that only fetal LC grafts retard seizure development in kindling, and (iii) that the inability of SCG implants to influence kindling epileptogenesis could be due to a lack of synaptic contacts between the graft-derived ganglionic fibers and host hippocampal neurons.
19.	Kokaia, Merab, et al. (author) Seizure suppression in kindling epilepsy by intracerebral implants of GABA- but not by noradrenaline-releasing polymer matrices 1994 In: Experimental Brain Research. - 0014-4819. ; 100:3, s. 385-394 Journal article (peer-reviewed)abstract Gamma-aminobutyric acid (GABA)-releasing polymer matrices were implanted bilaterally, immediately dorsal to the substantia nigra, in rats previously kindled in the amygdala. Two days after implantation, rats with GABA-releasing matrices exhibited only focal limbic seizures in response to electrical stimulation, whereas animals with control matrices devoid of GABA had generalized convulsions. GABA release from the polymer matrices was high during the first days after implantation, as demonstrated both in vitro and, using microdialysis, in vivo. The anticonvulsant effect was no longer observed at 7 and 14 days at which time GABA release was found to be low. In a parallel experiment, polymer matrices containing noradrenaline (NA) were implanted bilaterally into the hippocampus of rats with extensive forebrain NA depletion induced by an intraventricular 6-hydroxydopamine injection. No effect on the development of hippocampal kindling was observed, despite extracellular NA levels exceeding those of rats with intrahippocampal locus coeruleus grafts that have previously been shown to retard kindling rate. The results indicate that GABA-releasing implants located in the substantia nigra region can suppress seizure generalization in epilepsy, even in the absence of synapse formation and integration with the host brain. In contrast, the failure of NA-releasing polymer matrices to retard the development of seizures in NA-depleted rats suggests that such an effect can only be exerted by grafts acting through a well-regulated, synaptic release of NA.
20.	Kokaia, Merab, et al. (author) Suppressed epileptogenesis in BDNF mutant mice 1995 In: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 133:2, s. 215-224 Journal article (peer-reviewed)abstract Kindling is an animal model of epilepsy in which repeated electrical stimulations lead to progressive and permanent amplification of seizure activity, culminating in generalized convulsions. Each brief period of seizure activity during kindling epileptogenesis causes a marked, transient increase of the synthesis of brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons. We find that the development of kindling is markedly suppressed in mice heterozygous for a deletion of the BDNF gene. In contrast, the maintenance of kindling is unaffected. The mutant mice show lower levels of BDNF mRNA in cortical and hippocampal neurons after seizures than do wild-type mice. Hippocampal mossy fiber sprouting is augmented in BDNF mutants but there are no other morphological abnormalities. These results show that BDNF plays an important role in establishing hyperexcitability during epileptogenesis, probably by increasing efficacy in stimulated synapses.
21.	Kokaia, Merab, et al. (author) Suppressed kindling epileptogenesis in mice with ectopic overexpression of galanin 2001 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 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.
22.	Kokaia, Zaal, et al. (author) Brain insults in rats induce increased expression of the BDNF gene through differential use of multiple promoters 1994 In: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 6:4, s. 587-596 Journal article (peer-reviewed)abstract The rat brain-derived neurotrophic factor (BDNF) gene consists of four short 5'-exons linked to separate promoters and one 3'-exon encoding the mature BDNF protein. Using in situ hybridization we demonstrate here that kindling-induced seizures, cerebral ischaemia and insulin-induced hypoglycaemic coma increase BDNF mRNA levels through insult- and region-specific usage of three promoters within the BDNF gene. Both brief (2 min) and longer (10 min) periods of forebrain ischaemia induced significant and major increases only of exon III mRNA in the dentate gyrus. Following hypoglycaemic coma (1 and 30 min), exon III mRNA was markedly elevated in the dentate gyrus and, in addition, exon I mRNA showed a moderate increase. Single and recurrent (n = 40) hippocampal seizures significantly increased expression of exon I, II and III mRNAs in the dentate gyrus granule cells. After recurrent seizures, including generalized convulsions, there were also major increases of both exon I and III mRNAs in the CA3 region, amygdala, piriform cortex and neocortex, whereas in the hippocampal CA1 sector marked elevations were detected only for exon III mRNA. The insults had no effect on the level of exon IV mRNA in the brain. The region- and insult-specific pattern of promoter activation might be of importance for the effectiveness of protective responses as well as for the regulation of plastic changes following brain insults.
23.	Kokaia, Zaal, et al. (author) Changes in GABA(B) receptor immunoreactivity after recurrent seizures in rats 2001 In: Neuroscience Letters. - 0304-3940. ; 315:1-2, s. 85-88 Journal article (peer-reviewed)abstract GABA(B) receptors play an important role in the excitability of neuronal networks and can influence seizure activity. Here we demonstrate for the first time that kindling, an animal model for human temporal lobe epilepsy, leads to both early and delayed changes of GABA(B) receptor immunoreactivity in hippocampal and cortical areas. We propose that the altered GABA(B) receptor levels might be a compensatory mechanism to reduce excitability induced by recurrent kindled seizures, or alternatively, may promote the development of kindled epilepsy.
24.	Kokaia, Zaal, et al. (author) Co-expression of TrkB and TrkC receptors in CNS neurones suggests regulation by multiple neurotrophins 1995 In: NeuroReport. - : Ovid Technologies (Wolters Kluwer Health). - 1473-558X .- 0959-4965. ; 6:5, s. 769-772 Journal article (peer-reviewed)abstract Using double-label in situ hybridization, we have explored the possibility that individual CNS neurones can co-express mRNAs for the high-affinity receptors of brain-derived neurotrophic factor and neurotrophin-3, TrkB and TrkC, respectively. The vast majority of TrkC mRNA-containing neurones in the hippocampal formation and cerebral cortex were also labelled for TrkB mRNA. Cells expressing only TrkB or TrkC mRNA were very scarce in these regions, representing < 15% of all labelled cells. These findings suggest that the same cortical or hippocampal neurone can be regulated by several members of the neurotrophin family, which may be important both during development and in response to physiological activity and pathological conditions.
25.	Kokaia, Zaal, et al. (author) Regional brain-derived neurotrophic factor mRNA and protein levels following transient forebrain ischemia in the rat 1996 In: Brain Research. Molecular Brain Research. - 0169-328X. ; 38:1, s. 139-144 Journal article (peer-reviewed)abstract Levels of BDNF mRNA and protein were measured in the rat brain using in situ hybridization and a two-site enzyme immunoassay. Under basal conditions, the highest BDNF concentration was found in the dentate gyrus (88 ng/g), while the levels in CA3 (50 ng/g), CA1 (18 ng/g) and parietal cortex (8 ng/g) were markedly lower. Following 10 min of forebrain ischemia, BDNF protein increased transiently in the dentate gyrus (to 124% of control at 6 h after the insult) and CA3 region (to 131% of control, at 1 week after the insult). In CA1 and parietal cortex, BDNF protein decreased to 73-75% of control at 24 h. In contrast, BDNF mRNA expression in dentate granule cells and CA3 pyramidal layer was transiently elevated to 287 and 293% of control, respectively, at 2 h, whereas no change was detected in CA1 or neocortex. The regional BDNF protein levels shown here correlate at least partly with regional differences in cellular resistance to ischemic damage, which is consistent with the hypothesis of a neuroprotective role of BDNF.

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