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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adult mammalian cortex is characterized by a distinct laminar structure generated through a well-defined pattern of neuronal migration. Successively generated neurons are layered in an "inside-out" manner to produce six cortical laminae. We demonstrate here that p35, the neuronal-specific activator of cyclin-dependent kinase 5, plays a key role in proper neuronal migration. Mice lacking p35, and thus p35/cdk5 kinase activity, display severe cortical lamination defects and suffer from sporadic adult lethality and seizures. Histological examination reveals that the mutant mice lack the characteristic laminated structure of the cortex. Neuronal birth-dating experiments indicate a reversed packing order of cortical neurons such that earlier born neurons reside in superficial layers and later generated neurons occupy deep layers. The phenotype of p35 mutant mice thus demonstrates that the formation of cortical laminar structure depends on the action of the p35/cdk5 kinase.
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PMID:Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. 901 Feb 3

Apoptosis is a cell-suicide process that appears to play a central role not only during normal neuronal development but also in several neuropathological disease states. An important component of this process is a proteolytic cascade involving a family of cysteine proteases called caspases. Caspase inhibitors have been demonstrated to be effective in inhibiting neuronal cell death in various apoptotic paradigms. We have created transgenic mice that neuronally express the baculoviral caspase inhibitor p35. Neuronal expression of the p35 protein was found to confer functional caspase inhibitory activity and prevent apoptosis in isolated cerebellar granular cultures induced to undergo apoptosis either via staurosporine treatment or through withdrawal of extracellular potassium. Neuronal expression of p35 was also found to attenuate neurodegeneration associated with the excitotoxic glutamate analogue kainic acid (KA) in vitro and in vivo. Organotypic hippocampal cultures isolated from p35 transgenics demonstrated lowered caspase activity and decreased apoptosis compared with wild type when exposed to KA. In vivo injection of KA also produced decreased caspase activity and cell death in p35 transgenics vs. wild type. These results suggest that the presence of p35 in neurons in vivo is protective against various types of apoptosis, including seizure-related neurodegeneration, and that caspases may be attractive potential targets for preventing neuronal injury associated with diseases such as epilepsy. These mice also provide a valuable tool for exploring the role of caspases in other neuropathological conditions in which apoptosis has been implicated.
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PMID:Transgenic mice neuronally expressing baculoviral p35 are resistant to diverse types of induced apoptosis, including seizure-associated neurodegeneration. 1068 43

Cortical dysplasia is a major cause of intractable epilepsy in children. However, the precise mechanisms linking cortical malformations to epileptogenesis remain elusive. The neuronal-specific activator of cyclin-dependent kinase 5, p35, has been recognized as a key factor in proper neuronal migration in the neocortex. Deletion of p35 leads to severe neocortical lamination defects associated with sporadic lethality and seizures. Here we demonstrate that p35-deficient mice also exhibit dysplasia/ heterotopia of principal neurons in the hippocampal formation, as well as spontaneous behavioral and electrographic seizures. Morphological analyses using immunocytochemistry, electron microscopy, and intracellular labeling reveal a high degree of abnormality in dentate granule cells, including heterotopic localization of granule cells in the molecular layer and hilus, aberrant dendritic orientation, occurrence of basal dendrites, and abnormal axon origination sites. Dentate granule cells of p35-deficient mice also demonstrate aberrant mossy fiber sprouting. Field potential laminar analysis through the dentate molecular layer reflects the dispersion of granule cells and the structural reorganization of this region. Similar patterns of cortical disorganization have been linked to epileptogenesis in animal models of chronic seizures and in human temporal lobe epilepsy. The p35-deficient mouse may therefore offer an experimental system in which we can dissect out the key morphological features that are causally related to epileptogenesis.
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PMID:Abnormal morphological and functional organization of the hippocampus in a p35 mutant model of cortical dysplasia associated with spontaneous seizures. 1115 84

Studies utilizing gene delivery to the nervous system indicate that various strategies are protective following acute neurological insults such as seizure and stroke. We have found that inhibitors of apoptosis are protective against excitotoxicity and heat stress but not energetic impairment in vitro. Here we studied the neuroprotective efficacy in vivo of these mediators: viral genes (crmA, p35, gamma34.5 KsBcl-2) that have evolved to suppress suicidal host responses to infection, by inhibiting apoptosis. We investigated these effects by utilizing modified herpes vectors to deliver the anti-apoptotic agents intracerebrally and examined them in the face of excitotoxic and metabolic insults. We found that p35 and gamma34.5 reduced by 45% a hippocampal CA3 lesion caused by kainic acid, while crmA and KsBcl-2 did not. None of the inhibitors protected the dentate gyrus of the hippocampus following 3-acetylpyridine, a hypoglycemia model, but we found crmA to worsen the damage. These data are similar to our results in neuronal cultures where the inhibitors protected against the excitotoxin domoic acid, but not against the metabolic poison, cyanide. Together, the results suggest that inhibitors of various apoptotic elements are capable of protecting under acute insult conditions both in vitro and in vivo, suggesting possible future therapeutic applications.
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PMID:HSV-mediated delivery of virally derived anti-apoptotic genes protects the rat hippocampus from damage following excitotoxicity, but not metabolic disruption. 1185 25

There is a high correlation between pediatric epilepsies and neuronal migration disorders. What remains unclear is whether there are intrinsic features of the individual dysplastic cells that give rise to heightened seizure susceptibility, or whether these dysplastic cells contribute to seizure activity by establishing abnormal circuits that alter the balance of inhibition and excitation. Mice lacking a functional p35 gene provide an ideal model in which to address these questions, because these knock-out animals not only exhibit aberrant neuronal migration but also demonstrate spontaneous seizures. Extracellular field recordings from hippocampal slices, characterizing the input-output relationship in the dentate, revealed little difference between wild-type and knock-out mice under both normal and elevated extracellular potassium conditions. However, in the presence of the GABA(A) antagonist bicuculline, p35 knock-out slices, but not wild-type slices, exhibited prolonged depolarizations in response to stimulation of the perforant path. There were no significant differences in the intrinsic properties of dentate granule cells (i.e., input resistance, time constant, action potential generation) from wild-type versus knock-out mice. However, antidromic activation (mossy fiber stimulation) evoked an excitatory synaptic response in over 65% of granule cells from p35 knock-out slices that was never observed in wild-type slices. Ultrastructural analyses identified morphological substrates for this aberrant excitation: recurrent axon collaterals, abnormal basal dendrites, and mossy fiber terminals forming synapses onto the spines of neighboring granule cells. These studies suggest that granule cells in p35 knock-out mice contribute to seizure activity by forming an abnormal excitatory feedback circuit.
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PMID:Physiological and morphological characterization of dentate granule cells in the p35 knock-out mouse hippocampus: evidence for an epileptic circuit. 1617 15

Abnormal brain development, induced by genetic influences or resulting from a perinatal trauma, has been recognized as a cause of seizure disorders. To understand how and when these structural abnormalities form, and how they are involved in epileptogenesis, it is important to generate and investigate animal models. We have studied one such model, a mouse in which deletion of the p35 gene (p35-/-) gives rise to both structural disorganization and seizure-like function. We now report that aberrant dentate development can be recognized in the organotypic hippocampal slice culture preparation generated from p35-/- mouse pups. In these p35-/- cultures, an abnormally high proportion of dentate granule cells migrates into the hilus and molecular layer, and develops aberrant dendritic and axonal morphology. In addition, astrocyte formation in the dentate gyrus is disturbed, as is the distribution of GABAergic interneurons. Although the p35-/- brain shows widespread abnormalities, the disorganization of the hippocampal dentate region is particularly intriguing since a similar pathology is often found in hippocampi of temporal lobe epilepsy patients. The abnormal granule cell features occur early in development, and are independent of seizure activity. Further, these aberrant patterns and histopathological features of p35-/- culture preparations closely resemble those observed in p35 knockout mice in vivo. This culture preparation thus provides an experimentally accessible window for studying abnormal developmental factors that can result in seizure propensity.
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PMID:Dentate development in organotypic hippocampal slice cultures from p35 knockout mice. 1714 53

Neuronal ceroid lipofuscinoses (NCL) are lysosomal storage disorders and constitute the most common group of progressive neurodegenerative diseases in childhood. Most NCLs are inherited in a recessive manner and are clinically characterised by a variable age at onset, epileptic seizures, psychomotor decline, visual impairment and premature death. To date, eight causative genes have been identified to underlie various clinical forms of NCL. We performed a genome-wide linkage analysis followed by sequencing the recently described NCL gene MFSD8 in three affected and three unaffected members of a consanguineous Egyptian family with an autosomal recessively inherited progressive neurodegenerative disorder. The clinical picture of the patients was compatible with a late infantile NCL (LINCL); however, impairment of the visual system was not a cardinal symptom in the respective family. By linkage analysis, we identified two putative loci on chromosome 1p36.11-p35.1 and 4q28.1-q28.2. The latter locus (4q28.1-q28.2) contained the MFSD8 gene, comprising a novel homozygous missense mutation in exon 5 (c.362a>g /p.Tyr121Cys), which segregated with the disease in the three affected sibs. We describe a novel mutation in the previously identified MFSD8 gene in a family with a common phenotype of LINCL, but no clinical report of vision loss. Our results enlarge the mutational and perhaps the nosological spectrum of one of the recently identified subtypes of NCL, called CLN7.
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PMID:A novel mutation in the MFSD8 gene in late infantile neuronal ceroid lipofuscinosis. 1885 Jan 19

Benign familial infantile seizures (BFIS) is an autosomal dominant epileptic syndrome characterized by afebrile partial seizures with or without secondary generalized tonic-clonic seizures beginning at three to ten months of age. Genetic studies have revealed three susceptibility chromosomal loci on 19q12-q13.1, 16p12-q12 and 2q24. Previously we described the novel locus on 1p36.12-p35.1 for a Chinese family affected with BFIS, and below is a subsequent mutation analysis of candidate genes for the mapped chromosome region. Forty-five genes were selected and subjected to mutation analysis. Thirty-six nucleotide variants were found, none of which led to pathogenic changes, thereby were identified as nucleotide polymorphisms. The analyses suggest those candidate genes that were detected might not be involved in the epileptogenesis of pure BFIS, at least in the Chinese family we studied.
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PMID:Mutation detection in candidate genes for benign familial infantile seizures on a novel locus. 2037 90

Cortical dysplasia of various types, reflecting abnormalities of brain development, have been closely associated with epileptic activities. Yet, there remains considerable discussion about if/how these structural lesions give rise to seizure phenomenology. Animal models have been used to investigate the cause-effect relationships between aberrant cortical structure and epilepsy. In this article, we discuss three such models: (1) the Eker rat model of tuberous sclerosis, in which a gene mutation gives rise to cortical disorganization and cytologically abnormal cellular elements; (2) the p35 knockout mouse, in which the genetic dysfunction gives rise to compromised cortical organization and lamination, but in which the cellular elements appear normal; and (3) the methylazoxymethanol-exposed rat, in which time-specific chemical DNA disruption leads to abnormal patterns of cell formation and migration, resulting in heterotopic neuronal clusters. Integrating data from studies of these animal models with related clinical observations, we propose that the neuropathologic features of these cortical dysplastic lesions are insufficient to determine the seizure-initiating process. Rather, it is their interaction with a more subtly disrupted cortical "surround" that constitutes the circuitry underlying epileptiform activities as well as seizure propensity and ictogenesis.
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PMID:Are developmental dysplastic lesions epileptogenic? 2261 7

The p35 knockout (p35-/-) mouse is an animal model of temporal lobe epilepsy that recapitulates key neuroanatomic abnormalities-granule cell dispersion and mossy fiber sprouting-observed in the hippocampal formation of humans, as well as spontaneous seizure activity. It is a useful model in which to study the relationship between the abnormal neuronal structure and seizure activity to further our understanding of cortical dysplasia in epileptogenesis. Our previous work using this mouse model characterized the anatomic features of the dentate granule cells and the functional implications of these abnormalities on increased recurrent excitation. These data also suggested that there might be compromised inhibition in this animal model. We pursued this possibility, focusing our investigation on inhibitory circuitry. In preliminary investigations using neuroanatomic tools (immunocytochemistry, camera lucida reconstructions of individually labeled interneurons, and electron microscopy) combined with intracellular electrophysiology, we observed no significant reduction in the number of symmetric versus asymmetric synaptic contacts on dentate granule cell somata, and no statistically significant changes in evoked early or late inhibition. Although there were some abnormalities in the morphology/distribution of inhibitory interneurons (as well as a larger population of dentate granule cells) of the dentate gyrus, overall inhibition in the p35 knockout mouse appeared to be largely intact.
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PMID:Inhibition and interneuron distribution in the dentate gyrus of p35 knockout mice. 2261 21


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