Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 10-year-old boy presented with a severe and diffuse mosaic skin hypopigmentation running (in narrow bands) along the lines of Blaschko associated with mosaic areas of alopecia, facial dysmorphism with midface hypoplasia, bilateral punctate cataract, microretrognathia, short neck, pectus excavatum, joint hypermobility, mild muscular hypotonia, generalized seizures, and mild mental retardation. Cranial magnetic resonance imaging revealed hypoplastic corpus callosum (primarily posterior), subcortical band heterotopia, and diffuse subcortical, periventricular cystic-like lesions. Similar dysmorphic features were observed in the child's mother, but with no imaging abnormalities. The facial phenotype coupled with the cysts in the brain was strongly reminiscent of the oculocerebrorenal Lowe syndrome. Full chromosome studies in the parents and the proband and mutation analysis on peripheral blood lymphocytes (and on skin cultured fibroblasts from affected and unaffected skin areas in the child) in the genes for subcortical band heterotopia (DCX (Xq22.3-q23)], lissencephaly (PAFAH1B1, alias LIS1, at 17p13.3), and oculocerebrorenal syndrome of Lowe (OCRL at Xq23-q24)] were unrevealing. This constellation of multiple congenital anomalies including skin hypopigmentation and eye, musculoskeletal, and nervous system abnormalities was sufficiently characterized to be regarded as a novel example of pigmentary mosaicism of the Ito type (i.e., hypomelanosis of Ito).
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PMID:Pigmentary mosaicism, subcortical band heterotopia, and brain cystic lesions. 1938 77

Stroke in the neonatal brain is an understudied cause of neurologic morbidity. Recently we have characterized a new immature mouse model of stroke utilizing unilateral carotid ligation alone to produce infarcts and acute seizures in postnatal day 12 (P12) CD-1 mice. In this study, the amount of poststroke neural progenitor proliferation was examined in the subgranular (SGZ) of the dentate gyrus and the subventricular zone (SVZ) 7, 14, and 21days after ischemia (DAI). A single IP injection (50 mg/kg) of bromodeoxyuridine (BrdU) given 2 hr before perfusion fixation labeled newborn cells. Early cell phenotypes were quantified by colabeling with GFAP, nestin, and DCX. Control mice revealed an age-dependent decrease in neural proliferation, with an approximately 50% drop in BrdU-labeled cell counts at P33 compared with P19 both in the SGZ and in the SVZ. Significant reduction in the amount of neural proliferation in the ipsilateral injured SGZ of ligated mice correlated with both the severity of the stroke-injury and the acute seizure scores. Similar correlations were not detected contralaterally. Contralateral SGZ neural proliferation was initially lowered at 7 DAI but normalized by 21 DAI. In both injured and control brains, approximately 90% of newborn SGZ cells colabeled with nestin, approximately 30% colabeled with GFAP, and a few colabeled with DCX. In contrast, poststroke SVZ cell proliferation was enhanced ipsi- more than contralaterally at 7 DAI. In the SVZ, the enhanced neural proliferation normalized to control levels by P33. In conclusion, the neural cell proliferation was differentially altered in the SGZ vs. SVZ after neonatal stroke.
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PMID:Poststroke subgranular and rostral subventricular zone proliferation in a mouse model of neonatal stroke. 1939 74

Certain antiepileptic drugs (AEDs) that are commonly used to treat seizures in children also affect cognition, and these effects can persist into adulthood, long after drug withdrawal. Widespread enhancement of apoptosis may be one mechanism underlying these lasting cognitive changes. Whether AEDs affect other processes in brain development during early postnatal life has not, however, been systematically analyzed. Here we determined whether chronic administration of common AEDs during early life alters cell proliferation and neurogenesis in the hippocampus. Postnatal day 7 (P7) rats received phenobarbital, clonazepam, carbamazepine, valproate, topiramate, or vehicle for 28 days. Bromodeoxyuridine was administered on P34 to label dividing cells. Cell proliferation was assessed 24 hr later, and cell survival and differentiation were assessed 28 days later. Phenobarbital and clonazepam significantly inhibited cell proliferation by 63% and 59%, respectively, and doublecortin immunoreactivity (indicator of neurogenesis) in the dorsal hippocampus was also significantly decreased by 26% and 24%, respectively. Survival of new cells steadily decreased in phenobarbital and clonazepam groups over 28 days. Reduced cell proliferation and survival resulted in fewer new neurons in the dentate gyrus, as confirmed by neuronal counting on P62. There were, however, no differences in cell distribution pattern or differentiation toward neuron and glial cells when phenobarbital and clonazepam groups were compared with controls. There were no changes in rats exposed to carbamazepine, valproate, or topiramate. Thus, inhibiting cell proliferation, survival, and neurogenesis in the developing hippocampus may be another potential mechanism underlying brain impairment associated with certain AED therapies in early life.
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PMID:Long-term antiepileptic drug administration during early life inhibits hippocampal neurogenesis in the developing brain. 1943 54

A partial kindling procedure was used to investigate the correlation between focal seizure development and changes in dendritic spine morphology, ongoing neurogenesis and reactive astrogliosis in the adult rat dentate gyrus (DG). The processes of neurogenesis and astrogliosis were investigated using markers for doublecortin (DCX), 5-bromo-2-deoxyuridine (BrdU) and glial fibrillary acidic protein (GFAP). Our data demonstrate that mild focal seizures induce a complex series of cellular events in the DG one day after cessation of partial rapid kindling stimulation consisting (in comparison to control animals that were electrode implanted but unkindled), firstly, of an increase in the number of postmitotic BrdU labeled cells, and secondly, an increase in the number of DCX labeled cells, mainly in subgranular zone. Ultrastructural changes were examined using qualitative electron microscope analysis and 3-D reconstructions of both dendritic spines and postsynaptic densities. Typical features of kindling in comparison to control tissue included translocation of mitochondria to the base of the dendritic spine stalks; a migration of multivesicular bodies into mushroom dendritic spines, and most notably formation of "giant" spinules originating from the head of the spines of DG neurons. These morphological alterations arise at seizure stages 2-3 (focal seizures) in the absence of signs of the severe generalized seizures that are generally recognized as potentially harmful for neuronal cells. We suggest that an increase in ongoing neurogenesis, reactive astrogliosis and dendritic spine reorganization in the DG is the crucial step in the chain of events leading to the progressive development of seizure susceptibility in hippocampal circuits.
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PMID:Partial kindling induces neurogenesis, activates astrocytes and alters synaptic morphology in the dentate gyrus of freely moving adult rats. 1944 63

Neural migration defects lead to various types of human malformations of cortical development including subcortical band heterotopia, which shows formation of a secondary cortical plate beneath the primary cortex and is typically caused by mutation of the DCX (doublecortin) gene. Subcortical band heterotopia is usually associated with mental retardation and epilepsy. We previously discovered RA-GEF-1 as a guanine nucleotide exchange factor (GEF) for Rap1 small GTPase. Here we have analysed its in-vivo role in formation of the adult cerebral cortex by using telencephalon-specific RA-GEF-1 conditional knockout (cKO) mice, generated by mating RA-GEF-1(flox/flox) mice with Emx1-cre knockin mice. RA-GEF-1 cKO mice showed severe defects in their brain structures including an ectopic cortical mass underlying a relatively normal cortex. The ectopic cortical mass lacked the normal six-layered lamination but preserved the subcortical connectivity as revealed by retrograde tracing. Further, RA-GEF-1 cKO mice exhibited a lower threshold for the induction of epileptic seizures. These phenotypes have a resemblance to those of human subcortical band heterotopia. In addition, the agenesis of anterior commissures, the dorsal hippocampus commissure, the corpus callosum and the enlargement of the lateral ventricles were observed in cKO mice. Our findings suggest a crucial function of RA-GEF-1 in neural migration.
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PMID:Dorsal telencephalon-specific RA-GEF-1 knockout mice develop heterotopic cortical mass and commissural fiber defect. 1945 29

Temporal lobe seizures can induce the proliferation and abnormal migration of newly generated dentate granule cells, but little is known about the molecular mechanisms that govern these pathological events. Reelin and DISC1 (disrupted-in-schizophrenia 1) are proteins that play a regulatory role in the maturation and integration of new neurons in the developing and adult brain. In this study, we examined whether amygdala kindling results in aberrant neurogenesis and altered expression of reelin and DISC1 in the adult dentate gyrus. Using doublecortin immunohistochemistry, we found that short-term kindling (i.e., 30 electrical stimulations) significantly increased the number of immature neurons in the dentate subgranular zone (SGZ), whereas long-term kindling (i.e., 99 electrical stimulations) did not. However, doublecortin-labeled neurons in long-term kindled rats showed greater dendritic complexity than they did in short-term kindled or control rats. We also found that long-term kindling decreased the number of reelin-positive cells and decreased DISC1 expression in the dentate granule cell layer and subgranular zone. Interestingly, kindling-induced changes in reelin and DISC1 expression coincided with the appearance of ectopically located Prox1-labeled granule cells in the hilus. These effects occurred independently of alterations in granule cell layer length, dentate volume, or the number of hilar neurons. Taken together, these findings suggest a novel role for DISC1 in the pathophysiology of temporal lobe epilepsy and further suggest that changes in reelin and DISC1 expression may contribute to aberrant neurogenesis in the kindling model.
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PMID:The effect of amygdala kindling on hippocampal neurogenesis coincides with decreased reelin and DISC1 expression in the adult dentate gyrus. 1949 87

Angelman syndrome (AS) is a severe neurodevelopmental disorder characterized by mental retardation, seizures and sleep disturbances. It results from lack of the functional maternal allele of UBE3A gene. Ube3a maternal-deficient mice (Ube3a m-/p+), animal models for AS, are impaired in hippocampal-dependent learning tasks as compared with control (Ube3a m+/p+) mice. We first examined the basal expression of immediate early genes which expression is required for synaptic plasticity and memory formation. We found that basal expression of c-fos and Arc genes is reduced in the DG of Ube3a maternal deficient mice compared to their non-transgenic littermates. We then examined whether adult hippocampal neurogenesis, which likely serves as a mechanism toward brain plasticity, is altered in these transgenic mice. Neurogenesis occurs throughout life in mammalian dentate gyrus (DG) and recent findings suggest that newborn granule cells are involved in some forms of learning and memory. Whether maternal Ube3a deletion is detrimental on hippocampal neurogenesis is unclear. Herein, we show, using the mitotic marker Ki67, the birthdating marker 5-bromo-2'-dexoyuridine (BrdU) and the marker doublecortin (DCX) to respectively label cell proliferation, cell survival or young neuron production, that the Ube3a maternal deletion does not affect the proliferation nor the survival of newborn cells in the hippocampus. In contrast, using the postmitotic neuronal marker (NeuN), we show that Ube3a maternal deletion is associated with a lower fraction of BrdU+/NeuN+ newborn neurons among the population of surviving new cells in the hippocampus. Collectively, these findings suggest that some aspects of adult neurogenesis and plasticity are affected by Ube3a deletion and may contribute to the hippocampal dysfunction observed in AS mice.
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PMID:Impaired hippocampal plasticity and altered neurogenesis in adult Ube3a maternal deficient mouse model for Angelman syndrome. 1978 83

The mechanism of status epilepticus-induced neuronal death in the immature brain is not fully understood. In the present study, we examined the contribution of caspases in our lithium-pilocarpine model of status epilepticus in 14 days old rat pups. In CA1, upregulation of caspase-8, but not caspase-9, preceded caspase-3 activation in morphologically necrotic cells. Pretreatment with a pan-caspase inhibitor provided neuroprotection, showing that caspase activation was not an epiphenomenon but contributed to neuronal necrosis. By contrast, upregulation of active caspase-9 and caspase-3, but not caspase-8, was detected in apoptotic dentate gyrus neurons, which were immunoreactive for doublecortin and calbindin-negative, two features of immature neurons. These results suggest that, in cells which are aligned in series as parts of the same excitatory hippocampal circuit, the same seizures induce neuronal death through different mechanisms. The regional level of neuronal maturity may be a determining factor in the execution of a specific death program.
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PMID:Vulnerability of postnatal hippocampal neurons to seizures varies regionally with their maturational stage. 1987 60

Lamotrigine (LTG) and topiramate (TPM), two of the most commonly used new-generation antiepileptic drugs (AEDs), have been shown to produce no adverse and impaired cognitive effects in patients with epilepsy, respectively. As seizure-induced neurogenesis might contribute to cognitive deficits that are associated with status epilepticus (SE), we examined whether these two drugs produce differential effects on seizure-induced neurogenesis in the hippocampus of adult rats. Lithium pilocarpine model was used to mimic human temporal-lobe epilepsy. Five hours after SE, LTG and TPM were administered intragastrically twice daily throughout the entire length of the experiment with total daily dose of 20 and 80 mg/kg, respectively. The hippocampal neurogenesis was examined using 5-bromodeoxyuridine and doublecortin immunohistochemistry. Both LTG and TPM treatments significantly inhibited seizure-induced proliferation of neural progenitors in the hippocampus, but did not affect the neuronal differentiation of newborn cells. Long-term treatment with both AEDs decreased the number of spontaneous recurrent seizures after SE and alleviated chronic seizure-induced neuronal injury in the dentate hilus. Eventually, TPM significantly increased the number of newborn neurons in the dentate granular cell layer after seizures likely by promoting the survival of newborn neurons. In contrast, LTG treatment significantly reduced the number of ectopic hilar newborn neurons after seizures. Neither of them prevented the formation of hilar basal dendrites of newborn neurons in the epileptic hippocampus. These results indicate that TPM but not LTG promotes aberrant neuron regeneration in the hippocampus after SE, which might be partially related to their differential effects on cognitive function.
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PMID:Effects of lamotrigine and topiramate on hippocampal neurogenesis in experimental temporal-lobe epilepsy. 2002 52

Previous reports indicate that in utero knockdown of doublecortin (DCX) results in the genesis of a subcortical heterotopia reminiscent of the doublecortex observed in female patients with DCX mutations. It has also been shown that these rats display an increased susceptibility to convulsant agents and increased cortical neurons excitability; but it is presently unknown whether they display spontaneous seizures. Furthermore, the link between the size of heterotopia and the clinical manifestation remained to be elucidated. Using video-electrocorticogram recordings, we now report that DCX knockdown induces frequent spontaneous seizures commonly associated with myoclonic jerks in adult rats. Surprisingly, epilepsy occurred even in rats with very small subcortical heterotopias, as revealed by histological analysis of recorded animals. Moreover, the severity of the epileptic manifestations was positively correlated with both the size of the subcortical heterotopia and the age of recorded animals; thus, epileptic features were not detected in immature affected rats. In conclusion, our data demonstrate for the first time that subtle alterations can yield epilepsy and reveal a strong correlation between thicknesses of subcortical heterotopia, age of affected individuals and clinical impairment.
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PMID:Spontaneous epileptic manifestations in a DCX knockdown model of human double cortex. 2016 25


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