Consequences of recurrent seizures during early brain development

Liu, Z; Yang, Yongjie; Silveira, Diosely C.; Sarkisian, Matthew R.; Tandon, Pushpa; Huang, Laura; Stafstrom, Carl E.; Holmes, Gregory L.

doi:10.1016/s0306-4522(99)00064-0

Cited by 130 publications

(90 citation statements)

References 82 publications

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“…Animals experiencing pilocarpine-induced SE had abundant VGluT1-positive elements in the CA3 stratum pyramidale which extend massively to the stratum oriens in a zone immediately surrounding the outer boundaries of stratum pyramidale but also in the area corresponding to the infrapyramidal region in stratum oriens) (Fig. 4Ad, see arrows) consistent with previous findings of abnormally sprouted mossy fiber projections in epileptic rats Liu et al, 1999).…”

Section: Immunofluorescence Of Bk Channel and Vglut1 In The Hippocampsupporting

confidence: 90%

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Otalora¹,

Hernandez²,

Arshadmansab³

et al. 2008

Brain Research

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In the hippocampus, BK channels are preferentially localized in presynaptic glutamatergic terminals including mossy fibers where they are thought to play an important role regulating excessive glutamate release during hyperactive states. Large conductance calcium-activated potassium channels (BK, MaxiK, Slo) have recently been implicated in the pathogenesis of genetic epilepsy. However, the role of BK channels in acquired mesial temporal lobe epilepsy (MTLE) remains unknown. Here we used immunohistochemistry, laser scanning confocal microscopy (LSCM), western immunoblotting and RT-PCR to investigate the expression pattern of the alpha-pore forming subunit of BK channels in the hippocampus and cortex of chronically epileptic rats obtained by the pilocarpine model of MTLE. All epileptic rats experiencing recurrent spontaneous seizures exhibited a significant down-regulation of BK channel immunostaining in the mossy fibers at the hilus and stratum lucidum of the CA3 area. Quantitative analysis of immunofluorescence signals by LSCM revealed a significant 47% reduction in BK channel in epileptic rats when compared to age-matched non-epileptic control rats. These data correlate with a similar reduction in BK channel protein levels and transcripts in the cortex and hippocampus. Our data indicate a seizure-related down-regulation of BK channels in chronically epileptic rats. Further functional assays are necessary to determine whether altered BK channel expression is an acquired channelopathy or a compensatory mechanism affecting the network excitability in MTLE. Moreover, seizure-mediated BK down-regulation may disturb neuronal excitability and presynaptic control at glutamatergic terminals triggering exaggerated glutamate release and seizures.

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Section: Immunofluorescence Of Bk Channel and Vglut1 In The Hippocampsupporting

confidence: 90%

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Otalora¹,

Hernandez²,

Arshadmansab³

et al. 2008

Brain Research

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“…Following neonatal seizures there is impairment of visual spatial memory in the Morris water maze with rats subjected to recurrent flurothyl seizures during the neonatal period requiring longer times to find the platform than controls [84,86,87,92,93]. This impairment occurs when the rats are tested either during adolescence or when fully mature.…”

Section: Recurrent Seizuresmentioning

confidence: 99%

“…Recurrent flurothyl seizures during the first two weeks of life result in no discernible cell loss [84][85][86]. However, when the animals are studied as adults, there is extensive synaptic reorganization of the axons and terminals of the dentate granule cells, the so-called mossy fibers [86,87].…”

Section: Recurrent Seizuresmentioning

confidence: 99%

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Choosing the Correct Antiepileptic Drugs: From Animal Studies to the Clinic

Holmes¹,

Zhao²

2008

Pediatric Neurology

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Epilepsy is a chronic condition caused by an imbalance of normal excitatory and inhibitory forces in the brain. Antiepileptic drug therapy has been directed primarily toward reducing excitability through blockage of voltage-gated Na + or Ca 2+ channels, or increasing inhibition through enhancement of γ-aminobutyric acid currents. Prior to clinical studies, putative antiepileptic drugs are screened in animals, usually rodents. Maximal electrical shock, pentylenetetrazol, and kindling are typically used as non-mechanistic screens for antiseizure properties and the rotorod test for assessing acute toxicity. While antiseizure drug screening has been successful in bringing drugs to the market and improving our understanding of the pathophysiology of seizures, it should be emphasized that the vast majority of drug screening occurs in mature male rodents and involves models of seizures, not epilepsy. Effective drugs in acute seizures may not be effective in chronic models of epilepsy. Seizure type, clinical and electroencephalographic phenotype, syndrome, and etiology are often quite different in children with epilepsy than adults. Despite these age-related unique features, drugs used in children are generally the same as used in adults. As awareness of the unique features of seizures during development increases, it is anticipated that more drug screening in the immature animal will occur.

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“…The observation that changes in the hippocampus tend to be region specific may explain the many conflicting reports on hippocampal alterations following excitatory intervention, particularly in the neonate. Some authors report longterm hippocampal changes following neonatal excitotoxicity [44][45][46][47][48][49], while others report that the hippocampus is relatively resistant to these changes [28,[50][51][52][53][54]. It is possible that some of these discrepancies result from methodological differences whereby only select regions of the hippocampus were examined.…”

Section: Discussionmentioning

confidence: 99%

Progressive changes in hippocampal cytoarchitecture in a neurodevelopmental rat model of epilepsy: implications for understanding presymptomatic epileptogenesis, predictive diagnosis, and targeted treatments

et al. 2017

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Epilepsies affect about 4% of the population and are frequently characterized by a prolonged Bsilent^period before the onset of spontaneous seizures. Most current animal models of epilepsy either involve acute seizure induction or kindling protocols that induce repetitive seizures. We have developed a rat model of epilepsy that is characterized by a slowly progressing series of behavioral abnormalities prior to the onset of behavioral seizures. In the current study, we further describe an accompanying progression of cytoarchitectural changes in the hippocampal formation. Groups of male and female SD rats received serial injections of a low dose of domoic acid (0.020 mg/kg) (or vehicle) throughout the second week of life. Postmortem hippocampal tissue was obtained on postnatal days 29, 64, and 90 and processed for glial fibrillary acidic protein (GFAP), NeuN, and calbindin expression. The data revealed no significant changes on postnatal day (PND) 29 but a significant increase in hilar NeuN-positive cells in some regions on PND 64 and 90 that were identified as ectopic granule cells. Further, an increase in GFAP positive cell counts and evidence of reactive astrogliosis was found on PND 90 but not at earlier time points. We conclude that changes in cellular expression, possibly due to on-going non-convulsive seizures, develop slowly in this model and may contribute to progressive brain dysfunction that culminates in a seizure-prone phenotype.

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Consequences of recurrent seizures during early brain development

Cited by 130 publications

References 82 publications

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Choosing the Correct Antiepileptic Drugs: From Animal Studies to the Clinic

Progressive changes in hippocampal cytoarchitecture in a neurodevelopmental rat model of epilepsy: implications for understanding presymptomatic epileptogenesis, predictive diagnosis, and targeted treatments

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