Relations between Brain Pathology and Temporal Lobe Epilepsy

Zhang, Xia; Cui, Shusen; Wallace, Amy E.; Hannesson, Darren K.; Schmued, Larry C.; Saucier, Deborah M.; Honer, William G.; Corcoran, Michael E.

doi:10.1523/jneurosci.22-14-06052.2002

Cited by 155 publications

(104 citation statements)

References 68 publications

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“…Kindling, a widely used animal model of limbic epilepsy, has no detectable neuronal cell loss. Rats experienced two priming kainic acid-induced short seizure episodes, and one kainic acid-induced sustained episodes of status epilepticus also displayed no detectable neuronal loss but did develop epilepsy (Zhang et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Differential Roles of NR2A- and NR2B-Containing NMDA Receptors in Activity-Dependent Brain-Derived Neurotrophic Factor Gene Regulation and Limbic Epileptogenesis

Qian

He²,

Hu³

et al. 2007

J. Neurosci.

138

103

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Fleeting activation of NMDA receptors (NMDARs) induces long-term modification of synaptic connections and refinement of neuronal circuits, which may underlie learning and memory and contribute to pathogenesis of a diversity of neurological diseases, including epilepsy. Here, we found that NR2A and NR2B subunit-containing NMDARs were coupled to distinct intracellular signaling, resulting in differential BDNF expression and extracellular signal-regulated kinase 1/2 (ERK1/2) activation. Selective activation of NR2A-containing NMDARs increased BDNF gene expression. Activation of NR2B-containing NMDARs led to ERK1/2 phosphorylation. Furthermore, selectively blocking NR2A-containing NMDARs impaired epileptogenesis and the development of mossy fiber sprouting in the kindling and pilocarpine rat models of limbic epilepsy, whereas inhibiting NR2B-containing NMDARs had no effects in epileptogenesis and mossy fiber sprouting. Interestingly, blocking either NR2A- or NR2B-containing NMDARs decreased status epilepticus-induced neuronal cell death. The specific requirement of NR2A and its downstream signaling for epileptogenesis implicates attractive new targets for the development of drugs that prevent epilepsy in patients with brain injury.

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Section: Discussionmentioning

confidence: 99%

Differential Roles of NR2A- and NR2B-Containing NMDA Receptors in Activity-Dependent Brain-Derived Neurotrophic Factor Gene Regulation and Limbic Epileptogenesis

Qian

He²,

Hu³

et al. 2007

J. Neurosci.

138

103

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“…TLE is characterized pathologically by hippocampal sclerosis, a characteristic morphologic change associated with massive hippocampal neuronal loss localized in the hilus of the dentate gyrus, as well as in the CA1 and CA3 hippocampal regions 53 .…”

Section: Downregulation Of Neuronal Related Proteins Is Indicative Ofmentioning

confidence: 99%

High-Throughput LC–MS/MS Proteomic Analysis of a Mouse Model of Mesiotemporal Lobe Epilepsy Predicts Microglial Activation Underlying Disease Development

Bitsika

Duveau²,

Simon-Areces

et al. 2016

J. Proteome Res.

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Uncovering the molecular mechanisms of Mesial temporal lobe epilepsy (MTLE) is critical to identify therapeutic targets. In this study, we performed global protein expression analysis of a kainic acid (KA) MTLE mouse model at various time-points (1d, 3d, 30d post KA injection -dpi), representing specific stages of the syndrome.High resolution liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), in combination to label-free protein quantification, using three processing approaches for quantification, was applied. Following comparison of KA versus NaCl-injected mice, 22, 53 and 175 proteins were differentially (statistically significant) expressed at 1, 3 and 30dpi respectively, according to all 3 quantification approaches. Selected findings were confirmed by multiple reaction monitoring LC-MS/MS. As a positive control, the astrocyte marker GFAP was found to be upregulated (3dpi:1.9 fold; 30dpi:12.5 fold), also verified by IHC. The results collectively suggest that impairment in synaptic transmission occurs even right after initial status epilepticus (1dpi), with neurodegeneration becoming more extensive during epileptogenesis (3dpi) and sustained at the chronic phase (30dpi), where also extensive glial and astrocyte-mediated inflammation is evident. This molecular profile is in line with observed phenotypic changes in human MTLE, providing the basis for future studies on new molecular targets for the disease.

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“…GCs are dispersed into aberrant locations and form basal dendrites, presenting postsynaptic targets in the region in which normal MFs make synaptic contacts, the hilus (Austin and Buckmaster, 2004). Thus, the argument that MF sprouting (and/or cell loss in the hilus) is not necessary for epileptogenesis (Zhang et al, 2002;Raol et al, 2003) may not speak to the critical epileptogenic role played by recurrent excitatory circuitry in the dentate gyrus.…”

Section: Structural and Functional Evidence Of Recurrent Excitationmentioning

confidence: 99%

Physiological and Morphological Characterization of Dentate Granule Cells in the p35 Knock-Out Mouse Hippocampus: Evidence for an Epileptic Circuit

Patel¹,

Wenzel²,

Schwartzkroin³

2004

J. Neurosci.

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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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Relations between Brain Pathology and Temporal Lobe Epilepsy

Cited by 155 publications

References 68 publications

Differential Roles of NR2A- and NR2B-Containing NMDA Receptors in Activity-Dependent Brain-Derived Neurotrophic Factor Gene Regulation and Limbic Epileptogenesis

Differential Roles of NR2A- and NR2B-Containing NMDA Receptors in Activity-Dependent Brain-Derived Neurotrophic Factor Gene Regulation and Limbic Epileptogenesis

High-Throughput LC–MS/MS Proteomic Analysis of a Mouse Model of Mesiotemporal Lobe Epilepsy Predicts Microglial Activation Underlying Disease Development

Physiological and Morphological Characterization of Dentate Granule Cells in the p35 Knock-Out Mouse Hippocampus: Evidence for an Epileptic Circuit

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