Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain

During, Matthew J.; Spencer, Dennis D.

doi:10.1016/0140-6736(93)90754-5

Cited by 850 publications

(554 citation statements)

References 23 publications

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“…Increased levels of extracellular glutamate are detected by in vivo dialysis in sclerotic seizure foci. 18,19 Some authors have reported a down regulation of EAAT1 and EAAT2 glutamate transporters 20,21 in sclerotic hippocampi and propose that this accounts for the observed increase in extracellular glutamate. However, others have been unable to confirm such an observation.…”

Section: Astrocyte Transporter Moleculesmentioning

confidence: 99%

“…24 In vivo microdialysis studies in human hippocampal seizure foci have demonstrated reduced levels of extracellular GABA in the epileptogenic seizure focus during the ictal state. 18 The increased expression of GAT3 in these hippocampi may contribute to excess removal of GABA and thus reduced extracellular levels in the ictal state.…”

Section: Astrocyte Transporter Moleculesmentioning

confidence: 99%

“…70 In vivo dialysis studies show that glutamate release during a seizure is increased and its clearance prolonged, in the epileptogenic (sclerotic) hippocampus compared to the contralateral nonsclerotic one. 18 It was subsequently shown that interictal extracellular glutamate levels are also higher in the epileptogenic hippocampus compared to nonepileptogenic ones. 43 The increased interictal basal extracellular glutamate levels negatively correlate with hippocampal volume being significantly increased in the atrophic 43 hippocampus compared to nonatrophic ones.…”

Section: Glutamate Glutamine Cyclingmentioning

confidence: 99%

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Astrocytes and Epilepsy

2010

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Summary: Astrocytes form a significant constituent of seizure foci in the human brain. For a long time it was believed that astrocytes play a significant role in the causation of seizures. With the increase in our understanding of the unique biology of these cells, their precise role in seizure foci is receiving renewed attention. This article reviews the information now available on the role of astrocytes in the hippocampal seizure focus in patients with temporal lobe epilepsy with hippocampal sclerosis. Our intent is to try to integrate the available data. Astrocytes at seizure foci seem to not be a homogeneous population of cells, and in addition to typical glial fibrillary acidic protein, positive reactive astrocytes also include a population of neuron glia-2-like cells The astrocytes in sclerotic hippocampi differ from those in nonsclerotic hippocampi in their membrane physiology, having elevated Naϩ channels and reduced inwardly rectifying potassium ion channels, and some having the capacity to generate action potentials. They also have reduced glutamine synthetase and increased glutamate dehydrogenase activity. The molecular interface between the astrocyte and microvasculature is also changed. The astrocytes are also associated with increased expression of many molecules normally concerned with immune and inflammatory functions. A speculative mechanism postulates that neuron glia-2-like cells may be involved in creating a high glutamate environment, whereas the function of more typical reactive astrocytes contribute to maintain high extracellular Kϩ levels; both factors contributing to the hyperexcitability of subicular neurons to generate epileptiform activity. The functions of the astrocyte vascular interface may be more critical to the processes involved in epileptogenesis.

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Section: Astrocyte Transporter Moleculesmentioning

confidence: 99%

Section: Astrocyte Transporter Moleculesmentioning

confidence: 99%

Section: Glutamate Glutamine Cyclingmentioning

confidence: 99%

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Astrocytes and Epilepsy

2010

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“…25 Elevated extracellular glutamate levels have also been reported in animal models of epilepsy and epilepsy patients alike, particularly in individuals with temporal lobe epilepsy. [26][27][28][29] EAAT2 p.Gly82Arg (subject A) substitutes a small hydrophobic and neutrally charged glycine with hydrophilic, positively charged arginine within the cytoplasmic loop joining the first pair of transmembrane domains ( Figure 1). The same substitution is reported in the Epi4K-EPGP dataset in a subject with infantile spasms 4 and two additional individuals with a severe EE, and de novo variants (EAAT2 p.Gly82Arg and p.Leu85Pro) were reported 33 during the preparation of this manuscript.…”

mentioning

confidence: 99%

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

Guella

McKenzie

Evans

et al. 2017

The American Journal of Human Genetics

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Massively parallel sequencing has revealed many de novo mutations in the etiology of developmental and epileptic encephalopathies (EEs), highlighting their genetic heterogeneity. Additional candidate genes have been prioritized in silico by their co-expression in the brain. Here, we evaluate rare coding variability in 20 candidates nominated with the use of a reference gene set of 51 established EE-associated genes. Variants within the 20 candidate genes were extracted from exome-sequencing data of 42 subjects with EE and no previous genetic diagnosis. We identified 7 rare non-synonymous variants in 7 of 20 genes and performed Sanger sequence validation in affected probands and parental samples. De novo variants were found only in SLC1A2 (aka EAAT2 or GLT1) (c.244G>A [p.Gly82Arg]) and YWHAG (aka 14-3-3g) (c.394C>T [p.Arg132Cys]), highlighting the potential cause of EE in 5% (2/42) of subjects. Seven additional subjects with de novo variants in SLC1A2 (n ¼ 1) and YWHAG (n ¼ 6) were subsequently identified through online tools. We identified a highly significant enrichment of de novo variants in YWHAG, establishing their role in early-onset epilepsy, and we provide additional support for the prior assignment of SLC1A2. Hence, in silico modeling of brain co-expression is an efficient method for nominating EE-associated genes to further elucidate the disorder's etiology and genotype-phenotype correlations.

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“…Further evidence for the involvement of aspartate comes from push-pull perfusion combined with depth electrode recording after electrical stimulation (Do et al, 1991). In complex partial epilepsy, a sustained increase in extracellular glutamate was observed (During and Spencer, 1993).…”

Section: Discussionmentioning

confidence: 99%