Excitotoxicity

Haglid, Kenneth G.; Wang, S.; Qiner, Y.; Hamberger, Anders

doi:10.1007/bf02816125

Cited by 28 publications

(9 citation statements)

References 21 publications

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“…Our results suggest increased glutamate in the CSF of PKC patients could lead to neuronal hyperexcitability. In fact, high extracellular glutamate concentrations in the brain have been identified as a likely trigger of epileptic seizures in mesial temporal lobe epilepsy (MTLE) [ 13 , 28 ]; these might be associated with decreased hippocampal volumes [ 29 ]. By studying genetic absence epilepsy rats from Strasbourg (GAERS), Sirvanci et al [ 30 ] found that the glutamate density in the CA3 region of GAERS hippocampus was significantly increased compared to the control group.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, SNAP25 plays an important role in the regulation of excitatory amino acids (EAAs) neurotransmitter release. The dysfunction of EAA transmission, especially glutamate transmission, plays a role in many nervous diseases, including epilepsy, migraines and children with high functioning autism [ 13 , 14 , 15 ]. A recent high-resolution proteomics analysis offered another important clue into the function of PRRT2.…”

Section: Introductionmentioning

confidence: 99%

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PRRT2 Mutant Leads to Dysfunction of Glutamate Signaling

Niu

Zhu

et al. 2015

IJMS

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Paroxysmal kinesigenic choreoathetosis (PKC) is an inherited disease of the nervous system. We previously identified PRRT2 as the causative gene of PKC. However, as little is known about the function of PRRT2, elucidating its function will benefit not only PKC studies, but also many other related disorders. Here, we reveal higher levels of glutamate in the plasma of PKC patients and the culture medium of neurons following knock-out Prrt2 expression. Using double immunostaining assays we confirm Prrt2 is located at the glutamatergic neurons in accordance with its function. Our co-immunoprecipitation assays reveal mutant PRRT2 interferes with SNAP25 and GRIA1 interactions, respectively. Furthermore, using live-labeling techniques, we confirmed co-transfection with mutant PRRT2 caused an increase in GRIA1 distribution on the cell surface. Therefore, our results suggest that mutant PRRT2, probably through its weakened interaction with SNAP25, affects glutamate signaling and glutamate receptor activity, resulting in the increase of glutamate release and subsequent neuronal hyperexcitability.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PRRT2 Mutant Leads to Dysfunction of Glutamate Signaling

Niu

Zhu

et al. 2015

IJMS

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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.…”

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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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“…The glutamate levels are directly correlated with the occurrence of epilepsy. Elevated glutamate levels have been reported in human brain tissues and animal models of epilepsy 22 . During the seizure period, glutamate levels increased to approximately 10 times their normal values, and then gradually returned to normal when a seizure has ceased 23 .…”

Section: Discussionmentioning

confidence: 99%

Hsp90 inhibitor HSP990 in very low dose upregulates EAAT2 and exerts potent antiepileptic activity

et al. 2020

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Rationale: Dysfunction or reduced levels of EAAT2 have been documented in epilepsy. We previously demonstrated the antiepileptic effects of Hsp90 inhibitor 17AAG in temporal lobe epilepsy by preventing EAAT2 degradation. Because of the potential toxicities of 17AAG, this study aimed to identify an alternative Hsp90 inhibitor with better performance on Hsp90 inhibition, improved blood-brain barrier penetration and minimal toxicity. Methods: We used cell-based screening and animal models of epilepsy, including mouse models of epilepsy and Alzheimer's disease, and a cynomolgus monkey model of epilepsy, to evaluate the antiepileptic effects of new Hsp90 inhibitors. Results: In both primary cultured astrocytes and normal mice, HSP990 enhanced EAAT2 levels at a lower dose than other Hsp90 inhibitors. In epileptic mice, administration of 0.1 mg/kg HSP990 led to upregulation of EAAT2 and inhibition of spontaneous seizures. Additionally, HSP990 inhibited seizures and improved cognitive functions in the APPswe/PS1dE9 transgenic model of Alzheimer's disease. In a cynomolgus monkey model of temporal lobe epilepsy, oral administration of low-dose HSP990 completely suppressed epileptiform discharges for up to 12 months, with no sign of hepatic and renal toxicity. Conclusions: These results support further preclinical studies of HSP990 treatment for temporal lobe epilepsy.

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Excitotoxicity

Cited by 28 publications

References 21 publications

PRRT2 Mutant Leads to Dysfunction of Glutamate Signaling

PRRT2 Mutant Leads to Dysfunction of Glutamate Signaling

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

Hsp90 inhibitor HSP990 in very low dose upregulates EAAT2 and exerts potent antiepileptic activity

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