Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy

Chen, Shuang; Xu, Da; Liu, Fan; Fang, Zhi; Wang, Xiufeng; Li, Man

doi:10.3389/fnmol.2021.797253

Cited by 22 publications

(18 citation statements)

References 252 publications

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“…Numerous studies have revealed that glutamate is involved in the mechanism and treatment of epilepsy. For example, abnormalities in glutamatergic function have been observed in animal models of epilepsy, 5 and biochemical analysis in human epileptic brain tissue revealed an increase in glutamate levels. 6,7 In addition, glutamate agonists induce seizures while glutamate antagonists inhibit seizures, 8 and several antiepileptic drugs (AEDs) decrease synaptic glutamate.…”

Section: Introductionmentioning

confidence: 99%

Rutin prevents seizures in kainic acid-treated rats: evidence of glutamate levels, inflammation and neuronal loss modulation

Chang

Wang

2022

Food Funct.

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Section: Introductionmentioning

confidence: 99%

Rutin prevents seizures in kainic acid-treated rats: evidence of glutamate levels, inflammation and neuronal loss modulation

Chang

Wang

2022

Food Funct.

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“…An imbalance in the regulatory mechanisms of neuronal excitation and inhibition leads to excessive synchronous firing of neurons. In this process, glutamate and other neurotransmitters are widely involved in the regulation process between neuronal excitation and inhibition by activating corresponding receptors (4). The occurrence of PTE is related to excessive release of glutamate.…”

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confidence: 99%

Identification of miRNA–mRNA regulatory network associated with the glutamatergic system in post-traumatic epilepsy rats

Zhang

Zhou

et al. 2022

Front. Neurol.

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BackgroundGlutamate is one of the most important excitatory neurotransmitters in the mammalian brain and is involved in a variety of neurological disorders. Increasing evidence also shows that microRNA (miRNA) and mRNA pairs are engaged in a variety of pathophysiological processes. However, the miRNA and mRNA pairs that affect the glutamatergic system in post-traumatic epilepsy (PTE) remain unknown.MethodsPTE rats were induced by injecting 0.1 mol/L, 1 μL/min FeCl2 solution. Behavioral scores and EEG monitoring were used to evaluate whether PTE was successfully induced. RNA-seq was used to obtain mRNA and miRNA expression profiles. Bioinformatics analysis was performed to screen differentially expressed mRNAs and miRNAs associated with the glutamatergic system and then predict miRNA–mRNA interaction pairs. Real-time quantitative reverse transcription PCR was used to further validate the expression of the differential miRNAs and mRNAs. The microRNA–mRNA was subject to the Pearson correlation analysis.ResultsEight of the 91 differentially expressed mRNAs were associated with the glutamatergic system, of which six were upregulated and two were downregulated. Forty miRNAs were significantly differentially expressed, with 14 upregulated and 26 downregulated genes. The predicted miRNA–mRNA interaction network shows that five of the eight differentially expressed mRNAs associated with the glutamatergic system were targeted by multiple miRNAs, including Slc17a6, Mef2c, Fyn, Slc25a22, and Shank2, while the remaining three mRNAs were not targeted by any miRNAs. Of the 40 differentially expressed miRNAs, seven miRNAs were found to have multiple target mRNAs associated with the glutamatergic system. Real-time quantitative reverse transcription PCR validation and Pearson correlation analysis were performed on these seven targeted miRNAs—Slc17a6, Mef2c, Fyn, Slc25a22, and Shank2—and six additional miRNAs selected from the literature. Real-time quantitative reverse transcription PCR showed that the expression levels of the mRNAs and miRNAs agreed with the predictions in the study. Among them, the miR-98-5p–Slc17a6, miR-335-5p–Slc17a6, miR-30e-5p–Slc17a6, miR-1224–Slc25a22, and miR-211-5p–Slc25a22 pairs were verified to have negative correlations.ConclusionsOur results indicate that miRNA–mRNA interaction pairs associated with the glutamatergic system are involved in the development of PTE and have potential as diagnostic biomarkers and therapeutic targets for PTE.

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“…36 Accordingly, altered glycine metabolism is implicated in various neurodevelopmental defects. [37][38][39][40] Furthermore, increased levels of glycine and serine were detected in the plasma samples of individuals with Rett syndrome (RTT; MIM #312750), a condition including epilepsy, microcephaly and DD/ID among cardinal clinical features. 41 GLDC, encoding the glycine decarboxylase, one of the four proteins forming the mitochondrial glycine cleavage system (GCS), and GAMT, encoding the guanidinoacetate Nmethyltransferase, were among the top downregulated genes in the RNA-seq analysis.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, it is well known that NMDARs belong to a family of ionotropic glutamate receptors that play essential roles in excitatory neurotransmission and synaptic plasticity in the mammalian CNS. 40 Furthermore, several studies suggest that NMDARs contribute to the genesis and spread of the abnormal paroxysmal discharges, neuron injury and in ammation, and thus may participate in epileptogenesis. 40 Furthermore, glycine level affects L-serine one and the latter amino acid is the precursor of D-serine [42][43] : the observed increase in proband's LCL D-serine level could further induce NMDA receptor hyperactivation.…”

Section: Discussionmentioning

confidence: 99%

“…40 Furthermore, several studies suggest that NMDARs contribute to the genesis and spread of the abnormal paroxysmal discharges, neuron injury and in ammation, and thus may participate in epileptogenesis. 40 Furthermore, glycine level affects L-serine one and the latter amino acid is the precursor of D-serine [42][43] : the observed increase in proband's LCL D-serine level could further induce NMDA receptor hyperactivation. On the other hand, GAMT de ciency leads to creatine depletion and guanidinoacetate (GAA) accumulation in brain, which may in turn interfere with neuronal γ-aminobutyric acid (GABA) receptors type A and cause seizures, DD/ID, prominent speech delay, autistic/hyperactive behavioural disorders, and various types of pyramidal and/or extra-pyramidal manifestations in humans.…”

Section: Discussionmentioning

confidence: 99%

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Further evidence supporting the role of GTDC1 in glycine metabolism and neurodevelopmental disorders

Bonaglia,

Errichiello,

Lecca

et al. 2023

Preprint

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Copy number variants (CNVs) represent the genetic cause of about 15–20% of neurodevelopmental disorders (NDDs). We identified a ~ 67 kb de novo intragenic deletion on chromosome 2q22.3 in a female individual showing a developmental encephalopathy characterized by epilepsy, severe intellectual disability, speech delay, microcephaly, and thin corpus callosum with facial dysmorphisms. The microdeletion involved exons 5–6 of GTDC1, encoding a putative glycosyltransferase, whose expression is particularly enriched in the nervous system. In a previous study, a balanced de novo translocation encompassing GTDC1 was reported in a male child with global developmental delay and delayed speech and language development. Based on these premises, we explored the transcriptomic profile of our proband to evaluate the functional consequences of the novel GTDC1 de novo intragenic deletion in relation to the observed neurodevelopmental phenotype. RNA-seq on the proband’s lymphoblastoid cell line (LCL) showed expression changes of glycine/serine and cytokine/chemokine signalling pathways, which are related to neurodevelopment and epileptogenesis. Subsequent analysis by ELISA (enzyme-linked immunosorbent assay) and HPLC (high-performance liquid chromatography) revealed increased levels of glycine in the proband’s LCL and serum compared to matched controls. Given that an increased level of glycine has been observed in the plasma samples of individuals with Rett syndrome, a condition sharing epilepsy, microcephaly, and intellectual disability with our proband, we proposed that the GTDC1 downregulation is implicated in neurodevelopmental impairment by altering glycine metabolism. Furthermore, our findings expanded the phenotypic spectrum of the novel GTDC1-related condition, including microcephaly and epilepsy among relevant clinical features.

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Roles of N-Methyl-D-Aspartate Receptors (NMDARs) in Epilepsy

Cited by 22 publications

References 252 publications

Rutin prevents seizures in kainic acid-treated rats: evidence of glutamate levels, inflammation and neuronal loss modulation

Rutin prevents seizures in kainic acid-treated rats: evidence of glutamate levels, inflammation and neuronal loss modulation

Identification of miRNA–mRNA regulatory network associated with the glutamatergic system in post-traumatic epilepsy rats

Further evidence supporting the role of GTDC1 in glycine metabolism and neurodevelopmental disorders

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