Cortical NMDAR-1 gene expression is rapidly upregulated after seizure

Jensen, Penny; Millan, Noemi; Mack, Kenneth J.

doi:10.1016/s0169-328x(96)00262-8

Cited by 23 publications

(7 citation statements)

References 15 publications

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“…Kainate receptors were up-regulated, as described by Bidmon et al (2002), although other studies have shown decreased (DeFelipe et al, 1994;Gonzalez-Albo et al, 2001) or unaltered kainate receptor densities or unchanged GluR5/6/7 immunoreactivity (Grigorenko et al, 1997). The NMDA receptor down-regulation partially reflects previous descriptions of increased, decreased, and unchanged receptor densities or subunit mRNA and protein expression in human temporal neocortex (Glass et al, 1996;Jensen et al, 1997;Zilles et al, 1999;Bidmon et al, 2002). BZ binding site densities were upregulated in FS, np, and n-ss cases, confirming previous studies (Nagy et al, 1999;Koepp et al, 2000;Hammers et al, 2001).…”

Section: Discussionsupporting

confidence: 82%

Multireceptor analysis in human neocortex reveals complex alterations of receptor ligand binding in focal epilepsies

et al. 2012

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Summary Purpose: A disturbed balance between excitatory and inhibitory neurotransmission underlies epileptic activity, although reports concerning neurotransmitter systems involved remain controversial. Methods: We quantified densities of 15 receptors in neocortical biopsies from patients with pharmacoresistant focal temporal lobe epilepsy and autopsy controls, and searched for correlations between density alterations and clinical factors or the occurrence of spontaneous synaptic potentials in vitro. Key Findings: α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA), kainate, N‐methyl‐d‐aspartate (NMDA), peripheral benzodiazepine, muscarinic (M)1, M2, nicotinic, α1, α2h, serotonin (5‐HT)1A, and adenosine (A)1 receptor densities were significantly altered in biopsies. The epileptic cohort was subdivided based on clinical (febrile seizures, hippocampal sclerosis, neocortical pathologies, surgery outcome) or electrophysiologic (spontaneous field potentials) criteria, resulting in different patterns of significantly altered receptor types when comparing a given epileptic group with controls. Only AMPA, kainate, M2, and 5‐HT1A receptors were always significantly altered. γ‐Aminobutyric acid (GABA)A, GABAB, and 5‐HT2 receptor alterations were never significant. Correlation patterns between receptor alterations and illness duration or seizure frequency varied depending on whether the epileptic cohort was considered as a whole or subdivided. Significance: Neocortical temporal lobe epilepsy is associated with a generalized receptor imbalance resulting in a net potentiation of excitatory neurotransmission. Peripheral benzodiazepine receptor alterations highlight that astrocytes are also impaired by seizure activity.

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Section: Discussionsupporting

confidence: 82%

Multireceptor analysis in human neocortex reveals complex alterations of receptor ligand binding in focal epilepsies

et al. 2012

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“…In different experimental epilepsia models it was observed that NMDAR mRNA and protein expression are rapidly increased in pentilenetetrazol induce-seizures [3]. The antagonist 3 H-MK801 binding to NMDA receptors is altered in different brain regions after 3-mercaptopropionic acid (MP) administration [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

The NMDAR Subunit NR2B Expression is Modified in Hippocampus after Repetitive Seizures

2008

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NMDA receptor is involved in synaptic plasticity, learning, memory and neurological diseases like epilepsia and it is the major mediator of excitotoxicity. NR2B-containing NMDA receptors may be playing a crucial role in epileptic disorders. In the present study the effect of the convulsant drug 3-mercaptopropionic acid (MP) repetitive administration (4-7 days) on the hippocampal NR2B subunit was studied. A significant decrease in NR2B in the whole hippocampus was observed after MP4 with a tendency to recover to normal values in MP7 by western blot assay. Immunohistochemical studies showed a decrease in several CA1 and CA2/3 strata (21-73%). MP7 showed a reversion of the drop observed at 4 days in stratum oriens, pyramidal cell layer in CA1, CA2/3 and CA1 stratum radiatum. A significant fall in the lacunosum molecular layer of both areas and stratum radiatum of CA2/3 was observed. The immunostaining in MP4 showed a decrease in the granulare layer from dentate gyrus (20%), in hillus (71%) and subicullum (63%) as compared with control and these decreases were similar at MP7 values. Results showed decreases in NR2B subunit expression in different areas following repeated MP-induce seizures, suggesting that NR2B expression is altered depending on the diverse hippocampal input and output signals of each region that could be differently involved in modulating MP-induced hyperactivity.

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“…Furthermore, expression analysis has shown that GRIN1 expression in mice is limited to the nervous system at the tested developmental stages 19 . Seizure activity alters the expression of GRIN1 in the motor cortex at both the messenger RNA and protein levels 20 . In our previous study, 21 SNPs in the ACTH receptor gene ( MC2R ) in the promoter region are associated with infantile spasms.…”

Section: Discussionmentioning

confidence: 95%

“…19 Seizure activity alters the expression of GRIN1 in the motor cortex at both the messenger RNA and protein levels. 20 In our previous study, 21 SNPs in the ACTH receptor gene (MC2R) in the promoter region are associated with infantile spasms. Meanwhile, NMDA receptors, which are restricted to the regions responsible for seizure generation and are present in the hypothalamus, can affect the hypothalamic-pituitary-adrenal axis and further lead to glucocorticoid secretion disorder.…”

Section: Discussionmentioning

confidence: 96%

A possible association of responsiveness to adrenocorticotropic hormone with specific GRIN1 haplotypes in infantile spasms

Ding

Zhang

et al. 2010

Develop Med Child Neuro

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AIM Adrenocorticotropic hormone (ACTH) has been used as the major therapy for infantile spasms since 1958 because it effectively suppresses seizures; it also normalizes the electroencephalogram in the short-term treatment of infantile spasms. G protein-regulated inducer of neurite outgrowth 1 (GRIN1, also known as N-methyl-D-aspartate receptor 1, NMDAR1), a glutamate receptor, is the main component of functional N-methyl-D-aspartic acid receptors that are involved in the glucocorticoid-induced neuronal damage. Thus, it may be a candidate gene to be tested for responsiveness to ACTH in infantile spasms. In the present study, polymorphisms in the GRIN1 gene in infantile spasms were investigated using a case-control design.METHOD Twelve single nucleotide polymorphisms in the GRIN1 gene were genotyped in a Chinese case-control set consisting of 97 unrelated patients with infantile spasms (60 males, 37 females; mean age 6.4mo, SD 2.7) and 96 healthy individuals (63 males, 33 females; mean age 7.3mo, SD 3.8). Association analysis was performed on the genotyped data.RESULTS Five estimated haplotypes with a frequency of more than 3% were detected. Results of the study showed that responsiveness to treatment with ACTH in homozygous carriers of the CTA haplotype was higher than that in heterozygous carriers and non-carriers (p=0.022). Furthermore, CTG, a rare haplotype, was strongly associated with infantile spasms (p=0.013). INTERPRETATIONThe results suggest that haplotypes of GRIN1 may influence responsiveness to ACTH. The findings necessitate further study for confirmation.Infantile spasms is an age-specific epileptic encephalopathy that occurs in infancy and is considered refractory to conventional antiepileptic drugs. Adrenocorticotropic hormone (ACTH) has been identified as a drug that is effective in the treatment of infantile spasms.1 However, some patients are clinically resistant to ACTH therapy, and the exact molecular mechanism remains to be explained. Data from pharmacogenetic studies of epilepsy have shown that the variations in some receptor genes can contribute to the pathogenesis and mechanisms of antiepileptic drug resistance towards infantile spasms.Several models and hypotheses have been proposed to explain the pathogenesis of infantile spasms and its unique sensitivity to ACTH.2 However, none of them has been accepted as a satisfactory model for drug testing. Recently, the clinical features of flexion seizures induced by N-methyl-Daspartic acid (NMDA) in rat pups have been shown to be correlated with human infantile spasms. For instance, flexion spasms and electroencephalogram (EEG) in the rat model correlate with ictal electrodecrement, or after discharges in infantile spasms.3 Interestingly, this model, which is based on the prenatally 'stressed' brain, also shows an acute and partial response to ACTH treatment. In addition, an expression peak of the NMDA receptor was observed in the cortex and hippocampus of children aged 1 to 3 years old. In contrast, the axon and dendrite are mostly developed in ...

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Cortical NMDAR-1 gene expression is rapidly upregulated after seizure

Cited by 23 publications

References 15 publications

Multireceptor analysis in human neocortex reveals complex alterations of receptor ligand binding in focal epilepsies

Multireceptor analysis in human neocortex reveals complex alterations of receptor ligand binding in focal epilepsies

The NMDAR Subunit NR2B Expression is Modified in Hippocampus after Repetitive Seizures

A possible association of responsiveness to adrenocorticotropic hormone with specific GRIN1 haplotypes in infantile spasms

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