Induced Expression of NMDAR2 Proteins and Differential Expression of NMDAR1 Splice Variants in Dysplastic Neurons of Human Epileptic Neocortex

Zhang, Ying; Babb, Thomas L.; Comair, Youssef G.; Bingaman, William; Bushey, Michael A.; Touhalisky, Kathy

doi:10.1097/00005072-199801000-00007

Cited by 100 publications

(88 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These results also demonstrated the absence of exon 22-containing NR1 splice variants in cultured fetal cortical neurons. In this regard, it is interesting to note that the human cerebral cortex also expresses only hNR1-3a, hNR1-3b, hNR1-4a, and hNR1-4b splice variants (33). More recently, a complete absence of exon 22 was reported in the central nervous system of Apteronotus leptorhynchus (34).…”

Section: Discussionmentioning

confidence: 98%

Differential Effects of Chronic Ethanol Treatment onN-Methyl-d-aspartate R1 Splice Variants in Fetal Cortical Neurons

Kumari

2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

Functional N-methyl-D-aspartate receptors consisting of NR1 and NR2 subunits are an important site of action of ethanol. Chronic ethanol treatment increases the NR1 polypeptide levels in vivo and in vitro. Chronic ethanol treatment in vitro does not significantly alter the NR1 mRNA levels, even though under similar culture conditions ethanol (50 mM, 5 days) enhances the half-life of NR1 mRNA in fetal cortical neurons. To address this phenomenon, we determined by reverse transcriptionpolymerase chain reaction and Western blotting whether ethanol (50 mM, 5 days) has a splice variantspecific effect on the expression of the NR1 subunit in mouse fetal cortical neurons. This report analyzes for the first time the distribution of all NR1 splice variants in these neurons. Our data indicate the presence of NR1-3a,b and NR1-4a,b splice variants in cortical neurons. Chronic ethanol treatment significantly decreased the mRNA levels of exon 5-containing NR1 splice variants (NR1-3b and NR1-4b) (؊E5/؉E5 ‫؍‬ 4.6 in untreated neurons and 6.1 in ethanol-treated neurons) and had no effect on the mRNA levels of NR1-3 (؉E21/؊E22) and NR1-4 (؊E21/؊E22) splice variants. At the polypeptide level, chronic ethanol treatment significantly reduced exon 5-containing splice variants (NR1-3b and NR1-4b). However, ethanol (50 mM, 5 days) induced a significant increase in polypeptide levels of NR1-4 (؊E21/؊E22), without any effect on NR1-3 (؉E21/؊E22) polypeptide levels. These results demonstrate that chronic ethanol treatment has a selective effect on the expression of NR1 splice variants at both the mRNA and polypeptide levels in mouse fetal cortical neurons. N-methyl-D-aspartate (NMDA)1 receptors, the excitatory receptors in the central nervous system, are involved in a variety of physiological and pathological processes (1). Molecular cloning and functional studies reveal that NMDA receptors are heteromeric and consist of three subunits named NR1, NR2, and NR3 in the rat (2). The NR1 and NR2 subunits are named and ⑀, respectively, in the mouse (3). The NR2 subunit has four members that combine with the NR1 subunit to form functional NMDA receptors with distinct pharmacological properties. Additional diversity of NMDA receptors is achieved by alternative splicing of the NR1 subunit (4). The NR1 subunit, a product of a single gene, has eight isoforms generated by alternative splicing of exons 5, 21, and 22 (5, 6). Exon 5 encodes the N1 splice cassette that lies in the extracellular aminoterminal domain of the NR1 subunit. Exons 21 and 22 encode the carboxyl-terminal splice cassettes C1 and C2, respectively, and are a part of the intracellular domain of the NR1 subunit. NR1 splice variants lacking exon 22 contain an additional cassette, C2Ј, at the carboxyl-terminal end. The presence or absence of the N1, C1, and C2 cassettes influence the function of the NMDA receptors (6 -12).Ethanol, one of the most abused drugs in our society, alters the expression and function of NMDA receptors in a treatmentdependent manner. Acute ethanol exposure in viv...

show abstract

Section: Discussionmentioning

confidence: 98%

Differential Effects of Chronic Ethanol Treatment onN-Methyl-d-aspartate R1 Splice Variants in Fetal Cortical Neurons

Kumari

2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Several groups have reported deficits in the distribution and structure of subtypes of nonpyramidal inhibitory interneurons in dysplasia (96-99) reminiscent of that reported in epileptogenic nonmalformed adult cortex (1 00). In parallel, excessive expression of glutamate receptors has been reported in human dysplastic cortex (101,102).…”

Section: Several Lines Of Evidences Support the Idea Of An In-mentioning

confidence: 88%

Cortical Malformations and Epilepsy: New Insights from Animal Models

et al. 1999

View full text Add to dashboard Cite

Summary:In the last decade, the recognition of the high frequency of cortical malformations among patients with epilepsy especially children, has led to a renewed interest in the study of the pathophysiology of cortical development. This field has also been spurred by the recent development of several experimental genetic and non-genetic, primarily rodent, models of cortical malformations. Epileptiform activity in these animals can appear as spontaneous seizure activity in vivo, in vitro hyperexcitability, or reduced seizure susceptibility in vitro and in vivo. In the neonatal freeze lesion model, that mimics human microgyria, hyperexcitability is caused by a reorganization of the network in the borders of the malformation. In the prenatal methylazoxymethanol model, that causes a diffuse cortical malformation, hyperexcitability is associated with alteration of firing properties of discrete neuronal subpopulations together with the formation of bridges between normally unconnected structures. In agreement with clinical evidence, these expenmental data suggest that cortical malformations can both form epileptogenic foci and alter brain development in a manner that causes a diffuse hyperexcitability of the cortical network. Key Words: Neocortex-Hippocampus-Development-Neuronal migration-Methylazoxymethanol.As early as the end of the nineteenth century, neuropathologists began to report an association between cortical malformations and epilepsy (1-3). Until recently, however, clinical and experimental research yielded few insights into the pathophysiology of this distinct class of epilepsies. In fact, the last decade has seen three major scientific advances that have directly contributed to the "rediscovery" and renewed interest in examining the cause of epilepsy in patients with cortical malformations: mation and epilepsy. Moreover, neuropathologic analysis of resected tissue has frequently demonstrated the presence of more subtle malformations that were not identified in vivo. 3. Recent progress in human molecular genetics has allowed the identification of several genes whose mutations lead to both malformations and epilepsy. In parallel, several genetic and nongenetic rodent models of cortical malformations were shown to be associated with either spontaneous seizures or hyperexcitability .Our goal is to review the contributions of these animal models to our understanding of the pathophysiology of cortical malformations and to discuss their possible link with epilepsy. CORTICAL MALFORMATIONS IN HUMANSHuman cortical malformations have been the subject of several reviews (4-8) and the histology of the major types of cortical malformations encountered is fairly well established (see Fig. 1). In addition, classification of cortical malformations (based on neuropathology, radiology, etiology, or a combination of these elements) has 811

show abstract

“…There is some evidence to suggest that balloon cells display intrinsic hyperexcitability, possibly because of a modification of N-methyl-d-aspartate receptors or decreased sensitivity of the γ-aminobutyric acid A receptors in these pacemaker cells. 10,18,19,31,32 In more diffuse cortical dysplasia, there may be abnormal connectivity of the cellular aggregate, which is associated with reorganization of cortical circuitry, and axons that would normally project out of the epileptic zone may also be interrupted and instead make excitatory synapses locally. These recurrent excitatory connections may cause feed-forward connectivity loops that drive the excitatory and consequent epileptic process.…”

Section: Volumetrics and Epileptogenesismentioning

confidence: 99%

The influence of lesion volume, perilesion resection volume, and completeness of resection on seizure outcome after resective epilepsy surgery for cortical dysplasia in children

Oluigbo¹,

Wang²,

Whitehead

et al. 2015

PED

View full text Add to dashboard Cite

OBJECT Focal cortical dysplasia (FCD) is one of the most common causes of intractable epilepsy leading to surgery in children. The predictors of seizure freedom after surgical management for FCD are still unclear. The objective of this study was to perform a volumetric analysis of factors shown on the preresection and postresection brain MRI scans of patients who had undergone resective epilepsy surgery for cortical dysplasia and to determine the influence of these factors on seizure outcome. METHODS The authors reviewed the medical records and brain images of 43 consecutive patients with focal MRI-documented abnormalities and a pathological diagnosis of FCD who had undergone surgical treatment for refractory epilepsy. Preoperative lesion volume and postoperative resection volume were calculated by manual segmentation using OsiriX PRO software. RESULTS Forty-three patients underwent first-time surgery for resection of an FCD. The age range of these patients at the time of surgery ranged from 2 months to 21.8 years (mean age 7.3 years). The median duration of follow-up was 20 months. The mean age at onset was 31.6 months (range 1 day to 168 months). Complete resection of the area of an FCD, as adjudged from the postoperative brain MR images, was significantly associated with seizure control (p = 0.0005). The odds of having good seizure control among those who underwent complete resection were about 6 times higher than those among the patients who did not undergo complete resection. Seizure control was not significantly associated with lesion volume (p = 0.46) or perilesion resection volume (p = 0.86). CONCLUSIONS The completeness of FCD resection in children is a significant predictor of seizure freedom. Neither lesion volume nor the further resection of perilesional tissue is predictive of seizure freedom.

show abstract

Induced Expression of NMDAR2 Proteins and Differential Expression of NMDAR1 Splice Variants in Dysplastic Neurons of Human Epileptic Neocortex

Cited by 100 publications

References 0 publications

Differential Effects of Chronic Ethanol Treatment onN-Methyl-d-aspartate R1 Splice Variants in Fetal Cortical Neurons

Differential Effects of Chronic Ethanol Treatment onN-Methyl-d-aspartate R1 Splice Variants in Fetal Cortical Neurons

Cortical Malformations and Epilepsy: New Insights from Animal Models

The influence of lesion volume, perilesion resection volume, and completeness of resection on seizure outcome after resective epilepsy surgery for cortical dysplasia in children

Contact Info

Product

Resources

About