Alterations in NMDA Receptors in a Rat Model of Cortical Dysplasia

Recent studies have demonstrated an important role for the N-methyl-d-aspartate receptor (NMDAR) in epilepsy. NMDARs have also been shown to play a critical role in hyperexcitability associated with several animal models of human epilepsy. Using whole-cell voltage clamp recordings in brain slices, we studied evoked paroxysmal discharges in the freeze-lesion model of neocortical microgyria. The voltage dependence of epileptiform discharges indicated that these paroxysmal events were produced by a complex pattern of excitatory and inhibitory inputs. We examined the effect of the NMDAR antagonist d-2-amino-5-phosphopentanoic acid (APV) and the NMDA receptor subunit type 2B (NR2B)-selective antagonist ifenprodil on the threshold, peak amplitude, and area of evoked epileptiform discharges in brain slices from lesioned animals. Both compounds consistently raised the threshold for evoking the discharge but had modest effects on the discharge peak and amplitude. For comparison with nonlesioned cortex, we examined the effects of ifenprodil on the epileptiform discharge evoked in the presence of 2 μM bicuculline (partial disinhibition). In slices from nonlesioned cortex, 10 μM ifenprodil had little effect on the threshold whereas 71% of the recordings in bicuculline-treated lesioned cortex showed a >25% increase in threshold. These results suggest that NR2B-containing receptors are functionally enhanced in freeze-lesioned cortex and may contribute to the abnormal hyperexcitability observed in this model of neocortical microgyria.

Download Full-text

Early modifications in N-methyl-d-aspartate receptor subunit mRNA levels in an oxygen and glucose deprivation model using rat hippocampal brain slices

Neuroscience ◽

10.1016/j.neuroscience.2009.09.019 ◽

2009 ◽

Vol 164 (3) ◽

pp. 1119-1126 ◽

Cited By ~ 15

Author(s):

S. Dos-Anjos ◽

B. Martínez-Villayandre ◽

S. Montori ◽

C.C. Pérez-García ◽

A. Fernández-López

Keyword(s):

Brain Slices ◽

Glucose Deprivation ◽

Mrna Levels ◽

Receptor Subunit ◽

Oxygen And Glucose Deprivation ◽

Subunit Mrna ◽

Aspartate Receptor ◽

Deprivation Model

Download Full-text

Activation of a Calcium-Activated Cation Current During Epileptiform Discharges and Its Possible Role in Sustaining Seizure-Like Events in Neocortical Slices

Journal of Neurophysiology ◽

10.1152/jn.00972.2003 ◽

2004 ◽

Vol 92 (2) ◽

pp. 862-872 ◽

Cited By ~ 35

Author(s):

Yitzhak Schiller

Keyword(s):

Brain Slices ◽

Reversal Potential ◽

Cell Voltage ◽

Epileptic Seizures ◽

Flufenamic Acid ◽

Calcium Stores ◽

Epileptiform Discharges ◽

Cation Current ◽

Paroxysmal Depolarization Shift ◽

Internal Calcium

Epileptic seizures are composed of recurrent bursts of intense firing separated by periods of electrical quiescence. The mechanisms responsible for sustaining seizures and generating recurrent bursts are yet unclear. Using whole cell voltage recordings combined with intracellular calcium fluorescence imaging from bicuculline (BCC)-treated neocortical brain slices, I showed isolated paroxysmal depolarization shift (PDS) discharges were followed by a sustained afterdepolarization waveform (SADW) with an average peak amplitude of 3.3 ± 0.9 mV and average half-width of 6.2 ± 0.6 s. The SADW was mediated by the calcium-activated nonspecific cation current ( Ican) as it had a reversal potential of –33.1 ± 6.8 mV, was unaffected by changing the intracellular chloride concentrations, was markedly diminished by buffering [Ca2+]i with intracellular bis-( o-aminophenoxy)- N,N,N′,N′-tetraacetic acid (BAPTA), and was reversibly abolished by the Ican blocker flufenamic acid (FFA). The Ca2+ influx responsible for activation of Ican was mediated by both N-methyl-d-aspartate-receptor channels, voltage-gated calcium channels and, to a lesser extent, internal calcium stores. In addition to isolated PDS discharges, BCC-treated brain slices also produced seizure-like events, which were accompanied by a prolonged depolarizing waveform underlying individual ictal bursts. The similarities between the initial part of this waveform and the SADW and the fact it was markedly reduced by buffering [Ca2+]i with BAPTA strongly suggested it was mediated, at least in part, by Ican. Addition of FFA reversibly eliminated recurrent bursting, and transformed seizure-like events into isolated PDS responses. These results indicated Ican was activated during epileptiform discharges and probably participated in sustaining seizure-like events.

Download Full-text

Epileptogenicity Correlated with Increased N-Methyl-d-Aspartate Receptor Subunit NR2A/B in Human Focal Cortical Dysplasia

Epilepsia ◽

10.1111/j.1528-1157.2000.tb00281.x ◽

2000 ◽

Vol 41 (8) ◽

pp. 971-976 ◽

Cited By ~ 90

Author(s):

Imad M. Najm ◽

Zhong Ying ◽

Thomas Babb ◽

Armin Mohamed ◽

Jennifer Hadam ◽

...

Keyword(s):

Focal Cortical Dysplasia ◽

Cortical Dysplasia ◽

Receptor Subunit ◽

Aspartate Receptor

Download Full-text

Transient microstructural brain anomalies and epileptiform discharges in mice defective for epilepsy and language-related NMDA receptor subunit gene Grin2a

Epilepsia ◽

10.1111/epi.14543 ◽

2018 ◽

Vol 59 (10) ◽

pp. 1919-1930 ◽

Cited By ~ 11

Author(s):

Manal Salmi ◽

Radu Bolbos ◽

Sylvian Bauer ◽

Marat Minlebaev ◽

Nail Burnashev ◽

...

Keyword(s):

Nmda Receptor ◽

Receptor Subunit ◽

Subunit Gene ◽

Nmda Receptor Subunit ◽

Brain Anomalies ◽

Epileptiform Discharges

Download Full-text

Electroacupuncture ameliorates CUMS-induced depression-like behavior: involvement of the glutamatergic system and apoptosis in rats

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207323666201027121423 ◽

2020 ◽

Vol 23 ◽

Author(s):

Qin Guo ◽

Xian-Ming Lin ◽

Zhong Di ◽

Quan-Ai Zhang ◽

Shuo Jiang

Keyword(s):

Nmda Receptor ◽

Caspase 3 ◽

B Cell Lymphoma ◽

Sucrose Preference ◽

Expression Level ◽

Receptor Subunit ◽

Glutamatergic System ◽

Ionotropic Receptor ◽

Nmda Receptor Subunit ◽

Expression Levels

Background: Converging evidence indicates that glutamatergic system and glia are directly implicated in the pathophysiology of depression. Clinical studies indicate that electroacupuncture (EA) has antidepressant-like effect with low side effects for depression. However, the underlying antidepressant mechanism of acupuncture remains obscure. Methods: Chronic unpredictable mild stress (CUMS)-induced depressive rats were used to induce depressive-like behavior, and evaluated by the weight change, open field test, sucrose preference test, and novelty suppressed feeding test. EA, NMDA receptor subunit 2A antagonist (NR2A RA) or NMDA receptor subunit 2B antagonist (NR2B RA) was used for comparison. High performance liquid chromatography (HPLC) was performed to detect the content of hippocampal glutamate, while western blot for the hippocampal protein expression levels of calcium/calmodulin-dependent protein kinase II (CaMKII), Bax, caspase 3 and B-cell lymphoma-2 (Bcl-2). The distribution of glutamate ionotropic receptor NMDA type subunit 2A (NR2A), neuronal nuclear protein (NeuN), glutamate ionotropic receptor NMDA type subunit 2B (NR2B) and glial fibrillary acidic protein (GFAP) were detected by immunofluorescence. Results: Significant depression behavior (reduced body weight and sucrose preference, increased feeding and immobility time) was produced in CUMS-induced depressive rats, which was reversed significantly by EA. EA decreased hippocampal glutamate level. EA led to a significant decrease in expression levels of Bax, caspase 3 and CaMKⅡ accompanied by increased Bcl-2 expression level. Furthermore, EA significantly increased NR2A expression level as well as decreased NR2B expression level in hippocampus. Conclusion: EA ameliorated depression-like behavior in CUMS rats, which might be mediated, at least in part, by regulating the glutamate, NMDA receptors and apoptosis in the hippocampus.

Download Full-text