scholarly journals Common synaptic phenotypes arising from diverse mutations in the human NMDA receptor subunit GluN2A

2020 ◽  
Author(s):  
M. Elmasri ◽  
D. Hunter ◽  
G. Winchester ◽  
W. Aziz ◽  
E. Bates ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Pyramidal Neurons ◽  
Single Gene ◽  
Synaptic Activity ◽  
Molecular Defect ◽  
Loss Of Function ◽  
Nmda Receptor Subunit ◽  
Ca1 Neurons ◽  
Current Decay ◽  
Nmdar Subunit

Dominant mutations in the human gene GRIN2A, encoding NMDA receptor (NMDAR) subunit GluN2A, make a significant and growing contribution to the catalogue of published single-gene epilepsies. Understanding the disease mechanism in these epilepsy patients is complicated by the surprising diversity of effects that the mutations have on NMDARs. We have examined the cell-autonomous impact of 5 severe GluN2A mutations by measuring NMDAR-mediated synaptic currents (NMDAR-EPSCs) in CA1 pyramidal neurons following rescue with human GluN2A mutants. Surprisingly, prolonged NMDAR-EPSC current decay and smaller peak amplitudes were common features of both gain- and loss-of-function mutants despite there being drastic differences between their effects on receptor function and enrichment at synapses. Modelling of NMDARs with mutant properties in CA1 neurons indicates that mutant NMDARs may contribute to broadening of depolarizations during bursts of high-frequency synaptic activity. Overall, the implication is that similar therapeutic approaches may be more widely applicable to patients with GRIN2A-related disorders irrespective of their molecular defect.

Fast NMDA Receptor–Mediated Synaptic Currents in Neurons From Mice Lacking the ε2 (NR2B) Subunit

2000 ◽  
Vol 83 (1) ◽  
pp. 616-620 ◽  
Author(s):  
Kenneth R. Tovar ◽  
Kathleen Sprouffske ◽  
Gary L. Westbrook
Keyword(s):  
Nmda Receptor ◽  
Hippocampal Neurons ◽  
Postsynaptic Membrane ◽  
Synaptic Activity ◽  
Wild Type ◽  
Nmda Receptor Subunit ◽  
Deactivation Kinetics ◽  
Low Concentrations ◽  
Specific Antagonist

The N-methyl-d-aspartate (NMDA) receptor has been implicated in the formation of synaptic connections. To investigate the role of the ε2 (NR2B) NMDA receptor subunit, which is prominently expressed during early development, we used neurons from mice lacking this subunit. Although ε2−/− mice die soon after birth, we examined whether NMDA receptor targeting to the postsynaptic membrane was dependent on the ε2 subunit by rescuing hippocampal neurons from these mice and studying them in autaptic cultures. In voltage-clamp recordings, excitatory postsynaptic currents (EPSCs) from ε2−/− neurons expressed an NMDA receptor–mediated EPSC that was apparent as soon as synaptic activity developed. However, compared with wild-type neurons, NMDA receptor–mediated EPSC deactivation kinetics were much faster and were less sensitive to glycine, but were blocked by Mg2+ or AP5. Whole cell currents from ε2−/− neurons were also more sensitive to block by low concentrations of Zn2+ and much less sensitive to the ε2-specific antagonist ifenprodil than wild-type currents. The rapid NMDA receptor–mediated EPSC deactivation kinetics and the pharmacological profile from ε2−/−neurons are consistent with the expression of ζ1/ε1 diheteromeric receptors in excitatory hippocampal neurons from mice lacking the ε2 subunit. Thus ε1 can substitute for the ε2 subunit at synapses and ε2 is not required for targeting of NMDA receptors to the postsynaptic membrane.

scholarly journals Medial prefrontal cortical NMDA receptors regulate depression-like behavior and dictate limbic thalamus innervation

2017 ◽  
Author(s):  
Oliver H. Miller ◽  
Andreas Bruns ◽  
Imen Ben Ammar ◽  
Thomas Mueggler ◽  
Benjamin J. Hall
Keyword(s):  
Viral Vectors ◽  
Pyramidal Neurons ◽  
Synaptic Activity ◽  
Dependent Manner ◽  
Prefrontal Cortical ◽  
Limbic Thalamus ◽  
Level Function ◽  
Nmdar Subunit ◽  
Circuit Function ◽  
Activity Dependent

AbstractDepression is a pervasive and debilitating neuropsychiatric disorder. A single, low dose of the NMDA receptor (NMDAR) antagonist ketamine elicits a long-lasting antidepressant response in patients with treatment-resistant major depressive disorder. Developing mechanistic understanding of how NMDAR antagonism alters synapse and circuit function is pivotal to developing translatable, circuit-based therapies for depression. Here using viral vectors, anatomical tracing, fMRI, and optogenetic-assisted circuit analysis, we assessed the role of the NMDAR subunit GluN2B in regulating cellular, synaptic, and circuit-level function and depression-related behavior. We demonstrate that post-developmental deletion of GluN2B from pyramidal neurons in medial prefrontal cortex enhances action potential output in a synaptic activity-dependent manner. GluN2B deletion dictates functional connectivity between mPFC and limbic thalamus but not ventral hippocampus and elicits antidepressant-like behavior. Our findings demonstrate that postsynaptic GluN2B exerts input-specific control of pyramidal neuron innervation, and identify a novel circuit for regulating depression-like behaviors in mice.

Effects of a spider toxin and its analogue on glutamate-activated currents in the hippocampal CA1 neuron after ischemia

1995 ◽  
Vol 74 (1) ◽  
pp. 218-225 ◽  
Author(s):  
H. Tsubokawa ◽  
K. Oguro ◽  
T. Masuzawa ◽  
T. Nakaima ◽  
N. Kawai
Keyword(s):  
Nmda Receptor ◽  
Patch Clamp ◽  
Pyramidal Neurons ◽  
Single Channel ◽  
Patch Clamp Recording ◽  
Ca1 Neurons ◽  
Ca1 Pyramidal Neurons ◽  
Spider Toxin ◽  
Single Channel Currents ◽  
Channel Currents

1. We studied the effects of polyamine toxins derived from a spider venom on CA1 pyramidal neurons in gerbil hippocampal slices by patch-clamp recording. Joro spider toxin (JSTX) and its synthetic analogue, 1-naphthyl acetyl spermine (Naspm), which are known to block non-N-methyl-D-aspartate (non-NMDA) receptor in a subunit specific manner, were used. 2. Naspm depressed the excitatory postsynaptic currents (EPSCs) mediated by non-NMDA receptor channels. A further reduction of EPSCs occurred with addition of 6-cyano-7-nitroquin-oxaline-2,3- dione (CNQX). Conversely, when CNQX was applied first, no further depression of EPSCs occurred on addition of Naspm, indicating that Naspm blocks a fraction of the CNQX-sensitive non-NMDA-receptor-mediated currents. 3. After ischemia, the time course of EPSCs of CA1 pyramidal neurons was slowed and Naspm depressed the slow EPSCs more strongly than those in control neurons. 4. Analysis of single-channel currents by outside-out patch-clamp recording from ischemic CA1 neurons revealed that Naspm blocked a subpopulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate- and kainate-induced single-channel currents. 5. Because the EPSCs in CA1 neurons after ischemia are mediated by Ca(2+)-permeable non-NMDA receptor-mediated conductances, the present results indicate that Naspm and JSTX are effective at blocking abnormal EPSCs that may induce Ca2+ accumulation leading to delayed neuronal death after transient ischemic insult.

Ischemic preconditioning protects the hippocampal CA1 neurons by inhibiting synaptic activity in rat

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S300-S300
Author(s):  
Thomas J Sick ◽  
Ami P Raval ◽  
Isabel Saul ◽  
Kunjan R Dave ◽  
Raul Busto ◽  
...  
Keyword(s):  
Ischemic Preconditioning ◽  
Synaptic Activity ◽  
Ca1 Neurons ◽  
Hippocampal Ca1 Neurons ◽  
Hippocampal Ca1

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

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.

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