CA1i pyramidal neurons mediate the role of NMDA receptor subunit GluN3A in depressive behavior and D-serine anti-depression DOI
Wei Zhang, Jiesi Wang,

Jiajie Dai

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 28, 2024

Abstract Depression is a heterogeneous psychiatric disorder characterized by multiple symptom clusters. N-methyl-d-aspartic acid receptors (NMDARs), consisting of various subunit proteins GluN1-3, are known to be critical molecular bases for the occurrence and treatment depression. However, involvement NMDAR GluN3A in heterogeneity depressive symptoms antidepressant effects remains unclear. Here, we found that chronic social defeat stress (CSDS) induced range depression-related behaviors, including decreased interest, increased helplessness anxiety-like behavior, reduced mRNA protein expression hippocampal CA1 intermediate (CA1i) region. Additionally, knockout (KO) mice exhibited pronounced behavior. Increasing CA1i both models specifically reversed behavior but not interest Furthermore, lack activity pyramidal neurons during phenomenon also upregulating expression. Further bidirectional modulation neuron directly mimicked or CSDS-induced Finally, injection D-serine into rapidly improved CSDS while increasing neurons, whereas inhibition prevented effect D-serine. Our study elucidates role regulating its mechanisms, as well rapid D-serine, which deepen understanding complex pathophysiology depression develop potential clinical new target.

Language: Английский

NMDA receptor functions in health and disease: Old actor, new dimensions DOI Creative Commons
Julien P. Dupuis, Olivier Nicole, Laurent Groc

et al.

Neuron, Journal Year: 2023, Volume and Issue: 111(15), P. 2312 - 2328

Published: May 25, 2023

Language: Английский

Citations

67
Synaptic and extrasynaptic distribution of NMDA receptors in the cortex of Alzheimer's disease patients DOI Creative Commons
Sergio Escamilla,

Raquel Badillos,

Joan X. Comella

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 25, 2024

Abstract BACKGROUND Synaptic and extrasynaptic distribution of N‐methyl‐D‐aspartate receptors (NMDARs) has not been addressed in the brain from Alzheimer´s disease (AD) subjects, despite their contribution to neurodegeneration. METHODS We have developed a protocol isolate synaptic membranes controls AD frontal cortex. characterized NMDAR subunits GluN2B, GluN2A, GluN1, GluN3A, as well post‐translational modifications, such phosphorylation glycosylation. RESULTS Lower levels GluN2B GluN2A were found fractions, while GluN1 significantly higher; GluN3A remained unaffected AD. also identified different glycoforms membranes. Tyr1472 was lower fractions. DISCUSSION Reduction subunits, particularly for is likely contribute transmission failure Additionally, increment could favor activation excitotoxicity Highlights New human Low High Specific GluN2A. at

Language: Английский

Citations

10
NMDA receptor autoantibodies primarily impair the extrasynaptic compartment DOI Creative Commons
Zoë Jamet,

Camille Mergaux,

Morgane Meras

et al.

Brain, Journal Year: 2024, Volume and Issue: 147(8), P. 2745 - 2760

Published: May 17, 2024

Abstract Autoantibodies directed against the N-methyl-D-aspartate receptor (NMDAR-Ab) are pathogenic immunoglobulins detected in patients suffering from NMDAR encephalitis. NMDAR-Ab alter membrane trafficking, synaptic transmission and neuronal network properties, leading to neurological psychiatric symptoms patients. Patients often have very little damage but rapid massive (treatment-responsive) brain dysfunctions related an unknown early mechanism of NMDAR-Ab. Our understanding this molecular cascade remains surprisingly fragmented. Here, we used a combination single molecule-based imaging proteins unveil spatiotemporal action on live hippocampal neurons. We first demonstrate that different clones primarily affect extrasynaptic (and not synaptic) NMDARs. In minutes, increase dynamics, declustering its surface interactome. also rapidly reshuffle all located compartment. Consistent with alteration multiple proteins, effects were mediated through sole interaction between EphB2 receptor. long term, reduce pool by slowing down dynamics cross-linking-independent manner. Remarkably, exposing only NMDARs was sufficient produce their full-blown effect receptors. Collectively, initially impair then ones. These data thus shed new unsuspected light mode and, probably, our (extra)synaptopathies.

Language: Английский

Citations

7
The GluN3-containing NMDA receptors DOI Creative Commons

Kunlong Xiong,

Shulei Lou,

Lian Zhou

et al.

Channels, Journal Year: 2025, Volume and Issue: 19(1)

Published: April 16, 2025

N-methyl-D-aspartate receptors (NMDARs) are heterotetrameric ion channels that play crucial roles in brain function. Among all the NMDAR subtypes, GluN1-N3 exhibit unique agonist binding and gating properties. Unlike "conventional" GluN1-N2 receptors, which require both glycine glutamate for activation, activated solely by glycine. Furthermore, display faster desensitization, reduced Ca2+ permeability, lower sensitivity to Mg2+ blockage compared receptors. Due these characteristics, thought critical eliminating redundant synapses pruning spines early stages of development. Recent studies have advanced pharmacological tools specifically targeting provided direct evidence glycine-activated excitatory native tissue. The structural basis has also been elucidated through cryo-EM artificial intelligence. These findings highlight not only involved essential functions but present potential targets drug

Language: Английский

Citations

0
Rapid sequential clustering of NMDARs, CaMKII, and AMPARs upon activation of NMDARs at developing synapses DOI Creative Commons

Yucui Chen,

Shangming Liu,

Ariel A. Jacobi

et al.

Frontiers in Synaptic Neuroscience, Journal Year: 2024, Volume and Issue: 16

Published: April 10, 2024

Rapid, synapse-specific neurotransmission requires the precise alignment of presynaptic neurotransmitter release and postsynaptic receptors. How glutamate receptor accumulation is induced during maturation not well understood. We find that in cultures dissociated hippocampal neurons at 11 days vitro (DIV) numerous synaptic contacts already exhibit pronounced accumulations pre- markers synaptotagmin, synaptophysin, synapsin, bassoon, VGluT1, PSD-95, Shank. The presence an initial set AMPARs NMDARs indicated by miniature excitatory currents (mEPSCs). However, AMPAR NMDAR immunostainings reveal rather smooth distributions throughout dendrites enrichment obvious. found brief periods Ca 2+ influx through a surprisingly rapid within 1 min, followed CaMKII then 2–5 min. Postsynaptic clustering was paralleled increase their mEPSC amplitudes. A peptide blocked interaction subunits with PSD-95 prevented clustering. persisted for 3 indicating elevated fosters permanent sites maturing synapses. These data support model strong glutamatergic stimulation immature synapses results fast substantial content required binding to or its homologues recruitment subsequently AMPARs.

Language: Английский

Citations

2
NMDARs in Alzheimer’s Disease: Between Synaptic and Extrasynaptic Membranes DOI Open Access
Sergio Escamilla, Javier Sáez‐Valero, Inmaculada Cuchillo‐Ibáñez

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(18), P. 10220 - 10220

Published: Sept. 23, 2024

N-methyl-D-aspartate receptors (NMDARs) are glutamate with key roles in synaptic communication and plasticity. The activation of NMDARs initiates plasticity stimulates cell survival. In contrast, the extrasynaptic can promote death underlying a potential mechanism neurodegeneration occurring Alzheimer's disease (AD). distribution versus has emerged as an important parameter contributing to neuronal dysfunction neurodegenerative diseases including AD. Here, we review concept NMDARs, this population is present numerous membranes but also various non-neuronal cells. Previous evidence regarding membranal NMDRs relation AD mice models brains patients will be reviewed.

Language: Английский

Citations

2
CA1i pyramidal neurons mediate the role of NMDA receptor subunit GluN3A in depressive behavior and D-serine anti-depression DOI
Wei Zhang, Jiesi Wang,

Jiajie Dai

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 28, 2024

Abstract Depression is a heterogeneous psychiatric disorder characterized by multiple symptom clusters. N-methyl-d-aspartic acid receptors (NMDARs), consisting of various subunit proteins GluN1-3, are known to be critical molecular bases for the occurrence and treatment depression. However, involvement NMDAR GluN3A in heterogeneity depressive symptoms antidepressant effects remains unclear. Here, we found that chronic social defeat stress (CSDS) induced range depression-related behaviors, including decreased interest, increased helplessness anxiety-like behavior, reduced mRNA protein expression hippocampal CA1 intermediate (CA1i) region. Additionally, knockout (KO) mice exhibited pronounced behavior. Increasing CA1i both models specifically reversed behavior but not interest Furthermore, lack activity pyramidal neurons during phenomenon also upregulating expression. Further bidirectional modulation neuron directly mimicked or CSDS-induced Finally, injection D-serine into rapidly improved CSDS while increasing neurons, whereas inhibition prevented effect D-serine. Our study elucidates role regulating its mechanisms, as well rapid D-serine, which deepen understanding complex pathophysiology depression develop potential clinical new target.

Language: Английский

Citations

1