Contrasting patterns of extrasynaptic NMDAR-GluN2B expression in macaque subgenual cingulate and dorsolateral prefrontal cortices

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

Abstract Expression of the N-methyl-D-aspartate receptor, particularly when containing GluN2B subunit (NMDAR-GluN2B) varies across prefrontal cortex (PFC). In humans, subgenual cingulate (SGC) contains among highest levels NMDAR-GluN2B expression, while dorsolateral (dlPFC) exhibits a more moderate level expression. are commonly associated with ionotropic synaptic function and plasticity, essential to neurotransmission underlying working memory in macaque dlPFC layer III circuits afflicted schizophrenia. However, can also be found at extrasynaptic sites, where they may trigger distinct events, including some linked neurodegenerative processes. The SGC is an early site tau pathology sporadic Alzheimer’s Disease (sAD), which mirrors its high Additionally, hyperactive depression, treated NMDAR antagonists. Given clinical relevance dlPFC, current study used immunoelectron microscopy (immunoEM) quantitatively compare expression patterns excitatory inhibitory neuron dendrites rhesus dlPFC. We larger population dendritic shafts spines putative pyramidal neurons as compared had higher proportion NMDAR-GluN2B. contrast, from both areas, was far frequently observed over These findings provide insight into varying cortical vulnerability alterations excitability forces. Scope Statement receptors that contribute second messenger signaling events. induce diverse array neuronal part due variation composition subcellular localization receptor humans. This highly expressed cingulate, area mood emotion, moderately cortex, cognitive Extrasynaptic NMDAR, often contain subunit, have been detrimental cellular events like neurodegeneration. Here, using resolution electron macaques, we evidence prominent than cortex. Conversely, consistent their contribution firing during memory. help illuminate propensity tonic hyperactivity major depression neurodegeneration disease, explain how rapid acting antidepressants exert therapeutic action neural circuits.

Language: Английский

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Future Perspectives of NMDAR in CNS Disorders

Molecules, Journal Year: 2025, Volume and Issue: 30(4), P. 877 - 877

Published: Feb. 14, 2025

Neurodegenerative diseases such as Alzheimer's and Parkinson's are among the leading causes of physical cognitive disability across globe. Fifty million people worldwide suffer these diseases, that number is expected to rise population ages. Ictus another pathology also courses with neurodegeneration a cause mortality long-term in developed countries. Schizophrenia not common other mental disorders, affecting approximately 24 worldwide. All disorders have still there an effective pharmacological treatment cure them. The N-methyl-D-aspartate (NMDA) receptor (NMDAR) has attracted attention potential therapeutic target due its important role learning memory implication excitotoxicity processes. Some drugs targeting NMDARs already being used treat symptoms central nervous system (CNS). Here, we aim review implications NMDAR CNS pathologies, target, future perspectives for developing new treatments focused on receptors.

Language: Английский

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Investigating the Impact of NMDA Receptor Organization and Biological Sex in the APPswe/PS1dE9 Mouse Model of Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1737 - 1737

Published: Feb. 18, 2025

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and cognitive decline, with women being disproportionately affected in both prevalence severity. A key feature of AD synaptic loss, particularly around amyloid-β (Aβ) aggregates, which correlates strongly the severity dementia. Oligomeric Aβ believed to be primary driver dysfunction impairing excitatory neurotransmission through interactions receptors, including N-methyl-D-aspartate (NMDA) receptors. However, influence sex on these changes NMDA receptor mislocalization not well understood. This study examined potential sex-specific differences synaptotoxicity role extrasynaptic GluN2B-containing receptors pathogenesis using APP/PS1 double transgenic mouse model. Although male female mice showed similar amyloid burden impairments, alterations were slightly less severe females, suggesting subtle pathology. Both sexes exhibited GluN2B subunits areas, was linked reduced PSD-95 levels accumulation Aβ1-42. Intrahippocampal injections DL-TBOA confirmed dysfunction. These findings emphasize importance targeting trafficking address AD-related deficits, potentially offering therapeutic approach for sexes.

Language: Английский

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From postsynaptic neurons to astrocytes: the link between glutamate metabolism, Alzheimer’s disease and Parkinson’s disease

Reviews in the Neurosciences, Journal Year: 2025, Volume and Issue: unknown

Published: March 18, 2025

Abstract Glutamate is not only the main excitatory neurotransmitter of human central nervous system, but also a potent neurotoxin. Therefore, maintaining low-dose, non-toxic extracellular glutamate concentrations between synapses to ensure reliability synaptic transmission essential for normal physiological functions neurons. More and more studies have confirmed that specific pathogenesis system diseases (such as Alzheimer’s disease) caused by neuronal damage or death due abnormal inter-synaptic concentration may be related function amino acid transporter proteins glutamine synthetase on astrocytes, expression above two transcription, translation, even modification both process astrocytes. oxidative stress, inflammatory responses occurring in astrocytes during their translation modification. this review, we mainly discuss relationship metabolism (from postsynaptic neurons astrocytes), disease Parkinson’s recent years.

Language: Английский

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Contrasting patterns of extrasynaptic NMDAR-GluN2B expression in macaque subgenual cingulate and dorsolateral prefrontal cortices

Frontiers in Neuroanatomy, Journal Year: 2025, Volume and Issue: 19

Published: April 4, 2025

Expression of the N-methyl-D-aspartate receptor, particularly when containing GluN2B subunit (NMDAR-GluN2B), varies across prefrontal cortex (PFC). In humans, subgenual cingulate (SGC) contains among highest levels NMDAR-GluN2B expression, while dorsolateral (dlPFC) exhibits a more moderate level expression. are commonly associated with ionotropic synaptic function and plasticity essential to neurotransmission underlying working memory in macaque dlPFC layer III circuits, which humans afflicted schizophrenia. However, can also be found at extrasynaptic sites, where they may trigger distinct events, including some linked neurodegenerative processes. The SGC is an early site tau pathology sporadic Alzheimer’s disease (sAD), mirrors its high Additionally, hyperactive depression, treated NMDAR antagonists. Given clinical relevance dlPFC, current study used immunoelectron microscopy (immunoEM) quantitatively compare expression patterns excitatory inhibitory neuron dendrites rhesus dlPFC. We larger population putative pyramidal neurons as compared had higher proportion NMDAR-GluN2B. contrast, from both areas, was far frequently observed over These findings provide insight into varying cortical vulnerability alterations excitability forces.

Language: Английский

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The GluN3-containing NMDA receptors

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

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Multiple Roles for Neuregulins and their ERBB Receptors in Neurodegenerative Disease Pathogenesis and Therapy

American Journal Of Pathology, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

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Role of Ion Channels in Alzheimer’s Disease Pathophysiology

The Journal of Membrane Biology, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Ion channels play an integral role in the normal functioning of brain. They regulate neuronal electrical properties like synaptic activity, generation action potentials, maintenance resting membrane potential and plasticity, modulate physiology non-neuronal cells astrocytes microglia. Dysregulation ionic homeostasis channelopathies are associated with various neurological disorders, including Alzheimer's disease (AD). Several families ion AD pathophysiology progression. In this review, we outline current research centered around channel dysregulation during discuss briefly possibility using as therapeutic targets.

Language: Английский

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NMDARs in Alzheimer’s Disease: Between Synaptic and Extrasynaptic Membranes

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

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