{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T23:06:04Z","timestamp":1785452764759,"version":"3.56.0"},"reference-count":81,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Extrasynaptic GluN2B N-methyl-D-aspartate receptors (ES-GluN2B) are localized outside synapses and promote excitotoxic signaling, apoptosis, and long-term depression (LTD) in Alzheimer\u2019s disease (AD). Polysialylated neural cell adhesion molecule (PSA-NCAM) physiologically inhibits ES-GluN2B activity, and its downregulation is associated with impaired synaptic plasticity. However, the spatiotemporal changes of ES-GluN2B and PSA-NCAM during brain aging versus AD remain poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated GluN2A, GluN2B, ES-GluN2B, and PSA-NCAM expression across brain regions in young and old Tg2576 AD and wild-type (WT) mice. Additional experiments included PSD-95 pulldown assays, analysis of GluN2B phosphorylation at Ser1480, CRISPRa-driven ST8Sia4 upregulation in IMR-32 neuroblastoma cells, and A\u03b2 treatment to assess effects on PSA-NCAM biosynthetic enzymes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Normal aging was associated with decreased GluN2B, increased GluN2A, stable ES-GluN2B, and elevated PSA-NCAM levels. In contrast, AD aging showed elevated ES-GluN2B and reduced PSA-NCAM, particularly in the hippocampus and cortex, with no change in total NCAM expression. PSD-95 pulldown revealed increased extrasynaptic GluN2B in aged AD brains. AD aging was associated with elevated phosphorylation of GluN2B at Ser1480 by casein kinase 2 (CK2), promoting GluN2B redistribution to extrasynaptic sites. CRISPRa-driven ST8Sia4 upregulation increased PSA-NCAM and reduced pGluN2B expression supporting a direct regulatory role for PSA-NCAM in GluN2B trafficking. Additionally, A\u03b2 suppressed PSA-NCAM biosynthetic enzymes ST8Sia4 and UDP-E linking A\u03b2 to impaired polysialylation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings highlight distinct regulatory patterns of ES-GluN2B and PSA-NCAM in AD versus normal aging and support a model in which impaired PSA-NCAM buffering facilitates pathological ES-GluN2B signaling and plasticity loss in AD progression.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnins.2025.1649625","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T12:55:24Z","timestamp":1756472124000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Spatiotemporal differential regulation of extrasynaptic GluN2B receptor subunits and PSA-NCAM in brain aging and Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"19","author":[{"given":"Oghenetega E.","family":"Imiruaye","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isis G.","family":"Perez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian C.","family":"Carson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Crouzet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome","family":"Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derick","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhrajit","family":"Bhattacharya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"ref9001","doi-asserted-by":"crossref","first-page":"e73366","DOI":"10.1371\/journal.pone.0073366","article-title":"Pharmacological inhibition of polysialyltransferase ST8SiaII modulates tumour cell migration","volume":"8","author":"Al-Saraireh","year":"2013","journal-title":"PLoS One."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"570586","DOI":"10.3389\/fnmol.2020.570586","article-title":"Functions of p38 MAP kinases in the central nervous system","volume":"13","author":"Asih","year":"2020","journal-title":"Front. Mol. Neurosci."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.neuron.2005.08.034","article-title":"NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII","volume":"48","author":"Barria","year":"2005","journal-title":"Neuron"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/j.neuron.2018.06.010","article-title":"Triheteromeric GluN1\/GluN2A\/GluN2C NMDARs with unique single-channel properties are the dominant receptor population in cerebellar granule cells","volume":"99","author":"Bhattacharya","year":"","journal-title":"Neuron"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.nlm.2016.12.013","article-title":"Altered AMPA receptor expression plays an important role in inducing bidirectional synaptic plasticity during contextual fear memory reconsolidation","volume":"139","author":"Bhattacharya","year":"2017","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1002\/jnr.24230","article-title":"NMDA receptor blockade ameliorates abnormalities of spike firing of subthalamic nucleus neurons in a parkinsonian nonhuman primate","volume":"96","author":"Bhattacharya","year":"","journal-title":"J. Neurosci. Res."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1002\/hipo.20723","article-title":"Causal evidence for the involvement of the neural cell adhesion molecule, NCAM, in chronic stress-induced cognitive impairments","volume":"21","author":"Bisaz","year":"2011","journal-title":"Hippocampus"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.pneurobio.2006.08.003","article-title":"PSA-NCAM in mammalian structural plasticity and neurogenesis","volume":"80","author":"Bonfanti","year":"2006","journal-title":"Prog. Neurobiol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1875","DOI":"10.2174\/138161207780858384","article-title":"JNK signaling: a possible target to prevent neurodegeneration","volume":"13","author":"Borsello","year":"2007","journal-title":"Curr. Pharm. Des."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/1750-1326-4-27","article-title":"Neurodegeneration in Alzheimer's disease: caspases and synaptic element interdependence","volume":"4","author":"Bredesen","year":"2009","journal-title":"Mol. Neurodegener."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1083\/jcb.140.5.1177","article-title":"Regulation of neural cell adhesion molecule polysialylation: evidence for nontranscriptional control and sensitivity to an intracellular pool of calcium","volume":"140","author":"Brus\u00e9s","year":"1998","journal-title":"J. Cell Biol."},{"key":"ref9002","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.pharmthera.2018.11.006","article-title":"Synaptic dysfunction in Alzheimer\u2019s disease: Mechanisms and therapeutic strategies","volume":"195","author":"Chen","year":"2019","journal-title":"Pharmacology & therapeutics"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1038\/s41583-019-0141-5","article-title":"Preserving the balance: diverse forms of long-term GABAergic synaptic plasticity","volume":"20","author":"Chiu","year":"2019","journal-title":"Nat. Rev. Neurosci."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1016\/j.celrep.2019.06.030","article-title":"NMDAR-activated PP1 dephosphorylates GluN2B to modulate NMDAR synaptic content","volume":"28","author":"Chiu","year":"2019","journal-title":"Cell Rep."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"10248","DOI":"10.1523\/JNEUROSCI.0546-04.2004","article-title":"Regulation of the NMDA receptor complex and trafficking by activity-dependent phosphorylation of the NR2B subunit PDZ ligand","volume":"24","author":"Chung","year":"2004","journal-title":"J. Neurosci."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/j.molmed.2009.06.005","article-title":"p38MAPK: stress responses from molecular mechanisms to therapeutics","volume":"15","author":"Coulthard","year":"2009","journal-title":"Trends Mol. Med."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"11625","DOI":"10.3390\/ijms231911625","article-title":"TRAIL-R deficient mice are protected from neurotoxic effects of amyloid-\u03b2","volume":"23","author":"Di Benedetto","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.bbr.2014.05.046","article-title":"Behavioral analysis of male and female Fmr1 knockout mice on C57BL\/6 background","volume":"271","author":"Ding","year":"2014","journal-title":"Behav Brain Res"},{"key":"ref9003","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/S0031-6997(24)01394-2","article-title":"The glutamate receptor ion channels","volume":"51","author":"Dingledine","year":"1999","journal-title":"Pharmacological reviews"},{"key":"ref9004","doi-asserted-by":"crossref","first-page":"9372","DOI":"10.1523\/JNEUROSCI.1702-04.2004","article-title":"Polysialylated neural cell adhesion molecule promotes remodeling and formation of hippocampal synapses","volume":"24","author":"Dityatev","year":"2004","journal-title":"Journal of Neuroscience"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1041853","DOI":"10.3389\/fncel.2022.1041853","article-title":"Presentation and integration of multiple signals that modulate oligodendrocyte lineage progression and myelination","volume":"16","author":"Fekete","year":"2022","journal-title":"Front. Cell. Neurosci."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1007\/978-1-4419-1170-4_8","article-title":"The role of PSA-NCAM in adult neurogenesis","volume":"663","author":"Gascon","year":"2010","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"3295","DOI":"10.1007\/s12035-018-1283-6","article-title":"Brain-derived neurotrophic factor in brain disorders: focus on neuroinflammation","volume":"56","author":"Giacobbo","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1038\/nrn2911","article-title":"Synaptic versus extrasynaptic NMDA receptor signaling: implications for neurodegenerative disorders","volume":"11","author":"Hardingham","year":"2010","journal-title":"Nat. Rev. Neurosci."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/nn835","article-title":"Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways","volume":"5","author":"Hardingham","year":"2002","journal-title":"Nat. Neurosci."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"S141","DOI":"10.3233\/JAD-2012-129025","article-title":"GSK3 and tau: two convergence points in Alzheimer's disease","volume":"33","author":"Hern\u00e1ndez","year":"2013","journal-title":"J Alzheimer's Dis"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"371","DOI":"10.3233\/JAD-220986","article-title":"PSA-NCAM regulatory gene expression changes in the Alzheimer\u2019s disease entorhinal cortex revealed with multiplexed in situ hybridization","volume":"92","author":"Highet","year":"2023","journal-title":"J Alzheimer's Dis"},{"key":"ref9005","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1111\/j.1471-4159.2007.04716.x","article-title":"Dissecting polysialic acid and NCAM functions in brain development","volume":"103","author":"Hildebrandt","year":"2007","journal-title":"Journal of neurochemistry"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1201","DOI":"10.1016\/S0896-6273(00)80412-2","article-title":"NMDA receptor-dependent refinement of somatotopic maps","volume":"19","author":"Iwasato","year":"1997","journal-title":"Neuron"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"4171","DOI":"10.1523\/JNEUROSCI.5806-09.2010","article-title":"Neural cell adhesion molecule-associated polysialic acid regulates synaptic plasticity and learning by restraining the signaling through GluN2B-containing NMDA receptors","volume":"30","author":"Kochlamazashvili","year":"2010","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref29","first-page":"641","article-title":"Regional, developmental, and interspecies expression of the four NMDA receptor subunits, NR1, NR2A-D, in the rat brain","volume":"379","author":"Laurie","year":"1997","journal-title":"J. Comp. Neurol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"4258","DOI":"10.1096\/fj.08-107268","article-title":"Neuronal viability is controlled by a functional relation between synaptic and extrasynaptic NMDA receptors","volume":"22","author":"Leveille","year":"2008","journal-title":"FASEB J."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1016\/j.neuron.2009.05.012","article-title":"Soluble oligomers of amyloid \u03b2 protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake","volume":"62","author":"Li","year":"2009","journal-title":"Neuron"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"6627","DOI":"10.1523\/JNEUROSCI.0203-11.2011","article-title":"Soluble a\u03b2 oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors","volume":"31","author":"Li","year":"2011","journal-title":"J. Neurosci."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"161","DOI":"10.3892\/etm.2016.3306","article-title":"Increased extrasynaptic GluN2B expression is involved in cognitive impairment after isoflurane anesthesia","volume":"12","author":"Li","year":"2016","journal-title":"Exp. Ther. Med."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"e58752","DOI":"10.1371\/journal.pone.0058752","article-title":"Age-dependent neuroplasticity mechanisms in Alzheimer Tg2576 mice following modulation of brain amyloid-\u03b2 levels","volume":"8","author":"Lilja","year":"2013","journal-title":"PLoS One"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"949","DOI":"10.3389\/fnins.2019.00043","article-title":"A review of the role of NMDA receptors in Alzheimer's disease","volume":"35","author":"Liu","year":"","journal-title":"Neurosci. Bull."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"2846","DOI":"10.1523\/JNEUROSCI.0116-07.2007","article-title":"NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo","volume":"27","author":"Liu","year":"","journal-title":"J. Neurosci."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1038\/nrn3155","article-title":"Interneuron dysfunction in psychiatric disorders","volume":"13","author":"Mar\u00edn","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"2193","DOI":"10.1021\/jm011020u","article-title":"First non-ATP competitive glycogen synthase kinase 3 \u03b2 (GSK-3\u03b2) inhibitors: thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer's disease","volume":"44","author":"Mart\u00ednez","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"7821","DOI":"10.1523\/JNEUROSCI.1697-04.2004","article-title":"Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression","volume":"24","author":"Massey","year":"2004","journal-title":"J. Neurosci."},{"key":"ref41","first-page":"767","article-title":"Polysialic acid in Alzheimer\u2019s disease","volume":"24","author":"Mikkonen","year":"1999","journal-title":"Neurochem. Res."},{"key":"ref9006","doi-asserted-by":"publisher","first-page":"102815","DOI":"10.1016\/j.conb.2023.102815","article-title":"Mechanisms of NMDA receptor regulation","volume":"83","author":"Mony","year":"2023","journal-title":"Current Opinion in Neurobiology"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/0896-6273(94)90210-0","article-title":"Developmental and regional expression in the rat brain and functional properties of four NMDA receptors","volume":"12","author":"Monyer","year":"1994","journal-title":"Neuron"},{"key":"ref9007","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.neuropharm.2013.08.013","article-title":"Dysfunctional synapse in Alzheimer\u2019s disease\u2013A focus on NMDA receptors","volume":"76","author":"Mota","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1016\/j.neuroscience.2016.06.003","article-title":"Distribution of PSA-NCAM in normal, Alzheimer\u2019s and Parkinson\u2019s disease human brain","volume":"330","author":"Murray","year":"2016","journal-title":"Neuroscience"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1042\/BST0390902","article-title":"Hippocampal synaptic activity, pattern separation, and episodic-like memory: implications for mouse models of Alzheimer's disease pathology","volume":"39","author":"Palmer","year":"2011","journal-title":"Biochem. Soc. Trans."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1038\/nrn3504","article-title":"NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity, and disease","volume":"14","author":"Paoletti","year":"2013","journal-title":"Nat. Rev. Neurosci."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.cell.2012.06.029","article-title":"Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists","volume":"150","author":"Papouin","year":"2012","journal-title":"Cell"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.neuron.2014.03.030","article-title":"Extrasynaptic NMDA receptor involvement in central nervous system disorders","volume":"82","author":"Parsons","year":"2014","journal-title":"Neuron"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"2525","DOI":"10.3390\/cells12212525","article-title":"Prenatal cannabinoid exposure elicits memory deficits associated with reduced PSA-NCAM expression, altered glutamatergic signaling, and adaptations in hippocampal synaptic plasticity","volume":"12","author":"Pinky","year":"2023","journal-title":"Cells"},{"key":"ref9008","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1002\/alz.12362","article-title":"Population estimate of people with clinical Alzheimer\u2019s disease and mild cognitive impairment in the United States (2020\u20132060)","volume":"17","author":"Rajan","year":"2021","journal-title":"Alzheimer\u2019s and dementia"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/j.neuropharm.2013.12.003","article-title":"A role for hippocampal PSA-NCAM and NMDA-NR2B receptor function in flavonoid-induced spatial memory improvements in young rats","volume":"79","author":"Rendeiro","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"230","DOI":"10.3389\/fnsys.2014.00230","article-title":"Optogenetic dissection of medial prefrontal cortex circuitry","volume":"8","author":"Riga","year":"2014","journal-title":"Front. Syst. Neurosci."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"2219","DOI":"10.1016\/j.neurobiolaging.2010.01.011","article-title":"Early neuronal dysfunction by amyloid \u03b2 oligomers depends on activation of NR2B-containing NMDA receptors","volume":"32","author":"R\u00f6nicke","year":"2011","journal-title":"Neurobiol. Aging"},{"key":"ref9009","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1016\/j.neuron.2010.08.011","article-title":"Casein kinase 2 regulates the NR2 subunit composition of synaptic NMDA receptors","volume":"67","author":"Sanz-Clemente","year":"2010","journal-title":"Neuron"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1177\/1073858411435129","article-title":"Diversity in NMDA receptor composition: many regulators, many consequences","volume":"19","author":"Sanz-Clemente","year":"2013","journal-title":"Neuroscientist"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1007\/s10719-018-9832-9","article-title":"Mental disorders and an acidic glycan from the perspective of polysialic acid (PSA\/polySia) and the synthesizing enzyme, ST8SIA2","volume":"35","author":"Sato","year":"2018","journal-title":"Glycoconj. J."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1590\/S1807-59322011001300006","article-title":"Insights into Alzheimer disease pathogenesis from studies in transgenic animal models","volume":"66","author":"Schaeffer","year":"2011","journal-title":"Clinics"},{"key":"ref9010","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1002\/jnr.10366","article-title":"Hippocampal adult neurogenesis occurs in a microenvironment provided by PSA\u2010NCAM\u2010expressing immature neurons","volume":"69","author":"Seki","year":"2002","journal-title":"Journal of neuroscience research"},{"key":"ref59","first-page":"100","article-title":"Removal of polysialic acid-neural cell adhesion molecule induces alterations in the distribution of synaptic vesicles in developing cerebellar granule cells","volume":"395","author":"Seki","year":"1998","journal-title":"J. Comp. Neurol."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"10888","DOI":"10.1523\/JNEUROSCI.0878-06.2006","article-title":"Polysialylated neural cell adhesion molecule is involved in the induction of long-term potentiation and memory acquisition and consolidation in a fear-conditioning paradigm","volume":"26","author":"Senkov","year":"2006","journal-title":"J. Neurosci."},{"key":"ref9011","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1177\/1535370221989263","article-title":"Influence of glutamate and GABA transport on brain excitatory\/inhibitory balance","volume":"246","author":"Sheila","year":"2021","journal-title":"Experimental Biology and Medicine"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1038\/nn1503","article-title":"Regulation of NMDA receptor trafficking by amyloid-\u03b2","volume":"8","author":"Snyder","year":"2005","journal-title":"Nat. Neurosci."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"692","DOI":"10.3390\/ph15060692","article-title":"A pivotal role of Nrf2 in neurodegenerative disorders: a new way for therapeutic strategies","volume":"15","author":"Suzen","year":"2022","journal-title":"Pharmaceuticals (Basel, Switzerland)"},{"key":"ref63","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1016\/j.ajhg.2016.10.002","article-title":"Mechanistic insight into NMDA receptor dysregulation by rare variants in the GluN2A and GluN2B agonist binding domains","volume":"99","author":"Swanger","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref9012","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.2741\/2839","article-title":"The renin-angiotensin system, hypertension and cognitive dysfunction in Alzheimer\u2019s disease: new therapeutic potential","volume":"13","author":"Takeda","year":"2008","journal-title":"Frontiers in Bioscience-Landmark"},{"key":"ref9013","doi-asserted-by":"crossref","first-page":"E2518","DOI":"10.1073\/pnas.1306832110","article-title":"Ab induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss","volume":"110","author":"Talantova","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/1750-1326-7-60","article-title":"Caspase-9 mediates synaptic plasticity and memory deficits of Danish dementia knock-in mice: caspase-9 inhibition provides therapeutic protection","volume":"7","author":"Tamayev","year":"2012","journal-title":"Mol. Neurodegener."},{"key":"ref9014","doi-asserted-by":"crossref","first-page":"23S","DOI":"10.1177\/1535759719895279","article-title":"Epilepsy benchmarks area III: improved treatment options for controlling seizures and epilepsy-related conditions without side effects","volume":"20","author":"Traynelis","year":"2020","journal-title":"Epilepsy currents"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.mcn.2016.11.005","article-title":"Regulation of extrasynaptic signaling by polysialylated NCAM: impact for synaptic plasticity and cognitive functions","volume":"81","author":"Varbanov","year":"2017","journal-title":"Mol. Cell. Neurosci."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"106079","DOI":"10.1016\/j.nbd.2023.106079","article-title":"Rescue of synaptic and cognitive functions in polysialic acid-deficient mice and dementia models by short polysialic acid fragments","volume":"180","author":"Varbanov","year":"2023","journal-title":"Neurobiol. Dis."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1111\/jnc.14970","article-title":"Regulation of NMDA glutamate receptor functions by the GluN2 subunits","volume":"154","author":"Vieira","year":"2020","journal-title":"J. Neurochem."},{"key":"ref9015","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.3233\/JAD-160763","article-title":"Role of glutamate and NMDA receptors in Alzheimer\u2019s disease","volume":"57","author":"Wang","year":"2017","journal-title":"Journal of Alzheimer\u2019s Disease"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"1858","DOI":"10.1523\/JNEUROSCI.22-05-01858.2002","article-title":"The relationship between a\u03b2 and memory in the Tg2576 mouse model of Alzheimer's disease","volume":"22","author":"Westerman","year":"2002","journal-title":"J. Neurosci."},{"key":"ref69","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1016\/j.bbadis.2010.05.004","article-title":"Murine models of Alzheimer's disease and their use in developing immunotherapies","volume":"1802","author":"Wisniewski","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref70","doi-asserted-by":"publisher","first-page":"1644","DOI":"10.1152\/jn.2001.86.4.1644","article-title":"NR2B-containing NMDA autoreceptors at synapses on entorhinal cortical neurons","volume":"86","author":"Woodhall","year":"2001","journal-title":"J. Neurophysiol."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.neuron.2007.11.027","article-title":"Molecular dissociation of the role of PSD-95 in regulating synaptic strength and LTD","volume":"57","author":"Xu","year":"2008","journal-title":"Neuron"},{"key":"ref72","doi-asserted-by":"publisher","first-page":"660","DOI":"10.3389\/fnins.2020.00660","article-title":"GABAergic inhibitory interneuron deficits in Alzheimer's disease: implications for treatment","volume":"14","author":"Xu","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref73","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1038\/35037739","article-title":"Apoptosis in the nervous system","volume":"407","author":"Yuan","year":"2000","journal-title":"Nature"},{"key":"ref9016","doi-asserted-by":"publisher","first-page":"27016","DOI":"10.1074\/jbc.M604903200","article-title":"Roles for UDP-GlcNAc 2-epimerase\/ManNAc 6-kinase outside of sialic acid biosynthesis: modulation of sialyltransferase and BiP expression, GM3 and GD3 biosynthesis, proliferation, and apoptosis, and ERK1\/2 phosphorylation","volume":"281","author":"Zhiyun","year":"2006","journal-title":"J Biol Chem."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2025.1649625\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T12:55:27Z","timestamp":1756472127000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2025.1649625\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,29]]},"references-count":81,"alternative-id":["10.3389\/fnins.2025.1649625"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2025.1649625","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,29]]},"article-number":"1649625"}}