{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:57:36Z","timestamp":1791291456601,"version":"4.3.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"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. Behav. Neurosci."],"abstract":"<jats:p>The hippocampus is the brain structure responsible for spatial information processing, map formation, spatially guided behavior, and memory consolidation. Although these processes are often treated as overlapping or even unitary, emerging evidence suggests that they depend on partially dissociable mechanisms. All these processes depend on hippocampal plasticity; more specifically, on NMDA receptor (NMDAR) function and signaling. NMDARs are tetramers containing two obligatory GluN1 subunits and two regulatory subunits whose expression is tightly regulated. Among them, GluN2A, the regulatory subunit mainly expressed in mature structures, is considered a key determinant of synaptic plasticity. Constitutive GluN2A-knockout models have shown impairments in spatial tasks, contextual fear conditioning, and object location memory. However, these models are limited because compensatory mechanisms could be activated during development. To overcome this limitation, we developed an AAV-mediated shRNA knockdown of GluN2A (GluN2A-kd) targeted to the hippocampus in adult Wistar rats, avoiding developmental confounds and enabling the specific assessment of GluN2A function in mature neurons. Our results show that hippocampal GluN2A-kd in adult rats selectively alters spatial exploration and the ability to update spatially guided behavior across tasks, revealing a previously uncharacterized role for GluN2A in the organization of spatial performance rather than in general memory processes. Additionally, we identified a sex-dependent effect of reduced GluN2A expression, suggesting that GluN2A-kd females may exhibit impaired spatial learning or rely on alternative or less efficient spatial strategies to solve the tasks. Together, these findings position GluN2A as a key modulator of the precision and flexibility of spatial behavior required for successful performance in the adult hippocampus.<\/jats:p>","DOI":"10.3389\/fnbeh.2026.1935028","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:35:06Z","timestamp":1791290106000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Hippocampal GluN2A knockdown differentially alters spatial exploration and behavioral performance in male and female rats"],"prefix":"10.3389","volume":"20","author":[{"given":"Maria Florencia","family":"Acutain","sequence":"first","affiliation":[{"name":"Laboratorio de Sinapsis y Neurobiolog\u00eda Celular. Instituto de Biolog\u00eda Celular y Neurociencia (IBCN)-CONICET-UBA","place":["Ciudad de Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda Mariana","family":"Silva","sequence":"additional","affiliation":[{"name":"Laboratorio de Sinapsis y Neurobiolog\u00eda Celular. Instituto de Biolog\u00eda Celular y Neurociencia (IBCN)-CONICET-UBA","place":["Ciudad de Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisina","family":"Castellari","sequence":"additional","affiliation":[{"name":"Laboratorio de Sinapsis y Neurobiolog\u00eda Celular. Instituto de Biolog\u00eda Celular y Neurociencia (IBCN)-CONICET-UBA","place":["Ciudad de Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Ver\u00f3nica","family":"Baez","sequence":"additional","affiliation":[{"name":"Laboratorio de Sinapsis y Neurobiolog\u00eda Celular. Instituto de Biolog\u00eda Celular y Neurociencia (IBCN)-CONICET-UBA","place":["Ciudad de Buenos Aires, Argentina"]},{"name":"C\u00e1tedra de Biolog\u00eda Molecular y Gen\u00e9tica. Facultad de Medicina. UBA","place":["Ciudad de Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"4001","DOI":"10.1111\/jnc.16023","article-title":"Reduced expression of GluN2A induces a delay in neuron maturation","volume":"168","author":"Acutain","year":"2024","journal-title":"J. Neurochem."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"644100","DOI":"10.3389\/fnins.2021.644100","article-title":"Reduced expression of hippocampal GluN2A-NMDAR increases seizure susceptibility and causes deficits in contextual memory","volume":"15","author":"Acutain","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"e101090","DOI":"10.15252\/embj.2018101090","article-title":"Kinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice","volume":"39","author":"Alsabban","year":"2020","journal-title":"EMBO J."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"2039","DOI":"10.1093\/brain\/awaa147","article-title":"Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice","volume":"143","author":"Amador","year":"2020","journal-title":"Brain J. Neurol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1007\/s10339-011-0430-z","article-title":"The novel object recognition memory: neurobiology, test procedure, and its modifications","volume":"13","author":"Antunes","year":"2012","journal-title":"Cogn. Process."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2018\/5093048","article-title":"NMDA receptor subunits change after synaptic plasticity induction and learning and memory acquisition","volume":"2018","author":"Baez","year":"2018","journal-title":"Neural Plast."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"e55244","DOI":"10.1371\/journal.pone.0055244","article-title":"NMDA receptor subunits in the adult rat hippocampus undergo similar changes after 5 minutes in an open field and after LTP induction","volume":"8","author":"Baez","year":"2013","journal-title":"PLoS One"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1038\/nn.3166","article-title":"Dissecting spatial knowledge from spatial choice by hippocampal NMDA receptor deletion","volume":"15","author":"Bannerman","year":"2012","journal-title":"Nat. Neurosci."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"3623","DOI":"10.1523\/JNEUROSCI.3639-07.2008","article-title":"NMDA receptor subunit NR2A is required for rapidly acquired spatial working memory but not incremental spatial reference memory","volume":"28","author":"Bannerman","year":"2008","journal-title":"J. Neurosci."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"108805","DOI":"10.1016\/j.neuropharm.2021.108805","article-title":"Clinical and therapeutic significance of genetic variation in the GRIN gene family encoding NMDARs","volume":"199","author":"Benke","year":"2021","journal-title":"Neuropharmacology"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/s42003-020-01538-4","article-title":"Voltage-independent GluN2A-type NMDA receptor Ca2+ signaling promotes audiogenic seizures, attentional and cognitive deficits in mice","volume":"4","author":"Bertocchi","year":"2021","journal-title":"Commun. Biol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"242","DOI":"10.3389\/fnbeh.2016.00242","article-title":"GluN1 and GluN2A NMDA receptor subunits increase in the Hippocampus during memory consolidation in the rat","volume":"10","author":"Cercato","year":"2017","journal-title":"Front. Behav. Neurosci."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"e13437","DOI":"10.1111\/acel.13437","article-title":"Knockdown of astrocytic Grin2a aggravates \u03b2-amyloid-induced memory and cognitive deficits through regulating nerve growth factor","volume":"20","author":"Du","year":"2021","journal-title":"Aging Cell"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1111\/j.1582-4934.2004.tb00478.x","article-title":"Effects of estrogen and progesterone treatment on rat hippocampal NMDA receptors: relationship to Morris water maze performance","volume":"8","author":"El-Bakri","year":"2004","journal-title":"J. Cell. Mol. Med."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"3378","DOI":"10.1016\/j.neuron.2023.08.004","article-title":"Brain-region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice","volume":"111","author":"Farsi","year":"2023","journal-title":"Neuron"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1538","DOI":"10.3390\/ijms21041538","article-title":"Synaptic gluN2A-containing NMDA receptors: from physiology to pathological synaptic plasticity","volume":"21","author":"Franchini","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1016\/j.isci.2019.08.036","article-title":"Linking NMDA receptor synaptic retention to synaptic plasticity and cognition","volume":"19","author":"Franchini","year":"2019","journal-title":"iScience"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/s41380-021-01196-w","article-title":"Aberrant maturation and connectivity of prefrontal cortex in schizophrenia-contribution of NMDA receptor development and hypofunction","volume":"27","author":"Gao","year":"2022","journal-title":"Mol. Psychiatry"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00210-018-1589-y","article-title":"Assessment of spatial learning and memory in the Barnes maze task in rodents\u2014methodological consideration","volume":"392","author":"Gawel","year":"2019","journal-title":"Naunyn Schmiedeberg's Arch. Pharmacol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1016\/j.neuron.2011.08.007","article-title":"Distinct modes of AMPA receptor suppression at developing synapses by GluN2A and GluN2B: single-cell NMDA receptor subunit deletion in vivo","volume":"71","author":"Gray","year":"2011","journal-title":"Neuron"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.bbr.2008.10.015","article-title":"Endogenous anxiety and stress responses in water maze and Barnes maze spatial memory tasks","volume":"198","author":"Harrison","year":"2009","journal-title":"Behav. Brain Res."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41398-023-02393-7","article-title":"Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients","volume":"13","author":"Herzog","year":"2023","journal-title":"Transl. Psychiatry"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"100500","DOI":"10.1016\/j.bpsgos.2025.100500","article-title":"Grin2a hypofunction impairs spatial working memory and disrupts hippocampal network oscillations and excitatory-inhibitory balance","volume":"5","author":"Hosseini","year":"2025","journal-title":"Biol. Psychiatry Glob. Open Sci."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1111\/nyas.12547","article-title":"The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies","volume":"1338","author":"Hu","year":"2015","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"6704","DOI":"10.1523\/jneurosci.18-17-06704.1998","article-title":"Increased thresholds for long-term potentiation and contextual learning in mice lacking the NMDA-type glutamate receptor \u03b51 subunit","volume":"18","author":"Kiyama","year":"1998","journal-title":"J. Neurosci."},{"key":"ref26","volume-title":"AVMA Guidelines for the Euthanasia of Animals: 2020 edition","author":"Leary","year":"2020"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.nlm.2015.07.002","article-title":"The effects of acute social isolation on long-term social recognition memory","volume":"124","author":"Leser","year":"2015","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1038\/s41583-023-00742-5","article-title":"Excitation-transcription coupling, neuronal gene expression and synaptic plasticity","volume":"24","author":"Ma","year":"2023","journal-title":"Nat. Rev. Neurosci."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.cortex.2024.04.002","article-title":"Memory consolidation affects the interplay of place and response navigation","volume":"175","author":"Maier","year":"2024","journal-title":"Cortex"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1038\/297681a0","article-title":"Place navigation impaired in rats with hippocampal lesions","volume":"297","author":"Morris","year":"1982","journal-title":"Nature"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1101\/lm.41302","article-title":"Hippocampal damage and exploratory preferences in rats: memory for objects, places, and contexts","volume":"9","author":"Mumby","year":"2002","journal-title":"Learn. Mem."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"107426","DOI":"10.1016\/J.PHARMTHERA.2019.107426","article-title":"The origin of NMDA receptor hypofunction in schizophrenia","volume":"205","author":"Nakazawa","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"e41","DOI":"10.1371\/journal.pbio.1000041","article-title":"Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning","volume":"7","author":"Ng","year":"2009","journal-title":"PLoS Biol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1016\/j.bbr.2010.08.030","article-title":"Learning, memory and search strategies of inbred mouse strains with different visual abilities in the Barnes maze","volume":"216","author":"O\u2019Leary","year":"2011","journal-title":"Behav. Brain Res."},{"key":"ref35","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":"ref9001","volume-title":"The Rat Brain in Stereotaxic Coordinates","author":"Paxinos","year":"2007"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"e3000411","DOI":"10.1371\/journal.pbio.3000411","article-title":"Reporting animal research: explanation and elaboration for the ARRIVE guidelines 2.0","volume":"18","author":"Percie du Sert","year":"2020","journal-title":"PLoS Biol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1101\/lm.025254.111","article-title":"NMDA signaling in CA1 mediates selectively the spatial component of episodic memory","volume":"19","author":"Place","year":"2012","journal-title":"Learn. Mem. (Cold Spring Harb. N.Y.)"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1196\/annals.1401.013","article-title":"The contribution of the medial prefrontal cortex, orbitofrontal cortex, and dorsomedial striatum to behavioral flexibility","volume":"1121","author":"Ragozzino","year":"2007","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1038\/nature13725","article-title":"Bidirectional switch of the valence associated with a hippocampal contextual memory engram","volume":"513","author":"Redondo","year":"2014","journal-title":"Nature"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1111\/2041-210X.12874","article-title":"ToxTrac: a fast and robust software for tracking organisms","volume":"9","author":"Rodriguez","year":"2018","journal-title":"Methods Ecol. Evol."},{"key":"ref41","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":"ref42","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.3390\/cells12091212","article-title":"Cognitive flexibility in mice: effects of puberty and role of NMDA receptor subunits","volume":"12","author":"Seifried","year":"2023","journal-title":"Cells"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"20130163","DOI":"10.1098\/rstb.2013.0163","article-title":"GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity","volume":"369","author":"Shipton","year":"2014","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/nrn.2015.18","article-title":"The right time to learn: mechanisms and optimization of spaced learning","volume":"17","author":"Smolen","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"19537","DOI":"10.1073\/pnas.1008638107","article-title":"Relevance of synaptic tagging and capture to the persistence of long-term potentiation and everyday spatial memory","volume":"107","author":"Wang","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref46","volume-title":"Curr. Protoc. Neurosci.","author":"Yang","year":"2011"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"9938","DOI":"10.1073\/pnas.1301691110","article-title":"Prefrontal microcircuit underlies contextual learning after hippocampal loss","volume":"110","author":"Zelikowsky","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"1604378","DOI":"10.3389\/fnagi.2025.1604378","article-title":"NMDA receptors in neurodegenerative diseases: mechanisms and emerging therapeutic strategies","volume":"17","author":"Zhang","year":"2025","journal-title":"Front. Aging Neurosci."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"5599","DOI":"10.3390\/ijms20225599","article-title":"The role of the N-methyl-D-aspartate receptors in social behavior in rodents","volume":"20","author":"Zoicas","year":"2019","journal-title":"Int. J. Mol. Sci."}],"container-title":["Frontiers in Behavioral Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnbeh.2026.1935028\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:35:08Z","timestamp":1791290108000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnbeh.2026.1935028\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,6]]},"references-count":50,"alternative-id":["10.3389\/fnbeh.2026.1935028"],"URL":"https:\/\/doi.org\/10.3389\/fnbeh.2026.1935028","relation":{},"ISSN":["1662-5153"],"issn-type":[{"value":"1662-5153","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,6]]},"article-number":"1935028"}}