{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T07:48:38Z","timestamp":1791964118897,"version":"4.3.4"},"reference-count":57,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    D\u2010Aspartate (D\u2010Asp) is an endogenous NMDA receptor agonist that exhibits a pronounced developmental peak in the mammalian brain, suggesting a regulatory role in glutamatergic signaling and neurodevelopment. Disruption of D\u2010Asp homeostasis has been associated with neuropsychiatric disorders characterized by early\u2010life circuit vulnerability, including schizophrenia and autism spectrum disorders. However, its impact on hippocampal physiology remains incompletely defined. Here, we investigated how constitutive D\u2010Asp depletion affects synaptic function in the hippocampal CA1 region of\n                    <jats:italic>Ddo<\/jats:italic>\n                    \u2010knock\u2010in (\n                    <jats:italic>Ddo<\/jats:italic>\n                    \u2010KI) mice, in which zygotic overexpression of the D\u2010Asp\u2010degrading enzyme, D\u2010aspartate oxidase (DDO or DASPO), results in embryonic and persistent D\u2010Asp deficiency. Electrophysiological recordings were performed in acute hippocampal slices from male and female mice at postnatal Day 30 (P30) and Day 60 (P60). Analysis of basal synaptic transmission, assessed through paired\u2010pulse ratio and spontaneous excitatory\/inhibitory events, revealed no significant genotype\u2010dependent differences. In contrast, NMDA receptor (NMDAR)\u2010dependent synaptic plasticity was selectively altered, as theta\u2010burst stimulation induced significantly greater long\u2010term potentiation (LTP) in juvenile P30\n                    <jats:italic>Ddo<\/jats:italic>\n                    \u2010KI mice. This paradoxical enhancement was no longer observed at P60, indicating that the phenotype is developmentally restricted. Patch\u2010clamp recordings further revealed a reduced AMPAR\/NMDAR ratio in P30\n                    <jats:italic>Ddo<\/jats:italic>\n                    \u2010KI males, suggesting an altered balance between AMPAR\u2010 and NMDAR\u2010mediated synaptic currents. Importantly, acute bath application of exogenous D\u2010Asp rapidly restored LTP to wild\u2010type levels, indicating that the electrophysiological phenotype is acutely reversible and sensitive to D\u2010Asp availability. Biochemical analyzes confirmed increased DASPO activity and reduced D\u2010Asp levels in\n                    <jats:italic>Ddo<\/jats:italic>\n                    \u2010KI mice at both ages examined, indicating that the age\u2010dependent plasticity phenotype is unlikely to result from age\u2010dependent changes in D\u2010Asp catabolism. Overall, these findings demonstrate that early developmental D\u2010Asp deficiency induces a paradoxical, juvenile\u2010specific enhancement of hippocampal NMDAR\u2010dependent synaptic plasticity, highlighting the importance of D\u2010Asp homeostasis during brain development.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70566-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70566","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T07:30:33Z","timestamp":1791963033000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Embryonic Depletion of D\u2010Aspartate Perturbs\n                    <scp>NMDA<\/scp>\n                    Receptor\u2010Dependent Long\u2010Term Potentiation in the Hippocampus of Juvenile Mice"],"prefix":"10.1111","volume":"170","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3358-4068","authenticated-orcid":false,"given":"Dalila","family":"Mango","sequence":"first","affiliation":[{"name":"Department of Biology, School of Pharmacy University of Rome \u2018Tor Vergata\u2019  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3636-7395","authenticated-orcid":false,"given":"Francesco","family":"Errico","sequence":"additional","affiliation":[{"name":"CEINGE Biotecnologie Avanzate \u201cFranco Salvatore\u201d  Naples Italy"},{"name":"Department of Agricultural Sciences University of Naples \u201cFederico II\u201d  Portici Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2254-153X","authenticated-orcid":false,"given":"Zoraide","family":"Motta","sequence":"additional","affiliation":[{"name":"\u201cThe Protein Factory 2.0\u201d, Dipartimento di Biotecnologie e Scienze Della Vita Universit\u00e0 Degli Studi Dell'insubria  Varese Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sepideh","family":"Dashtiani","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Pharmacy University of Rome \u2018Tor Vergata\u2019  Rome Italy"},{"name":"Department of Physiology and Pharmacology \u201cV. Erspamer\u201d Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Di Maio","sequence":"additional","affiliation":[{"name":"CEINGE Biotecnologie Avanzate \u201cFranco Salvatore\u201d  Naples Italy"},{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies Universit\u00e0 Degli Studi Della Campania \u201cLuigi Vanvitelli\u201d  Caserta Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Nistic\u00f2","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Pharmacy University of Rome \u2018Tor Vergata\u2019  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5730-2996","authenticated-orcid":false,"given":"Maria Egle","family":"De Stefano","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnologies \u201cCharles Darwin\u201d Sapienza University of Rome  Rome Italy"},{"name":"Center for Research in Neurobiology \u201cDaniel Bovet\u201d Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1733-7243","authenticated-orcid":false,"given":"Loredano","family":"Pollegioni","sequence":"additional","affiliation":[{"name":"\u201cThe Protein Factory 2.0\u201d, Dipartimento di Biotecnologie e Scienze Della Vita Universit\u00e0 Degli Studi Dell'insubria  Varese Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Usiello","sequence":"additional","affiliation":[{"name":"CEINGE Biotecnologie Avanzate \u201cFranco Salvatore\u201d  Naples Italy"},{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies Universit\u00e0 Degli Studi Della Campania \u201cLuigi Vanvitelli\u201d  Caserta Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,14]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1111\/j.1476-5381.2009.00352.x","article-title":"Agonist Efficacy and Receptor Desensitization: From Partial Truths to a Fuller Picture","volume":"158","author":"Charlton S. J.","year":"2009","journal-title":"British Journal of Pharmacology"},{"key":"e_1_2_11_3_1","doi-asserted-by":"crossref","DOI":"10.3389\/fpsyt.2024.1362288","article-title":"Neuroplasticity of Children in Autism Spectrum Disorder","volume":"15","author":"Chen Z.","year":"2024","journal-title":"Frontiers in Psychiatry"},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.neuroscience.2024.11.069","article-title":"Long\u2010Term Potentiation in the Hippocampus: From Magnesium to Memory","volume":"578","author":"Collingridge G. L.","year":"2025","journal-title":"Neuroscience"},{"key":"e_1_2_11_5_1","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1016\/j.neurobiolaging.2015.02.003","article-title":"D\u2010Aspartate Oxidase Influences Glutamatergic System Homeostasis in Mammalian Brain","volume":"36","author":"Cristino L.","year":"2015","journal-title":"Neurobiology of Aging"},{"key":"e_1_2_11_6_1","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.brainresrev.2006.08.005","article-title":"D\u2010Aspartic Acid: An Endogenous Amino Acid With an Important Neuroendocrine Role","volume":"53","author":"D'Aniello A.","year":"2007","journal-title":"Brain Research Reviews"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18050941"},{"key":"e_1_2_11_8_1","doi-asserted-by":"crossref","first-page":"328","DOI":"10.3390\/biom12020328","article-title":"Abnormal RasGRP1 Expression in Post\u2010Mortem Brain and Blood Serum of Schizophrenia Patients","volume":"12","author":"De Rosa A.","year":"2022","journal-title":"Biomolecules"},{"key":"e_1_2_11_9_1","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1007\/s00726-020-02839-y","article-title":"Prenatal Expression of D\u2010Aspartate Oxidase Causes Early Cerebral D\u2010Aspartate Depletion and Influences Brain Morphology and Cognitive Functions in Adulthood","volume":"52","author":"De Rosa A.","year":"2020","journal-title":"Amino Acids"},{"key":"e_1_2_11_10_1","doi-asserted-by":"crossref","DOI":"10.1111\/jnc.70095","article-title":"Prenatal Exposure to Lipopolysaccharide or Valproate Leads to Abnormal Accumulation of the NMDA Receptor Agonist D\u2010Aspartate in Adolescent Rat Brain","volume":"169","author":"Di Maio A.","year":"2025","journal-title":"Journal of Neurochemistry"},{"key":"e_1_2_11_11_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0006-291X(86)80329-1","article-title":"Presence of Free D\u2010Aspartic Acid in Rodents and Man","volume":"141","author":"Dunlop D. S.","year":"1986","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2020.140471"},{"key":"e_1_2_11_13_1","doi-asserted-by":"crossref","DOI":"10.1038\/tp.2015.2","article-title":"A Role for D\u2010Aspartate Oxidase in Schizophrenia and Schizophrenia\u2010Related Symptoms Induced by Phencyclidine in Mice","volume":"5","author":"Errico F.","year":"2015","journal-title":"Translational Psychiatry"},{"key":"e_1_2_11_14_1","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1016\/j.jpsychires.2013.06.013","article-title":"Decreased Levels of D\u2010Aspartate and NMDA in Prefrontal Cortex and Striatum of Patients With Schizophrenia","volume":"40","author":"Errico F.","year":"2013","journal-title":"Journal of Psychiatric Research"},{"key":"e_1_2_11_15_1","doi-asserted-by":"crossref","DOI":"10.1038\/tp.2014.59","article-title":"Free D\u2010Aspartate Regulates Dendritic Morphology, Synaptic Plasticity, Gray Matter Volume and Brain Activity in Mammals","volume":"4","author":"Errico F.","year":"2014","journal-title":"Translational Psychiatry"},{"key":"e_1_2_11_16_1","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.1016\/j.neurobiolaging.2009.12.007","article-title":"Persistent Increase of D\u2010Aspartate in D\u2010Aspartate Oxidase Mutant Mice Induces Precocious Hippocampal Age\u2010Dependent Synaptic Plasticity and Spatial Memory Decay","volume":"32","author":"Errico F.","year":"2011","journal-title":"Neurobiology of Aging"},{"key":"e_1_2_11_17_1","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.1016\/j.neurobiolaging.2010.01.002","article-title":"Increased D\u2010Aspartate Brain Content Rescues Hippocampal Age\u2010Related Synaptic Plasticity Deterioration in Mice","volume":"32","author":"Errico F.","year":"2011","journal-title":"Neurobiology of Aging"},{"key":"e_1_2_11_18_1","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.mcn.2007.09.012","article-title":"Increased Levels of D\u2010Aspartate in the Hippocampus Enhance LTP but Do Not Facilitate Cognitive Flexibility","volume":"37","author":"Errico F.","year":"2008","journal-title":"Molecular and Cellular Neuroscience"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2018.00559"},{"key":"e_1_2_11_20_1","doi-asserted-by":"crossref","first-page":"10404","DOI":"10.1523\/JNEUROSCI.1618-08.2008","article-title":"D\u2010Aspartate Prevents Corticostriatal Long\u2010Term Depression and Attenuates Schizophrenia\u2010Like Symptoms Induced by Amphetamine and MK\u2010801","volume":"28","author":"Errico F.","year":"2008","journal-title":"Journal of Neuroscience"},{"key":"e_1_2_11_21_1","doi-asserted-by":"crossref","DOI":"10.1007\/s00018-025-05938-9","article-title":"Free D\u2010Aspartate Modulates the Expression of Proteins Linked to Schizophrenia and Autism Spectrum Disorder During Early Postnatal Life","volume":"83","author":"Errico F.","year":"2025","journal-title":"Cellular and Molecular Life Sciences"},{"key":"e_1_2_11_22_1","doi-asserted-by":"crossref","DOI":"10.3389\/fpsyt.2024.1408175","article-title":"Decreased Free D\u2010Aspartate Levels in Blood Serum of Schizophrenia Patients","volume":"15","author":"Garofalo M.","year":"2024","journal-title":"Frontiers in Psychiatry"},{"key":"e_1_2_11_23_1","doi-asserted-by":"crossref","DOI":"10.3389\/fnmol.2023.1190324","article-title":"GluN2B\u2010Containing NMDARs in the Mammalian Brain: Pharmacology, Physiology, and Pathology","volume":"16","author":"Ge Y.","year":"2023","journal-title":"Frontiers in Molecular Neuroscience"},{"key":"e_1_2_11_24_1","first-page":"147","article-title":"Sex Differences in the Glutamate System: Implications for Addiction","volume":"115","author":"Giacometti L. L.","year":"2020","journal-title":"Neuroscience & Biobehavioral Reviews"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.0c00622"},{"key":"e_1_2_11_26_1","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1111\/j.1471-4159.1993.tb03575.x","article-title":"Embryonic Development and Postnatal Changes in Free D\u2010Aspartate and D\u2010Serine in Human Prefrontal Cortex","volume":"61","author":"Hashimoto A.","year":"1993","journal-title":"Journal of Neurochemistry"},{"key":"e_1_2_11_27_1","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1111\/j.1460-9568.1995.tb00687.x","article-title":"Anatomical Distribution and Postnatal Changes of Endogenous Free D\u2010Aspartate and D\u2010Serine in Rat Brain and Periphery","volume":"7","author":"Hashimoto A.","year":"1995","journal-title":"European Journal of Neuroscience"},{"key":"e_1_2_11_28_1","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1002\/cbdv.200900250","article-title":"D\u2010Aspartate Oxidase: The Sole Catabolic Enzyme Acting on Free D\u2010Aspartate in Mammals","volume":"7","author":"Katane M.","year":"2010","journal-title":"Chemistry & Biodiversity"},{"key":"e_1_2_11_29_1","doi-asserted-by":"crossref","DOI":"10.3389\/fnbeh.2024.1455478","article-title":"Sex Differences in Glutamate Transmission and Plasticity in Reward\u2010Related Regions","volume":"18","author":"Kniffin A. R.","year":"2024","journal-title":"Frontiers in Behavioral Neuroscience"},{"key":"e_1_2_11_30_1","doi-asserted-by":"crossref","DOI":"10.1186\/s13293-022-00468-6","article-title":"Sex Differences in Medial Prefrontal Cortical Glutamate System","volume":"13","author":"Knouse M. C.","year":"2022","journal-title":"Biology of Sex Differences"},{"key":"e_1_2_11_31_1","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.neuropharm.2015.12.013","article-title":"Persistent Elevation of D\u2010Aspartate Enhances NMDA Receptor\u2010Mediated Responses in Substantia Nigra Dopamine Neurons","volume":"103","author":"Krashia P.","year":"2016","journal-title":"Neuropharmacology"},{"issue":"11","key":"e_1_2_11_32_1","first-page":"469","article-title":"Sex Differences in the Effects of Cortical NMDA Receptor Antagonism on Prefrontal Cortical Dopamine Neurotransmission in Adult Rats","volume":"70","author":"Locklear M. N.","year":"2016","journal-title":"Synapse"},{"key":"e_1_2_11_33_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41398-022-02088-5","article-title":"D\u2010Aspartate Oxidase Gene Duplication Induces Social Recognition Memory Deficits in Mice and Intellectual Disability in Humans","volume":"12","author":"Lombardo B.","year":"2022","journal-title":"Translational Psychiatry"},{"key":"e_1_2_11_34_1","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.neuropharm.2013.08.010","article-title":"Phosphodiesterase 10A Controls D1\u2010Mediated Facilitation of GABA Release in Striato\u2010Nigral Projections","volume":"76","author":"Mango D.","year":"2014","journal-title":"Neuropharmacology"},{"key":"e_1_2_11_35_1","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.phrs.2017.01.028","article-title":"Acid\u2010Sensing Ion Channel 1a Is Required for mGlu Receptor\u2010Dependent Long\u2010Term Depression in Hippocampus","volume":"119","author":"Mango D.","year":"2017","journal-title":"Pharmacological Research"},{"key":"e_1_2_11_36_1","doi-asserted-by":"crossref","DOI":"10.1111\/jnc.70223","article-title":"Central Neurophysiological Alterations in mdx Mice Correlate With Reduced Hippocampal D\u2010Aspartate","volume":"169","author":"Mastrostefano F.","year":"2025","journal-title":"Journal of Neurochemistry"},{"key":"e_1_2_11_37_1","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.neulet.2010.04.077","article-title":"D\u2010Aspartate Activates mGlu Receptors Coupled to Polyphosphoinositide Hydrolysis in Neonatal Rat Brain Slices","volume":"478","author":"Molinaro G.","year":"2010","journal-title":"Neuroscience Letters"},{"key":"e_1_2_11_38_1","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1096\/fj.201901703R","article-title":"Structure and Kinetic Properties of Human D\u2010Aspartate Oxidase","volume":"34","author":"Molla G.","year":"2020","journal-title":"FASEB Journal"},{"key":"e_1_2_11_39_1","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1021\/acschemneuro.5b00096","article-title":"Gender Differences in Hippocampal LTP and Spatial Learning in Rats","volume":"6","author":"Monfort P.","year":"2015","journal-title":"ACS Chemical Neuroscience"},{"key":"e_1_2_11_40_1","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1016\/0024-3205(90)90424-P","article-title":"Developmental Changes in Free D\u2010Aspartic Acid in Chicken Embryo and Neonatal Rat","volume":"46","author":"Neidle A.","year":"1990","journal-title":"Life Sciences"},{"key":"e_1_2_11_41_1","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/j.neuron.2015.07.033","article-title":"Excitation\/Inhibition Balance in Autism Spectrum Disorders","volume":"87","author":"Nelson S. 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