{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T06:46:12Z","timestamp":1784616372016,"version":"3.55.0"},"reference-count":106,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T00:00:00Z","timestamp":1635379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIH\/NIA R15AG045812"],"award-info":[{"award-number":["NIH\/NIA R15AG045812"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The greatest risk factor for developing Alzheimer\u2019s disease (AD) is increasing age. Understanding the changes that occur in aging that make an aged brain more susceptible to developing AD could result in novel therapeutic targets. In order to better understand these changes, the current study utilized mice harboring a regulatable mutant P301L human tau transgene (rTg(TauP301L)4510), in which P301L tau expression can be turned off or on by the addition or removal of doxycycline in the drinking water. This regulatable expression allowed for assessment of aging independent of prolonged mutant tau expression. Our results suggest that P301L expression in aged mice enhances memory deficits in the Morris water maze task. These behavioral changes may be due to enhanced late-stage tau pathology, as evidenced by immunoblotting and exacerbated hippocampal dysregulation of glutamate release and uptake measured by the microelectrode array technique. We additionally observed changes in proteins important for the regulation of glutamate and tau phosphorylation that may mediate these age-related changes. Thus, age and P301L tau interact to exacerbate tau-induced detrimental alterations in aged animals.<\/jats:p>","DOI":"10.3390\/ijms222111637","type":"journal-article","created":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T23:51:36Z","timestamp":1635465096000},"page":"11637","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Differential Effects of Human P301L Tau Expression in Young versus Aged Mice"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4797-9311","authenticated-orcid":false,"given":"Holly C.","family":"Hunsberger","sequence":"first","affiliation":[{"name":"Division of Systems Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH)\/New York State Psychiatric Institute (NYSPI), New York, NY 10032, USA"},{"name":"Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), NYSPI Kolb Research Annex, Room 736, 1051 Riverside Drive, Unit 87, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharay E.","family":"Setti","sequence":"additional","affiliation":[{"name":"Drug Discovery and Development, School of Pharmacy, Auburn University, Auburn, AL 36849, USA"},{"name":"Center for Neuroscience Initiative, Auburn University, Auburn, AL 36849, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn C.","family":"Rudy","sequence":"additional","affiliation":[{"name":"Department of Psychology, West Virginia University, Morgantown, WV 26506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel S.","family":"Weitzner","sequence":"additional","affiliation":[{"name":"Department of Psychology, West Virginia University, Morgantown, WV 26506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremiah C.","family":"Pfitzer","sequence":"additional","affiliation":[{"name":"Drug Discovery and Development, School of Pharmacy, Auburn University, Auburn, AL 36849, USA"},{"name":"Center for Neuroscience Initiative, Auburn University, Auburn, AL 36849, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelli L.","family":"McDonald","sequence":"additional","affiliation":[{"name":"Drug Discovery and Development, School of Pharmacy, Auburn University, Auburn, AL 36849, USA"},{"name":"Center for Neuroscience Initiative, Auburn University, Auburn, AL 36849, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhrajit","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"Drug Discovery and Development, School of Pharmacy, Auburn University, Auburn, AL 36849, USA"},{"name":"Center for Neuroscience Initiative, Auburn University, Auburn, AL 36849, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishnu","family":"Suppiramaniam","sequence":"additional","affiliation":[{"name":"Drug Discovery and Development, School of Pharmacy, Auburn University, Auburn, AL 36849, USA"},{"name":"Center for Neuroscience Initiative, Auburn University, Auburn, AL 36849, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8465-5594","authenticated-orcid":false,"given":"Miranda N.","family":"Reed","sequence":"additional","affiliation":[{"name":"Drug Discovery and Development, School of Pharmacy, Auburn University, Auburn, AL 36849, USA"},{"name":"Center for Neuroscience Initiative, Auburn University, Auburn, AL 36849, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s12264-009-0608-x","article-title":"NMDA receptor antagonist MK-801 reduces neuronal damage and preserves learning and memory in a rat model of traumatic brain injury","volume":"25","author":"Han","year":"2009","journal-title":"Neurosci. Bull."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1515\/rns.2011.018","article-title":"The role of CREB signaling in Alzheimer\u2019s disease and other cognitive disorders","volume":"22","author":"Saura","year":"2011","journal-title":"Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S0197-0186(00)00023-1","article-title":"Methylmercury alters glutamate transport in astrocytes","volume":"37","author":"Aschner","year":"2000","journal-title":"Neurochem. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1089\/neu.2011.2261","article-title":"Disruptions in the regulation of extracellular glutamate by neurons and glia in the rat striatum two days after diffuse brain injury","volume":"29","author":"Hinzman","year":"2012","journal-title":"J. Neurotrauma"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3408","DOI":"10.1038\/emboj.2010.211","article-title":"Neurotoxicity of Alzheimer\u2019s disease A\u03b2 peptides is induced by small changes in the A\u03b242 to A\u03b240 ratio","volume":"29","author":"Kuperstein","year":"2010","journal-title":"EMBO J."},{"key":"ref_6","doi-asserted-by":"crossref","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":"ref_7","doi-asserted-by":"crossref","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":"2007","journal-title":"J. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1113\/jphysiol.2006.123570","article-title":"Tonic activation of NMDA receptors by ambient glutamate of non-synaptic origin in the rat hippocampus","volume":"580","author":"Meur","year":"2007","journal-title":"J. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1007\/s11011-015-9783-9","article-title":"Riluzole rescues alterations in rapid glutamate transients in the hippocampus of rTg4510 mice","volume":"31","author":"Hunsberger","year":"2016","journal-title":"Metab. Brain Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1111\/jnc.12967","article-title":"P301L tau expression affects glutamate release and clearance in the hippocampal trisynaptic pathway","volume":"132","author":"Hunsberger","year":"2015","journal-title":"J. Neurochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1111\/jnc.13230","article-title":"Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression","volume":"135","author":"Hunsberger","year":"2015","journal-title":"J. Neurochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1097\/00005072-197503000-00005","article-title":"Cysteine-S-sulfate: Brain damaging metabolite in sulfite oxidase deficiency","volume":"34","author":"Olney","year":"1975","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nrn2911","article-title":"Synaptic versus extrasynaptic NMDA receptor signalling: Implications for neurodegenerative disorders","volume":"11","author":"Hardingham","year":"2010","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0301-0082(00)00067-8","article-title":"Glutamate uptake","volume":"65","author":"Danbolt","year":"2001","journal-title":"Prog. Neurobiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1093\/brain\/awl089","article-title":"Familial risk for Alzheimer\u2019s disease alters fMRI activation patterns","volume":"129","author":"Bassett","year":"2006","journal-title":"Brain"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1212\/01.WNL.0000150885.00929.7E","article-title":"fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease","volume":"64","author":"Bondi","year":"2005","journal-title":"Neurology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1056\/NEJM200008173430701","article-title":"Patterns of brain activation in people at risk for Alzheimer\u2019s disease","volume":"343","author":"Bookheimer","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1016\/j.cortex.2012.09.008","article-title":"Abnormal network connectivity in frontotemporal dementia: Evidence for prefrontal isolation","volume":"49","author":"Farb","year":"2013","journal-title":"Cortex"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7209","DOI":"10.1073\/pnas.0811879106","article-title":"Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele","volume":"106","author":"Filippini","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1002\/ana.22105","article-title":"Hippocampal hyperactivation in presymptomatic familial Alzheimer\u2019s disease","volume":"68","author":"Quiroz","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.neuron.2009.07.003","article-title":"Amyloid deposition is associated with impaired default network function in older persons without dementia","volume":"63","author":"Sperling","year":"2009","journal-title":"Neuron"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1212\/WNL.0b013e31822c61f2","article-title":"Altered functional connectivity in asymptomatic MAPT subjects A comparison to bvFTD","volume":"77","author":"Whitwell","year":"2011","journal-title":"Neurology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12887","DOI":"10.1523\/JNEUROSCI.2107-13.2013","article-title":"Antisense reduction of tau in adult mice protects against seizures","volume":"33","author":"DeVos","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1523\/JNEUROSCI.3191-12.2013","article-title":"Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy","volume":"33","author":"Holth","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.cell.2010.06.036","article-title":"Dendritic function of tau mediates amyloid-\u03b2 toxicity in Alzheimer\u2019s disease mouse models","volume":"142","author":"Ittner","year":"2010","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1523\/JNEUROSCI.4152-10.2011","article-title":"Amyloid-{beta}\/fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer\u2019s disease","volume":"31","author":"Roberson","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1126\/science.1141736","article-title":"Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer\u2019s disease mouse model","volume":"316","author":"Roberson","year":"2007","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0197-4580(90)90049-6","article-title":"Age-related alteration in excitatory amino acid neurotransmission in rat brain","volume":"11","author":"Najlerahim","year":"1990","journal-title":"Neurobiol. Aging"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/0531-5565(86)90069-0","article-title":"Time course of the aging of the high affinity L-glutamate transporter in rat cortical synaptosomes","volume":"21","author":"Wheeler","year":"1986","journal-title":"Exp. Gerontol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1016\/j.neurobiolaging.2006.07.015","article-title":"Reduced plasma membrane surface expression of GLAST mediates decreased glutamate regulation in the aged striatum","volume":"28","author":"Nickell","year":"2007","journal-title":"Neurobiol. Aging"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"13206","DOI":"10.1523\/JNEUROSCI.0193-15.2015","article-title":"Aging-Related Hyperexcitability in CA3 Pyramidal Neurons Is Mediated by Enhanced A-Type K+ Channel Function and Expression","volume":"35","author":"Simkin","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6877","DOI":"10.1523\/JNEUROSCI.1744-05.2005","article-title":"Age-associated alterations of hippocampal place cells are subregion specific","volume":"25","author":"Wilson","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1002\/hipo.20808","article-title":"Pattern separation deficits associated with increased hippocampal CA3 and dentate gyrus activity in nondemented older adults","volume":"21","author":"Yassa","year":"2011","journal-title":"Hippocampus"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1007\/s11064-018-2677-6","article-title":"Susceptibility to A\u03b2o and TBOA of LTD and Extrasynaptic NMDAR-Dependent Tonic Current in the Aged Rat Hippocampus","volume":"44","author":"Dutar","year":"2019","journal-title":"Neurochem. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1111\/j.1474-9726.2010.00593.x","article-title":"Reduction in glutamate uptake is associated with extrasynaptic NMDA and metabotropic glutamate receptor activation at the hippocampal CA1 synapse of aged rats","volume":"9","author":"Potier","year":"2010","journal-title":"Aging Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1111\/j.1460-9568.2008.06498.x","article-title":"Memantine protects rat cortical cultured neurons against beta-amyloid-induced toxicity by attenuating tau phosphorylation","volume":"28","author":"Song","year":"2008","journal-title":"Eur. J. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2892","DOI":"10.1073\/pnas.0511065103","article-title":"NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK\/MAPK activation","volume":"103","author":"Amadoro","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3992","DOI":"10.1523\/JNEUROSCI.4129-11.2012","article-title":"Opposing roles of synaptic and extrasynaptic NMDA receptor signaling in cocultured striatal and cortical neurons","volume":"32","author":"Kaufman","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e608","DOI":"10.1038\/cddis.2013.129","article-title":"NMDA receptor subunit composition determines beta-amyloid-induced neurodegeneration and synaptic loss","volume":"4","author":"Tackenberg","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/j.neuron.2010.11.030","article-title":"Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration","volume":"68","author":"Hoover","year":"2010","journal-title":"Neuron"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"10637","DOI":"10.1523\/JNEUROSCI.3279-05.2005","article-title":"Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L)","volume":"25","author":"Ramsden","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1126\/science.1113694","article-title":"Tau suppression in a neurodegenerative mouse model improves memory function","volume":"309","author":"Santacruz","year":"2005","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"762","DOI":"10.2353\/ajpath.2008.080175","article-title":"Amyloid plaque and neurofibrillary tangle pathology in a regulatable mouse model of Alzheimer\u2019s disease","volume":"173","author":"Paulson","year":"2008","journal-title":"Am. J. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.bbr.2014.06.057","article-title":"Effect size of memory deficits in mice with adult-onset P301L tau expression","volume":"272","author":"Hunsberger","year":"2014","journal-title":"Behav. Brain Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1002\/jgm.1178","article-title":"Enhancement of cell-specific transgene expression from a Tet-Off regulatory system using a transcriptional amplification strategy in the rat brain","volume":"10","author":"Liu","year":"2008","journal-title":"J. Gene Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1038\/nprot.2006.116","article-title":"Morris water maze: Procedures for assessing spatial and related forms of learning and memory","volume":"1","author":"Vorhees","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/0006-8993(92)91352-F","article-title":"A two-trial memory task with automated recording: Study in young and aged rats","volume":"588","author":"Dellu","year":"1992","journal-title":"Brain Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1021\/ac0010429","article-title":"Self-referencing ceramic-based multisite microelectrodes for the detection and elimination of interferences from the measurement of L-glutamate and other analytes","volume":"73","author":"Burmeister","year":"2001","journal-title":"Anal. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Hunsberger, H.C., Setti, S.E., Heslin, R.T., Quintero, J.E., Gerhardt, G.A., and Reed, M.N. (2017). Using Enzyme-based Biosensors to Measure Tonic and Phasic Glutamate in Alzheimer\u2019s Mouse Models. J. Vis. Exp., 55418.","DOI":"10.3791\/55418-v"},{"key":"ref_50","unstructured":"Paxinos, G., and Franklin, K. (2012). Mouse Brain in Stereotaxic Coordinates, Academic Press."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"14503","DOI":"10.1038\/s41598-020-71587-6","article-title":"Hippocampal alterations in glutamatergic signaling during amyloid progression in A\u03b2PP\/PS1 mice","volume":"10","author":"Hascup","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_52","first-page":"329","article-title":"Enhanced Cognition and Hypoglutamatergic Signaling in a Growth Hormone Receptor Knockout Mouse Model of Successful Aging","volume":"72","author":"Hascup","year":"2017","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_53","unstructured":"Michael, A.C., and Borland, L.M. (2007). Second-by-Second Measures of L-Glutamate and Other Neurotransmitters Using Enzyme-Based Microelectrode Arrays. Electrochemical Methods for Neuroscience, CRC Press\/Taylor & Francis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1089\/neu.2009.1238","article-title":"Diffuse brain injury elevates tonic glutamate levels and potassium-evoked glutamate release in discrete brain regions at two days post-injury: An enzyme-based microelectrode array study","volume":"27","author":"Hinzman","year":"2010","journal-title":"J. Neurotrauma"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1111\/j.1471-4159.2006.03673.x","article-title":"Microelectrode array studies of basal and potassium-evoked release of L-glutamate in the anesthetized rat brain","volume":"96","author":"Day","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"31891","DOI":"10.1074\/jbc.274.45.31891","article-title":"Na(+)-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood-brain barrier. A mechanism for glutamate removal","volume":"274","author":"DeJoseph","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1523\/JNEUROSCI.22-05-01858.2002","article-title":"The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer\u2019s disease","volume":"22","author":"Westerman","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.neubiorev.2004.06.006","article-title":"The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory","volume":"28","author":"Hughes","year":"2004","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/npp.2008.94","article-title":"Selective 5-HT6 receptor blockade improves spatial recognition memory and reverses age-related deficits in spatial recognition memory in the mouse","volume":"34","author":"Duchatelle","year":"2009","journal-title":"Neuropsychopharmacology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.bbr.2007.12.024","article-title":"Age-dependent and -independent behavioral deficits in Tg2576 mice","volume":"189","author":"Deacon","year":"2008","journal-title":"Behav. Brain Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.bbr.2014.01.044","article-title":"Intravenous ascorbate improves spatial memory in middle-aged APP\/PSEN1 and wild type mice","volume":"264","author":"Kennard","year":"2014","journal-title":"Behav. Brain Res."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Kokkinidis, L. (1989). Neurochemical and Neuroanatomical Correlates of Behavioral Habituation and Sensitization: An Overview and Elaboration of Animal Experimentation. Spontaneous Alternation Behavior, Springer.","DOI":"10.1007\/978-1-4613-8879-1_6"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.neurobiolaging.2009.05.009","article-title":"Age-related changes in glutamate release in the CA3 and dentate gyrus of the rat hippocampus","volume":"32","author":"Stephens","year":"2011","journal-title":"Neurobiol. Aging."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"7158","DOI":"10.1073\/pnas.0401764101","article-title":"An essential role for vesicular glutamate transporter 1 (VGLUT1) in postnatal development and control of quantal size","volume":"101","author":"Wojcik","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1006\/exnr.2000.7386","article-title":"Abnormal glutamate transport function in mutant amyloid precursor protein transgenic mice","volume":"163","author":"Masliah","year":"2000","journal-title":"Exp. Neurol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1056\/NEJM199205283262204","article-title":"Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis","volume":"326","author":"Rothstein","year":"1992","journal-title":"N. Engl. J. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"534705","DOI":"10.1155\/2012\/534705","article-title":"Riluzole-triggered GSH synthesis via activation of glutamate transporters to antagonize methylmercury-induced oxidative stress in rat cerebral cortex","volume":"2012","author":"Deng","year":"2012","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.neulet.2006.09.026","article-title":"Age-related changes in glycogen synthase kinase 3beta (GSK3beta) immunoreactivity in the central nervous system of rats","volume":"409","author":"Lee","year":"2006","journal-title":"Neurosci. Lett."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/S0014-5793(98)01090-4","article-title":"Tau is phosphorylated by GSK-3 at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A-kinase","volume":"436","author":"Wang","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1093\/aje\/kwf074","article-title":"Risk factors for Alzheimer\u2019s disease: A prospective analysis from the Canadian Study of Health and Aging","volume":"156","author":"Lindsay","year":"2002","journal-title":"Am. J. Epidemiol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.expneurol.2010.02.012","article-title":"Ionotropic glutamate receptors contribute to maintained neuronal hyperexcitability following spinal cord injury in rats","volume":"224","author":"Leem","year":"2010","journal-title":"Exp. Neurol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1111\/j.1460-9568.1994.tb00616.x","article-title":"Requirement of metabotropic glutamate receptors for the generation of inflammation-evoked hyperexcitability in rat spinal cord neurons","volume":"6","author":"Neugebauer","year":"1994","journal-title":"Eur. J. Neurosci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/0306-4522(96)00153-4","article-title":"Glutamate hyperexcitability and seizure-like activity throughout the brain and spinal cord upon relief from chronic glutamate receptor blockade in culture","volume":"74","author":"Obrietan","year":"1996","journal-title":"Neuroscience"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/0197-4580(87)90024-8","article-title":"Selective alteration of mouse brain neurotransmitter release with age","volume":"8","author":"Freeman","year":"1987","journal-title":"Neurobiol. Aging"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1046\/j.1471-4159.1997.69031151.x","article-title":"Glutamate uptake impairment and neuronal damage in young and aged rats in vivo","volume":"69","author":"Massieu","year":"1997","journal-title":"J. Neurochem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/BF00966793","article-title":"[3H]D-aspartic acid release in brain slices of adult and aged Fischer 344 rates","volume":"17","author":"Meldrum","year":"1992","journal-title":"Neurochem. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1093\/oxfordjournals.aje.a117597","article-title":"Risk of dementia in patients with Parkinson\u2019s disease, epilepsy, and severe head trauma: A register-based follow-up study","volume":"142","author":"Breteler","year":"1995","journal-title":"Am. J. Epidemiol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"S36","DOI":"10.1093\/ije\/20.Supplement_2.S36","article-title":"Medical history and the risk of Alzheimer\u2019s disease: A collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group","volume":"20","author":"Breteler","year":"1991","journal-title":"Int. J. Epidemiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"211","DOI":"10.3233\/JAD-170031","article-title":"Relative Incidence of Seizures and Myoclonus in Alzheimer\u2019s Disease, Dementia with Lewy Bodies, and Frontotemporal Dementia","volume":"60","author":"Beagle","year":"2017","journal-title":"J. Alzheimer Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.neuroscience.2014.11.051","article-title":"Seizures in Alzheimer\u2019s disease","volume":"286","author":"Born","year":"2015","journal-title":"Neuroscience"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/S1474-4422(17)30044-3","article-title":"Epileptic activity in Alzheimer\u2019s disease: Causes and clinical relevance","volume":"16","author":"Vossel","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_82","first-page":"49","article-title":"Progression to dementia in a population with amnestic mild cognitive impairment: Clinical variables associated with conversion","volume":"27","author":"Mauri","year":"2012","journal-title":"Funct. Neurol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1126\/science.1152882","article-title":"Pattern separation in the human hippocampal CA3 and dentate gyrus","volume":"319","author":"Bakker","year":"2008","journal-title":"Science"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.neuron.2012.03.023","article-title":"Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment","volume":"74","author":"Bakker","year":"2012","journal-title":"Neuron"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1038\/s41467-019-10428-1","article-title":"Factors other than hTau overexpression that contribute to tauopathy-like phenotype in rTg4510 mice","volume":"10","author":"Gamache","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.neurobiolaging.2018.06.002","article-title":"Doxycycline counteracts neuroinflammation restoring memory in Alzheimer\u2019s disease mouse models","volume":"70","author":"Balducci","year":"2018","journal-title":"Neurobiol. Aging"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/0197-4580(91)90071-Q","article-title":"Increase in perforant path quantal size in aged F-344 rats","volume":"12","author":"Foster","year":"1991","journal-title":"Neurobiol. Aging"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"10810","DOI":"10.1523\/JNEUROSCI.3269-07.2007","article-title":"Paradoxical upregulation of glutamatergic presynaptic boutons during mild cognitive impairment","volume":"27","author":"Bell","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1111\/j.1471-4159.2006.03935.x","article-title":"Down-regulation of vesicular glutamate transporters precedes cell loss and pathology in Alzheimer\u2019s disease","volume":"98","author":"Kirvell","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"S505","DOI":"10.1016\/j.jalz.2006.05.1712","article-title":"P3\u2013441: Expression of mRNAs regulating local translation in synaptic terminals of MCI and early ad brain","volume":"2","author":"Williams","year":"2006","journal-title":"Alzheimer Dement."},{"key":"ref_91","first-page":"262","article-title":"Recurrent synapses and circuits in the CA3 region of the hippocampus: An associative network","volume":"7","author":"Simonnet","year":"2014","journal-title":"Front. Cell Neurosci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1002\/jcp.22231","article-title":"Extracellular high K+ stimulates vesicular glutamate release from astrocytes by activating voltage-dependent calcium channels","volume":"225","author":"Yaguchi","year":"2010","journal-title":"J. Cell Physiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"12055","DOI":"10.1523\/JNEUROSCI.2556-06.2006","article-title":"Vesicular glutamate transporter VGLUT2 expression levels control quantal size and neuropathic pain","volume":"26","author":"Moechars","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/S0197-4580(98)00098-0","article-title":"Hippocampal neuron and synaptophysin-positive bouton number in aging C57BL\/6 mice","volume":"19","author":"Calhoun","year":"1998","journal-title":"Neurobiol. Aging."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/S0197-4580(02)00138-0","article-title":"Enrichment enhances spatial memory and increases synaptophysin levels in aged female mice","volume":"24","author":"Frick","year":"2003","journal-title":"Neurobiol. Aging"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/S0006-8993(98)00770-7","article-title":"Physical training modifies the age-related decrease of GAP-43 and synaptophysin in the hippocampal formation in C57BL\/6J mouse","volume":"806","author":"Chen","year":"1998","journal-title":"Brain Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"6587","DOI":"10.1523\/JNEUROSCI.20-17-06587.2000","article-title":"Circuit-specific alterations in hippocampal synaptophysin immunoreactivity predict spatial learning impairment in aged rats","volume":"20","author":"Smith","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.neuropharm.2013.10.018","article-title":"Synaptic gene dysregulation within hippocampal CA1 pyramidal neurons in mild cognitive impairment","volume":"79","author":"Counts","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.neurobiolaging.2005.11.003","article-title":"Differential expression of PSD proteins in age-related spatial learning impairments","volume":"28","author":"Nyffeler","year":"2007","journal-title":"Neurobiol. Aging"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1258\/ebm.2012.012020","article-title":"Increased postsynaptic density protein-95 expression in the frontal cortex of aged cognitively impaired rats","volume":"237","author":"Preissmann","year":"2012","journal-title":"Exp. Biol. Med."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/embor.2013.15","article-title":"Physiological release of endogenous tau is stimulated by neuronal activity","volume":"14","author":"Pooler","year":"2013","journal-title":"EMBO Rep."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological stageing of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Weitzner, D.S., Engler-Chiurazzi, E.B., Kotilinek, L.A., Ashe, K.H., and Reed, M.N. (2015). Morris Water Maze Test: Optimization for Mouse Strain and Testing Environment. J. Vis. Exp., e52706.","DOI":"10.3791\/52706-v"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1212\/WNL.42.3.631","article-title":"Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer\u2019s disease","volume":"42","author":"Arriagada","year":"1992","journal-title":"Neurology"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/0304-3940(93)90590-H","article-title":"Neuropathological staging of Alzheimer lesions and intellectual status in Alzheimer\u2019s and Parkinson's disease patients","volume":"162","author":"Bancher","year":"1993","journal-title":"Neurosci. Lett."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1001\/archneur.60.5.729","article-title":"Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment","volume":"60","author":"Guillozet","year":"2003","journal-title":"Arch. Neurol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11637\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:21:40Z","timestamp":1760167300000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/11637"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,28]]},"references-count":106,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222111637"],"URL":"https:\/\/doi.org\/10.3390\/ijms222111637","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,28]]}}}