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Using <jats:styled-content style=\"fixed-case\">APOE<\/jats:styled-content> knock\u2010in mice, we have previously shown that <jats:styled-content style=\"fixed-case\">APOE<\/jats:styled-content>\u2010\u03b54 Targeted Replacement (<jats:styled-content style=\"fixed-case\">TR<\/jats:styled-content>) mice have fewer dendritic spines and reduced branching in cortical neurons. As dendritic spines are post\u2010synaptic sites of excitatory neurotransmission, we used <jats:styled-content style=\"fixed-case\">APOE TR<\/jats:styled-content> mice to examine whether <jats:styled-content style=\"fixed-case\">APOE<\/jats:styled-content> genotype affected the various elements of the glutamate\u2013glutamine cycle. We found that levels of glutamine synthetase and glutamate uptake transporters were unchanged among the <jats:styled-content style=\"fixed-case\">APOE<\/jats:styled-content> genotypes. However, compared with <jats:styled-content style=\"fixed-case\">APOE<\/jats:styled-content>\u2010\u03b53 <jats:styled-content style=\"fixed-case\">TR<\/jats:styled-content> mice, <jats:styled-content style=\"fixed-case\">APOE<\/jats:styled-content>\u2010\u03b54 <jats:styled-content style=\"fixed-case\">TR<\/jats:styled-content> mice had decreased glutaminase levels (18%, <jats:italic>p\u00a0<\/jats:italic>&lt;<jats:italic>\u00a0<\/jats:italic>0.05), suggesting decreased conversion of glutamine to glutamate. <jats:styled-content style=\"fixed-case\">APOE<\/jats:styled-content>\u2010\u03b54 <jats:styled-content style=\"fixed-case\">TR<\/jats:styled-content> mice also had increased levels of the vesicular glutamate transporter 1 (20%, <jats:italic>p\u00a0<\/jats:italic>&lt;<jats:italic>\u00a0<\/jats:italic>0.05), suggesting that <jats:styled-content style=\"fixed-case\">APOE<\/jats:styled-content> genotype affects pre\u2010synaptic terminal composition. To address whether these changes affected normal neurotransmission, we examined the production and metabolism of glutamate and glutamine at 4\u20135\u00a0months and 1\u00a0year. Using high\u2010frequency <jats:sup>13<\/jats:sup>C\/<jats:sup>1<\/jats:sup>H nuclear magnetic resonance spectroscopy, we found that <jats:styled-content style=\"fixed-case\">APOE<\/jats:styled-content>\u2010\u03b54 <jats:styled-content style=\"fixed-case\">TR<\/jats:styled-content> mice have decreased production of glutamate and increased levels of glutamine. These factors may contribute to the increased risk of neurodegeneration associated with <jats:styled-content style=\"fixed-case\">APOE<\/jats:styled-content>\u2010\u03b54, and also act as surrogate markers for Alzheimer's disease risk.<\/jats:p>","DOI":"10.1111\/j.1471-4159.2012.07908.x","type":"journal-article","created":{"date-parts":[[2012,8,3]],"date-time":"2012-08-03T19:08:07Z","timestamp":1344020887000},"page":"4-14","source":"Crossref","is-referenced-by-count":52,"title":["<scp>APOE<\/scp> genotype affects the pre\u2010synaptic compartment of glutamatergic nerve terminals"],"prefix":"10.1111","volume":"124","author":[{"given":"Sonya B.","family":"Dumanis","sequence":"first","affiliation":[{"name":"Department of Neuroscience Georgetown University Medical Center Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda M.","family":"DiBattista","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Georgetown University Medical Center Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Miessau","sequence":"additional","affiliation":[{"name":"Drug Discovery Program Georgetown University Medical Center Washington District of Columbia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charbel E. 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