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It is reported that N-methyl-D-aspartate receptor (NMDAR)-mediated facilitation of long-term potentiation (LTP) and fear memory are impaired in <jats:italic>Fmr1<\/jats:italic> knockout (KO) mice. In this study, biological, pharmacological, and electrophysiological techniques were performed to determine the roles of D-aspartate (D-Asp), a modulator of NMDAR, and its metabolizing enzyme D-aspartate oxidase (DDO) in <jats:italic>Fmr1<\/jats:italic> KO mice. Levels of D-Asp were decreased in the <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/26233606\">medial prefrontal cortex (mPFC<\/jats:ext-link>); however, the levels of its metabolizing enzyme DDO were increased. Electrophysiological recordings indicated that oral drinking of D-Asp recovered LTP induction in mPFC from <jats:italic>Fmr1<\/jats:italic> KO mice. Moreover, chronic oral administration of D-Asp reversed behavioral deficits of cognition and locomotor coordination in <jats:italic>Fmr1<\/jats:italic> KO mice. The therapeutic action of D-Asp was partially through regulating functions of NMDARs and mGluR5\/mTOR\/4E-BP signaling pathways. In conclusion, supplement of D-Asp may benefit for synaptic plasticity and behaviors in <jats:italic>Fmr1<\/jats:italic> KO mice and offer a potential therapeutic strategy for FXS.<\/jats:p>","DOI":"10.1007\/s12035-023-03438-0","type":"journal-article","created":{"date-parts":[[2023,7,15]],"date-time":"2023-07-15T18:01:18Z","timestamp":1689444078000},"page":"6410-6423","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Improvement of Learning and Memory by Elevating Brain D-Aspartate in a Mouse Model of Fragile X Syndrome"],"prefix":"10.1007","volume":"60","author":[{"given":"Yu-Jiao","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Yan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shui-Bing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Mei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7539-3887","authenticated-orcid":false,"given":"Ming-Gao","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,7,15]]},"reference":[{"issue":"6","key":"3438_CR1","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1352\/2008.113:427-438","volume":"113","author":"SW Harris","year":"2008","unstructured":"Harris SW, Hessl D, Goodlin-Jones B, Ferranti J, Bacalman S, Barbato I, Tassone F, Hagerman PJ et al (2008) Autism profiles of males with fragile X syndrome. 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