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Recent findings report that cerebrospinal fluid (CSF) levels of L\u2010Glu positively correlate with pro\u2010inflammatory cytokines in MS patients. However, to date, there is no evidence about the relationship between the other primary excitatory amino acid, L\u2010aspartate (L\u2010Asp), its derivative D\u2010enantiomer, D\u2010aspartate, and the levels of pro\u2010inflammatory and anti\u2010inflammatory cytokines in the CSF of MS. In the present study, we measured by HPLC the levels of these amino acids in the cortex, hippocampus, cerebellum, and spinal cord of mice affected by experimental autoimmune encephalomyelitis (EAE). Interestingly, in support of glutamatergic neurotransmission abnormalities in neuroinflammatory conditions, we showed reduced L\u2010Asp levels in the cortex and spinal cord of EAE mice and increased D\u2010aspartate\/total aspartate ratio within the cerebellum and spinal cord of these animals. Additionally, we found significantly decreased CSF levels of L\u2010Asp in both relapsing\u2013remitting (<jats:italic>n<\/jats:italic>\u2009=\u2009157) MS (RR\u2010MS) and secondary progressive\/primary progressive (<jats:italic>n<\/jats:italic>\u2009=\u200922) (SP\/PP\u2010MS) patients, compared to control subjects with other neurological diseases (<jats:italic>n<\/jats:italic>\u2009=\u200940). Importantly, in RR\u2010MS patients, L\u2010Asp levels were correlated with the CSF concentrations of the inflammatory biomarkers G\u2010CSF, IL\u20101ra, MIP\u20101\u03b2, and Eotaxin, indicating that the central content of this excitatory amino acid, as previously reported for L\u2010Glu, reflects a neuroinflammatory environment in MS. In keeping with this, we revealed that CSF L\u2010Asp levels were positively correlated with those of L\u2010Glu, highlighting the convergent variation of these two excitatory amino acids under inflammatory synaptopathy occurring in MS.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15884-fig-0005-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.15884","type":"journal-article","created":{"date-parts":[[2023,6,19]],"date-time":"2023-06-19T05:42:17Z","timestamp":1687153337000},"page":"534-546","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Cerebrospinal fluid, brain, and spinal cord levels of L\u2010aspartate signal excitatory neurotransmission abnormalities in multiple sclerosis patients and experimental autoimmune encephalomyelitis mouse model"],"prefix":"10.1111","volume":"166","author":[{"given":"Francesco","family":"Errico","sequence":"first","affiliation":[{"name":"Department of Agricultural Sciences University of Naples \u201cFederico II\u201d  Portici Italy"},{"name":"CEINGE Biotecnologie Avanzate \u201cFranco Salvatore\u201d  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luana","family":"Gilio","sequence":"additional","affiliation":[{"name":"Unit of Neurology, IRCCS Neuromed  Pozzilli Italy"},{"name":"Faculty of Psychology, Uninettuno Telematic International University  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Mancini","sequence":"additional","affiliation":[{"name":"Section of Neurology, Department of Medicine and Surgery University of Perugia  Perugia 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