Cerebrospinal fluid, brain, and spinal cord levels of L‐aspartate signal excitatory neurotransmission abnormalities in multiple sclerosis patients and experimental autoimmune encephalomyelitis mouse model

The neuroinflammatory process characterizing multiple sclerosis (MS) is associated with changes in excitatory synaptic transmission and altered central concentrations of the primary excitatory amino acid, L‐glutamate (L‐Glu). Recent findings report that cerebrospinal fluid (CSF) levels of L‐Glu positively correlate with pro‐inflammatory cytokines in MS patients. However, to date, there is no evidence about the relationship between the other primary excitatory amino acid, L‐aspartate (L‐Asp), its derivative D‐enantiomer, D‐aspartate, and the levels of pro‐inflammatory and anti‐inflammatory 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‐Asp levels in the cortex and spinal cord of EAE mice and increased D‐aspartate/total aspartate ratio within the cerebellum and spinal cord of these animals. Additionally, we found significantly decreased CSF levels of L‐Asp in both relapsing–remitting (n = 157) MS (RR‐MS) and secondary progressive/primary progressive (n = 22) (SP/PP‐MS) patients, compared to control subjects with other neurological diseases (n = 40). Importantly, in RR‐MS patients, L‐Asp levels were correlated with the CSF concentrations of the inflammatory biomarkers G‐CSF, IL‐1ra, MIP‐1β, and Eotaxin, indicating that the central content of this excitatory amino acid, as previously reported for L‐Glu, reflects a neuroinflammatory environment in MS. In keeping with this, we revealed that CSF L‐Asp levels were positively correlated with those of L‐Glu, highlighting the convergent variation of these two excitatory amino acids under inflammatory synaptopathy occurring in MS. Multiple sclerosis (MS) is a chronic immune‐mediated disease characterized by inflammation, demyelination, gliosis, and neurodegeneration in the central nervous system. Neuroinflammatory processes in MS are associated with a remarkable overactivation of glutamate receptors; however, the specific involvement of excitatory amino acid levels remains unclear. In a cohort of relapsing–remitting MS patients but not controls, we showed a marked correlation between the cerebrospinal fluid (CSF) levels of the endogenous NMDA receptor agonist, L‐aspartate, and those of the cytokines G‐CSF, IL‐1ra, M