A number of evidences has put forward new players in the pathogenesis of Frontotemporal Dementia (FTD) claiming for a role of autoimmunity and altered glutamate neurotransmission in triggering disease onset. We reported the presence of autoantibodies recognizing the GluA3 subunit of AMPA receptors in about 25% of FTD cases. Here we evaluated the mechanisms involved in anti-GluA3 autoimmunity in FTD, through molecular/neurochemical analyses conducted on patients' brain specimens, corroborated by Transcranial Magnetic Stimulation (TMS) and analysis of glutamate, D-serine and L-serine levels in the CSF. We observed that GluA3 autoantibodies affect glutamatergic neurotransmission, decreasing glutamate release and altering GluA3-containing AMPA receptor levels. These alterations were accompanied by changes of scaffolding proteins involved in receptor synaptic retention/internalization. The above results were confirmed by TMS, suggesting a significant impairment of indirect measures of glutamate neurotransmission in FTD patients as compared to controls, with further add-on harmful effect in those FTD patients with anti-GluA3 antibodies. Finally, FTD patients showed a significant increase of glutamate, D-serine and L-serine levels in the CSF.

Excessive extracellular concentrations of L‐glutamate (L‐Glu) can be neurotoxic and contribute to neurodegenerative processes in multiple sclerosis (MS). The association between cerebrospinal fluid (CSF) L‐Glu levels, clinical features, and inflammatory biomarkers in patients with MS remains unclear. In 179 MS patients (relapsing remitting, RR, N = 157; secondary progressive/primary progressive, SP/PP, N = 22), CSF levels of L‐Glu at diagnosis were determined and compared with those obtained in a group of 40 patients with non‐inflammatory/non‐degenerative disorders. Disability at the time of diagnosis, and after 1 year follow‐up, was assessed using the Expanded Disability Status Scale (EDSS). CSF concentrations of lactate and of a large set of pro‐inflammatory and anti‐inflammatory molecules were explored. CSF levels of L‐Glu were slightly reduced in MS patients compared to controls. In RR‐MS patients, L‐Glu levels correlated with EDSS after 1 year follow‐up. Moreover, in MS patients, significant correlations were found between L‐Glu and both CSF levels of lactate and the inflammatory molecules interleukin (IL)‐2, IL‐6, and IL‐1 receptor antagonist. Altered expression of L‐Glu is associated with disability progression, oxidative stress, and inflammation. These findings identify CSF L‐Glu as a candidate neurochemical marker of inflammatory neurodegeneration in MS.

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