Potential glutamatergic and GABAergic false neurotransmitters in models of excitation-inhibition imbalance

We previously determined that 2-Methylglutamate (2MeGlu) and 4-aminopentanoic acid (4APA) have neurochemical properties of glutamatergic and GABAergic false neurotransmitters (FNTs); here, we tested whether their activity impacts mouse models with excitation-inhibition (E-I) imbalance. We first screened racemic agents using models caused by E-I imbalance; rac-2MeGlu, but not rac-4APA, suppressed 81% of excitotoxicity in hippocampal slices and increased survival by 105% in Aldh5a1^-/- mice. Enantiomers with the least receptor activity were further tested in more complex models. R-4APA (50 mg/kg) worsened startle behaviors in the Shank3^-/- autism model while S-2MeGlu (50 mg/kg/d over 19 days) improved motor performance by 77% in MPTP-treated mice without changing dopaminergic neurotoxicity; neither agent improved motor function in a human α-synuclein overexpressing mouse. S-2MeGlu (10 mg/kg/d for 8 weeks), but not R-4APA, reversed the spatial working memory deficit in T41 (Thy-1 hAPP^Lond/Swe+ ) mice without significantly changing Aβ plaque density. Single-nucleus transcriptomics following the same chronic exposures in WT mice yielded positively enriched pathways related to protein handling and synaptic regulation in excitatory neurons with S-2MeGlu; R-4APA caused metabolic pathway negative enrichments in multiple cell types. Our data reveal distinct behavioral and transcriptomic impacts of S-2MeGlu and R-4APA and further support S-2MeGlu as a glutamatergic FNT.