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<p>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 <i>Aldh5a1</i><sup>−/−</sup> mice. Enantiomers with the least receptor activity were further tested in more complex models. R-4APA (50&#xa0;mg/kg) worsened startle behaviors in the <i>Shank3</i><sup>−/−</sup> autism model while S-2MeGlu (50&#xa0;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&#xa0;mg/kg/d for 8 weeks), but not R-4APA, reversed the spatial working memory deficit in T41 (Thy-1 hAPP<sup>Lond/Swe+</sup> ) 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月20日

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  • Amalia Perna,
  • Jing Zhao,
  • Chandresh R. Gajera,
  • Marcus Schonemann,
  • Nay L. Saw,
  • Mehrdad Shamloo,
  • Kathleen S. Montine,
  • Albert W. Garofalo,
  • Thomas J. Montine

摘要

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 hAPPLond/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.