Synaptic silencing as metabolic self-defense: oxidative stress predicts receptor ratios across the Caenorhabditis elegans connectome

Abstract

Objectives: This study aimed to test, at single-neuron resolution, the central prediction of the synaptic silencing as metabolic self-defense framework — that neurons under greater metabolic pressure preferentially maintain glutamatergic synapses in a functionally silent state, retaining N-methyl-Daspartate (NMDA) receptors while withdrawing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors — and to determine which component of metabolic state (total bioenergetic load versus oxidative stress) is associated with receptor stoichiometry across the Caenorhabditis elegans connectome.

Materials and methods: This retrospective, cross-sectional in silico (computational) study was conducted between January 15^th 2026 and June 30^th 2026, utilizing integrated multi-omic data from 169 Caenorhabditis elegans (C. elegans) neuron classes. We tested predictions of this framework computationally, using single-neuron transcriptomic data from the Caenorhabditis elegans Neuronal Gene Expression Map (CeNGEN) integrated with the Witvliet developmental connectome.

Results: To evaluate receptor stoichiometry across 169 neuron classes, we calculated a Silent Synapse Index (SSI) based on the expression ratio of NMDA-type (nmr-1/nmr-2) to AMPA-type (glr-1–glr-8) receptor transcripts and integrated it with metabolic gene module scores. Oxidative stress defense expression was associated with higher SSI (ρ = 0.201, p = 0.009; false discovery rate-adjusted p = 0.050), whereas a principal component representing general bioenergetic load was not (ρ = 0.091, p = 0.24). At the single-gene level, xbp-1 expression correlated positively with glr-1 (ρ = 0.182) and ire-1 negatively (ρ = –0.205), a divergence consistent with their distinct roles in endoplasmic reticulum export and general stress signaling. A second principal component contrasting unfolded protein response against reactive oxygen species defense expression was also associated with SSI (ρ = –0.163, p = 0.034). Effect sizes are modest, and the analysis is correlational.

Conclusion: These findings refine the framework by nominating oxidative stress, rather than total metabolic load, as the candidate bioenergetic signal associated with receptor stoichiometry, and generate specific hypotheses for experimental test.

Cite this article as: Türkmen Ç, Topçular B. Synaptic silencing as metabolic self-defense: oxidative stress predicts receptor ratios across the Caenorhabditis elegans connectome. D J Med Sci 2026;12(2):69-78. doi: 10.5606/fng.btd.2026.249.

C.T., B.T.: Idea/concept, design, analysis and/or interpretation, literature review, writing the article, critical review, references, materials; B.T.: Control/supervision, data collection and/or processing.

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Data Sharing Statement
All data analyzed in this study are publicly available: the CeNGEN singlecell RNA-sequencing dataset via the WormBasecurated AnnData archive (data.caltech.edu/records/ qaqhb-r9m40) and the developmental connectome via the supplementary tables of Witvliet et al.[9] Derived data tables are available from the corresponding author upon reasonable request.

The authors received no financial support for the research and/or authorship of this article.

AI Disclosure
The authors declare that artificial intelligence (AI) tools were not used, or were used solely for language editing, and had no role in data analysis, interpretation, or the formulation of conclusions. All scientific content, data interpretation, and conclusions are the sole responsibility of the authors. The authors further confirm that AI tools were not used to generate, fabricate, or ‘hallucinate’ references, and that all references have been carefully verified for accuracy.

We thank the CeNGEN consortium and Daniel Witvliet for making their datasets publicly available, and WormBase for curating C. elegans single-cell data in standardised formats.