Çiğdem TÜRKMEN, Barış TOPÇULAR
Demiroğlu Bilim Üniversitesi Florence Nightingale Tıp Dergisi - 2026;12(2):69-78
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-D-aspartate (NMDA) receptors while withdrawing alpha-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 15th 2026 and June 30th 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 (rho = 0.201, p = 0.009; false discovery rate-adjusted p = 0.050), whereas a principal component representing general bioenergetic load was not (rho = 0.091, p = 0.24). At the single-gene level, xbp-1 expression correlated positively with glr-1 (rho = 0.182) and ire-1 negatively (rho = -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 (rho = -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.
