The gut microbiota-derived metabolite queuosine regulates neuronal development and network function through tRNA modification

Abstract

Queuosine (Q) modification is a hypermodified nucleoside derived from guanine on tRNAs that enhances the decoding of codons and equilibrates translational speed. Q is biosynthesized in bacteria, and eukaryotes salvage Q and the nucleobase queuine from the diet and the gut microbiome. In animals, Q deficiency causes impaired proteostasis, mitochondrial dysfunction, and neurological phenotypes, possibly due to the longevity and high metabolic demand of neurons. Yet, how Q affects isolated neurons has not been explored yet. Here, primary rat cortical neurons were cultured in Q-free synthetic medium to directly modulate Q modification levels independently of genetic perturbation, enabling assessment of its effects on neuronal development, survival, morphology, synaptic organization, and activity. Importantly, we found that the presence of Q modification facilitated neuronal arborization, decreased inhibitory synaptic density, and increased the frequency of spontaneous calcium transients, showing that tRNA Q modification enhances neuronal structural maturation and synaptic activity. Thus, the fine-tuning of neuronal translation programs by Q-tRNAs is required for proper network development and may influence neuronal resilience and synaptic function.