Neuron-Specific Glycine Metabolism Links Transfer RNA Epitranscriptomic Regulation to Complex Behaviors

Background: tRNA methyltransferase depletion in mature neurons elicits changes in complex behaviors relevant for fear, anxiety, and other neuropsychiatric phenotypes. However, it remains unclear whether this is due to dysregulated tRNAs or metabolic shifts that impact the neuronal translatome by activation of stress messengers together with alterations in amino acid supply. Methods: -deficient brain. Changes in extracellular glycine levels were monitored by an optical glycine Förster resonance energy transfer (FRET) sensor in the hippocampus, and behavioral phenotyping included cognition, anxiety-like behavior, and behavioral despair. Results: -deficient brain, dynamic glycine profiles in the hippocampal extracellular space were fully maintained at baseline and in the context of neuronal activity. Conclusions: Alterations in neuronal glycine metabolism, resulting from targeted ablation of the glycine cleavage system or disruption of the tRNA regulome, elicit changes in complex behaviors in mice relevant for neuropsychiatric phenotypes.