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@ARTICLE{Blaze:276277,
      author       = {Blaze, Jennifer and Evans, Viviana Dolores and Feria
                      Pliego, Jessica Abigail and Unichenko, Petr and Javidfar,
                      Behnam and Heissel, Soeren and Alwaseem, Hanan and
                      Pennington, Zachary and Cai, Denise and Molina, Henrik and
                      Henneberger, Christian and Akbarian, Schahram},
      title        = {{N}euron-{S}pecific {G}lycine {M}etabolism {L}inks
                      {T}ransfer {RNA} {E}pitranscriptomic {R}egulation to
                      {C}omplex {B}ehaviors},
      journal      = {Biological psychiatry: global open science},
      volume       = {5},
      number       = {2},
      issn         = {2667-1743},
      address      = {Amsterdam},
      publisher    = {Elsevier},
      reportid     = {DZNE-2025-00256},
      pages        = {100432},
      year         = {2025},
      abstract     = {Background: The presence of treatment resistance in
                      neuropsychiatric disease suggests that novel mechanism-based
                      discoveries and therapies could benefit the field, with a
                      viable candidate being transfer RNA (tRNA)
                      epitranscriptomics. Nsun2 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: To
                      link specific molecular alterations resulting from neuronal
                      Nsun2 ablation to neuropsychiatric phenotypes, we used
                      drug-induced phosphoactivation of stress response
                      translation initiation factors together with disruption of
                      NSUN2-regulated glycine tRNAs and cell type–specific
                      ablation of the glycine cleavage system modeling the
                      excessive upregulation of this amino acid in the
                      Nsun2-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: Increased
                      motivated escape behaviors were specifically observed in
                      mice with neuron-specific ablation of Gldc, resulting in an
                      excess in cortical glycine levels comparable to a similar
                      phenotype in mice after deletion of neuronal Nsun2. None of
                      these phenotypes were observed in mice treated with
                      tunicamycin for chemoactivation of integrative stress
                      response pathways or in mice genetically engineered for
                      decreased glycine tRNA gene dosage. In the Nsun2-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.},
      cin          = {AG Henneberger},
      ddc          = {610},
      cid          = {I:(DE-2719)1013029},
      pnm          = {351 - Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1016/j.bpsgos.2024.100432},
      url          = {https://pub.dzne.de/record/276277},
}