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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     = {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.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.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.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},
      pubmed       = {pmid:39911537},
      pmc          = {pmc:PMC11794161},
      doi          = {10.1016/j.bpsgos.2024.100432},
      url          = {https://pub.dzne.de/record/276277},
}