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@ARTICLE{Ioannidis:270139,
      author       = {Ioannidis, Valentin and Pandey, Rakshita and Bauer, Helen
                      Friedericke and Schön, Michael and Bockmann, Jürgen and
                      Boeckers, Tobias M and Lutz, Anne-Kathrin},
      title        = {{D}isrupted extracellular matrix and cell cycle genes in
                      autism-associated {S}hank3 deficiency are targeted by
                      lithium.},
      journal      = {Molecular psychiatry},
      volume       = {29},
      number       = {3},
      issn         = {1359-4184},
      address      = {London},
      publisher    = {Macmillan},
      reportid     = {DZNE-2024-00739},
      pages        = {704 - 717},
      year         = {2024},
      abstract     = {The Shank3 gene encodes the major postsynaptic scaffolding
                      protein SHANK3. Its mutation causes a syndromic form of
                      autism spectrum disorder (ASD): Phelan-McDermid Syndrome
                      (PMDS). It is characterized by global developmental delay,
                      intellectual disorders (ID), ASD behavior, affective
                      symptoms, as well as extra-cerebral symptoms. Although
                      Shank3 deficiency causes a variety of molecular alterations,
                      they do not suffice to explain all clinical aspects of this
                      heterogenic syndrome. Since global gene expression
                      alterations in Shank3 deficiency remain inadequately
                      studied, we explored the transcriptome in vitro in primary
                      hippocampal cells from Shank3∆11(-/-) mice, under control
                      and lithium (Li) treatment conditions, and confirmed the
                      findings in vivo. The Shank3∆11(-/-) genotype affected the
                      overall transcriptome. Remarkably, extracellular matrix
                      (ECM) and cell cycle transcriptional programs were
                      disrupted. Accordingly, in the hippocampi of adolescent
                      Shank3∆11(-/-) mice we found proteins of the collagen
                      family and core cell cycle proteins downregulated. In vitro
                      Li treatment of Shank3∆11(-/-) cells had a rescue-like
                      effect on the ECM and cell cycle gene sets. Reversed ECM
                      gene sets were part of a network, regulated by common
                      transcription factors (TF) such as cAMP responsive element
                      binding protein 1 (CREB1) and β-Catenin (CTNNB1), which are
                      known downstream effectors of synaptic activity and targets
                      of Li. These TFs were less abundant and/or
                      hypo-phosphorylated in hippocampi of Shank3∆11(-/-) mice
                      and could be rescued with Li in vitro and in vivo. Our
                      investigations suggest the ECM compartment and cell cycle
                      genes as new players in the pathophysiology of Shank3
                      deficiency, and imply involvement of transcriptional
                      regulators, which can be modulated by Li. This work supports
                      Li as potential drug in the management of PMDS symptoms,
                      where a Phase III study is ongoing.},
      keywords     = {Animals / Nerve Tissue Proteins: genetics / Nerve Tissue
                      Proteins: metabolism / Hippocampus: metabolism /
                      Extracellular Matrix: metabolism / Mice / Mice, Knockout /
                      beta Catenin: metabolism / beta Catenin: genetics /
                      Chromosome Disorders: genetics / Chromosome Disorders:
                      metabolism / Chromosome Deletion / Cell Cycle: drug effects
                      / Cell Cycle: genetics / Autistic Disorder: genetics /
                      Autistic Disorder: metabolism / Chromosomes, Human, Pair 22:
                      genetics / Cyclic AMP Response Element-Binding Protein:
                      metabolism / Cyclic AMP Response Element-Binding Protein:
                      genetics / Male / Transcriptome: genetics / Autism Spectrum
                      Disorder: genetics / Autism Spectrum Disorder: metabolism /
                      Autism Spectrum Disorder: drug therapy / Mice, Inbred C57BL
                      / Lithium: pharmacology / Microfilament Proteins: metabolism
                      / Microfilament Proteins: genetics / Cells, Cultured /
                      Shank3 protein, mouse (NLM Chemicals) / Nerve Tissue
                      Proteins (NLM Chemicals) / beta Catenin (NLM Chemicals) /
                      Creb1 protein, mouse (NLM Chemicals) / Cyclic AMP Response
                      Element-Binding Protein (NLM Chemicals) / CTNNB1 protein,
                      mouse (NLM Chemicals) / Lithium (NLM Chemicals) /
                      Microfilament Proteins (NLM Chemicals)},
      cin          = {AG Böckers},
      ddc          = {610},
      cid          = {I:(DE-2719)1910002},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC11153165},
      pubmed       = {pmid:38123724},
      doi          = {10.1038/s41380-023-02362-y},
      url          = {https://pub.dzne.de/record/270139},
}