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@ARTICLE{Sen:274003,
      author       = {Sen, Paromita and Ortiz, Oskar and Brivio, Elena and
                      Menegaz, Danusa and Sotillos Elliott, Laura and Du, Ying and
                      Ries, Clemens and Chen, Alon and Wurst, Wolfgang and Lopez,
                      Juan Pablo and Eder, Matthias and Deussing, Jan M},
      title        = {{A} bipolar disorder-associated missense variant alters
                      adenylyl cyclase 2 activity and promotes mania-like
                      behavior.},
      journal      = {Molecular psychiatry},
      volume       = {30},
      number       = {1},
      issn         = {1359-4184},
      address      = {London},
      publisher    = {Macmillan},
      reportid     = {DZNE-2024-01431},
      pages        = {97 - 110},
      year         = {2025},
      abstract     = {The single nucleotide polymorphism rs13166360, causing a
                      substitution of valine (Val) 147 to leucine (Leu) in the
                      adenylyl cyclase 2 (ADCY2), has previously been associated
                      with bipolar disorder (BD). Here we show that the
                      disease-associated ADCY2 missense mutation diminishes the
                      enzyme´s capacity to generate the second messenger
                      3',5'-cylic adenosine monophosphate (cAMP) by altering its
                      subcellular localization. We established mice specifically
                      carrying the Val to Leu substitution using CRISPR/Cas9-based
                      gene editing. Mice homozygous for the Leu variant display
                      symptoms of a mania-like state accompanied by cognitive
                      impairments. Mutant animals show additional characteristic
                      signs of rodent mania models, i.e., they are hypersensitive
                      to amphetamine, the observed mania-like behaviors are
                      responsive to lithium treatment and the Val to Leu
                      substitution results in a shifted excitatory/inhibitory
                      synaptic balance towards more excitation. Exposure to
                      chronic social defeat stress switches homozygous Leu variant
                      carriers from a mania- to a depressive-like state, a
                      transition which is reminiscent of the alternations
                      characterizing the symptomatology in BD patients.
                      Single-cell RNA-seq (scRNA-seq) revealed widespread Adcy2
                      mRNA expression in numerous hippocampal cell types.
                      Differentially expressed genes particularly identified from
                      glutamatergic CA1 neurons point towards ADCY2
                      variant-dependent alterations in multiple biological
                      processes including cAMP-related signaling pathways. These
                      results validate ADCY2 as a BD risk gene, provide insights
                      into underlying disease mechanisms, and potentially open
                      novel avenues for therapeutic intervention strategies.},
      keywords     = {Bipolar Disorder: genetics / Bipolar Disorder: metabolism /
                      Adenylyl Cyclases: genetics / Adenylyl Cyclases: metabolism
                      / Animals / Mice / Mutation, Missense: genetics / Male /
                      Humans / Mania: genetics / Polymorphism, Single Nucleotide:
                      genetics / Disease Models, Animal / Cyclic AMP: metabolism /
                      Hippocampus: metabolism / Mice, Inbred C57BL / Female /
                      Adenylyl Cyclases (NLM Chemicals) / adenylyl cyclase 2 (NLM
                      Chemicals) / Cyclic AMP (NLM Chemicals)},
      cin          = {AG Wurst},
      ddc          = {610},
      cid          = {I:(DE-2719)1140001},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC11649569},
      pubmed       = {pmid:39003412},
      doi          = {10.1038/s41380-024-02663-w},
      url          = {https://pub.dzne.de/record/274003},
}