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@ARTICLE{Meli:280233,
      author       = {Meli, Norisa and Sheran, Katherine and Pitsch, Julika and
                      Krabbe, Sabine and Borger, Valeri and Baumgartner, Tobias
                      and Becker, Albert and Blaess, Sandra},
      title        = {{A}lterations in dopaminergic innervation and receptors in
                      focal cortical dysplasia.},
      journal      = {Brain},
      volume       = {148},
      number       = {8},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2025-00911},
      pages        = {2899 - 2911},
      year         = {2025},
      abstract     = {Focal cortical dysplasia (FCD) type 2 is the most common
                      malformation of cortical development associated with
                      pharmaco-resistant focal epilepsy and frequently located in
                      the frontal cortex. Neuropathological hallmarks comprise
                      abnormal cortical layering and enlarged, dysmorphic neuronal
                      elements. Fundamentally altered local neuronal activity has
                      been reported in human FCD type 2 epilepsy surgical
                      biopsies. Of note, FCD type 2 emerges during brain
                      development and forms complex connectivity architectures
                      with surrounding neuronal networks. Local cortical
                      microcircuits, particularly in frontal localization, are
                      extensively modulated by monoaminergic axonal projections
                      originating from the brainstem. Previous analysis of
                      monoaminergic modulatory inputs in human FCD type 2 biopsies
                      suggested altered density and distribution of these
                      monoaminergic axons; however, a systematic investigation is
                      still pending. Here, we perform a comprehensive analysis of
                      dopaminergic (DA) innervation, in human FCD type 2 biopsies
                      and in the medial prefrontal cortex (mPFC) of an FCD type 2
                      mouse model [mechanistic target of rapamyin (mTOR)
                      hyperactivation model] during adolescent and adult stages.
                      In addition, we analyse the expression of dopamine receptor
                      transcripts via multiplex fluorescent RNA in situ
                      hybridization in human specimens and the mPFC of this mouse
                      model. In the mTOR hyperactivation mouse model, we observe a
                      transient alteration of DA innervation density during
                      adolescence and a trend towards decreased innervation in
                      adulthood. In human FCD type 2 areas, the overall DA
                      innervation density is decreased in adult patients compared
                      with control areas from these patients. Moreover, the DA
                      innervation shows an altered lamination pattern in the FCD
                      type 2 area compared with the control area. Dopamine
                      receptors 1 and 2 appear to be differentially expressed in
                      the dysmorphic neurons in human samples and mTOR-mutant
                      cells in mice compared with normally developed neurons.
                      Intriguingly, our results suggest complex molecular and
                      structural alterations putatively inducing impaired DA
                      neurotransmission in FCD type 2. We hypothesize that this
                      may have important implications for the development of these
                      malformations and the manifestation of seizures.},
      keywords     = {Humans / Animals / Mice / Male / Female / Malformations of
                      Cortical Development, Group I: pathology / Malformations of
                      Cortical Development, Group I: metabolism / Adult /
                      Adolescent / Prefrontal Cortex: metabolism / Prefrontal
                      Cortex: pathology / Disease Models, Animal / Young Adult /
                      Receptors, Dopamine: metabolism / Middle Aged / Dopaminergic
                      Neurons: metabolism / Dopaminergic Neurons: pathology /
                      Child / Malformations of Cortical Development: pathology /
                      Malformations of Cortical Development: metabolism / TOR
                      Serine-Threonine Kinases: metabolism / TOR Serine-Threonine
                      Kinases: genetics / Focal Cortical Dysplasia / Epilepsy /
                      cortical malformations (Other) / epileptogenesis (Other) /
                      neurodevelopmental disorders (Other) / neuromodulation
                      (Other) / neurotransmitter systems (Other) / Receptors,
                      Dopamine (NLM Chemicals) / TOR Serine-Threonine Kinases (NLM
                      Chemicals)},
      cin          = {AG Krabbe},
      ddc          = {610},
      cid          = {I:(DE-2719)5000059},
      pnm          = {351 - Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40235315},
      pmc          = {pmc:PMC12316006},
      doi          = {10.1093/brain/awaf080},
      url          = {https://pub.dzne.de/record/280233},
}