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Reelin cells and sex-dependent synaptopathology in autism following postnatal immune activation

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  • Maryam Ardalan
  • Tetyana Chumak, University of Gothenburg
  • ,
  • Alexandra Quist, University of Gothenburg
  • ,
  • Eva Hermans, Utrecht University, University of Gothenburg
  • ,
  • Ali H.Rafati
  • Giacomo Gravina, University of Gothenburg
  • ,
  • Seyedeh Marziyeh Jabbari Shiadeh, Aarhus University, University of Gothenburg
  • ,
  • Pernilla Svedin, University of Gothenburg
  • ,
  • Setareh Alabaf, University of Gothenburg
  • ,
  • Brian Hansen
  • Gregers Wegener
  • Lars Westberg, University of Gothenburg
  • ,
  • Carina Mallard, University of Gothenburg

Background and Purpose: Autism spectrum disorders (ASD) are heterogeneous neurodevelopmental disorders with considerably increased risk in male infants born preterm and with neonatal infection. Here, we investigated the role of postnatal immune activation on hippocampal synaptopathology by targeting Reelin+ cells in mice with ASD-like behaviours. Experimental Approach: C57/Bl6 mouse pups of both sexes received lipopolysaccharide (LPS, 1 mg·kg −1) on postnatal day (P) 5. At P45, animal behaviour was examined by marble burying and sociability test, followed by ex vivo brain MRI diffusion kurtosis imaging (DKI). Hippocampal synaptogenesis, number and morphology of Reelin+ cells, and mRNA expression of trans-synaptic genes, including neurexin-3, neuroligin-1, and cell-adhesion molecule nectin-1, were analysed at P12 and P45. Key Results: Social withdrawal and increased stereotypic activities in males were related to increased mean diffusivity on MRI-DKI and overgrowth in hippocampus together with retention of long-thin immature synapses on apical dendrites, decreased volume and number of Reelin+ cells as well as reduced expression of trans-synaptic and cell-adhesion molecules. Conclusion and Implications: The study provides new insights into sex-dependent mechanisms that may underlie ASD-like behaviour in males following postnatal immune activation. We identify GABAergic interneurons as core components of dysmaturation of excitatory synapses in the hippocampus following postnatal infection and provide cellular and molecular substrates for the MRI findings with translational value.

Original languageEnglish
JournalBritish Journal of Pharmacology
Pages (from-to)4400-4422
Number of pages23
Publication statusPublished - Sept 2022

    Research areas

  • MRI diffusion kurtosis, Reelin, autism, neonatal infection, preterm, synaptogenesis, SPECTRUM DISORDER, MOUSE, BRAIN-DEVELOPMENT, NEUROLIGINS, CHILDREN, HIPPOCAMPUS, CONCISE GUIDE, INFLAMMATION, GENE ALLELES, PLASTICITY, Humans, Male, Extracellular Matrix Proteins/genetics, Lipopolysaccharides, Female, Serine Endopeptidases/genetics, Autistic Disorder, Reelin Protein, Animals, Nerve Tissue Proteins/genetics, Hippocampus/metabolism, Mice

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