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Published on: March 2, 2018
Reelin cells and sex-dependent synaptopathology in autism following postnatal immune activation
Maryam Ardalan1,2, Tetyana Chumak1, Alexandra Quist1
1Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Insights
Postnatal infection in male mice causes autism spectrum disorder (ASD)-like behaviors, impacting hippocampal synapses and Reelin+ cells. This study reveals sex-specific immune activation mechanisms contributing to ASD pathogenesis.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Autism spectrum disorders (ASD) are complex neurodevelopmental conditions with higher prevalence in males.
- Preterm birth and neonatal infections are known risk factors for ASD.
- The role of early-life immune challenges in ASD pathogenesis remains incompletely understood.
Purpose of the Study:
- To investigate the impact of postnatal immune activation on hippocampal synaptopathology in a mouse model of ASD-like behaviors.
- To examine sex-specific effects of early-life infection on neuronal development and synaptic function.
- To identify cellular and molecular mechanisms underlying ASD-associated behavioral changes.
Main Methods:
- Lipopolysaccharide (LPS) administration to mouse pups on postnatal day 5 to simulate neonatal infection.
- Behavioral assessments including marble burying and sociability tests at postnatal day 45.
- Ex vivo MRI diffusion kurtosis imaging (DKI), analysis of hippocampal synaptogenesis, Reelin+ cell morphology, and gene expression of trans-synaptic and cell-adhesion molecules.
Main Results:
- Male mice exposed to LPS exhibited social withdrawal and increased stereotypic behaviors.
- MRI-DKI revealed increased mean diffusivity and hippocampal overgrowth in affected males.
- Decreased Reelin+ cell volume and number, immature synapses, and reduced expression of key synaptic genes were observed in males.
Conclusions:
- Postnatal immune activation contributes to sex-dependent ASD-like behaviors in males.
- GABAergic interneurons play a critical role in the dysmaturation of excitatory synapses in the hippocampus following infection.
- The findings provide cellular and molecular insights into MRI observations, with potential translational value for understanding ASD.
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.
