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

Maryam Ardalan; Tetyana  Chumak; Alexandra  Quist; Eva  Hermans; Ali H.Rafati; Giacomo  Gravina; Seyedeh  Marziyeh Jabbari Shiadeh; Pernilla  Svedin; Setareh Alabaf; Brian Hansen; Gregers Wegener; Lars Westberg; Carina Mallard

doi:10.1111/bph.15859

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

Maryam Ardalan, Tetyana Chumak, Alexandra Quist, Eva Hermans, Ali H.Rafati, Giacomo Gravina, Seyedeh Marziyeh Jabbari Shiadeh, Pernilla Svedin, Setareh Alabaf, Brian Hansen, Gregers Wegener, Lars Westberg, Carina Mallard^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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Abstract

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 language	English
Journal	British Journal of Pharmacology
Volume	179
Issue	17
Pages (from-to)	4400-4422
Number of pages	23
ISSN	0007-1188
DOIs	https://doi.org/10.1111/bph.15859
Publication status	Published - Sept 2022

Keywords

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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British J Pharmacology - 2022 - Ardalan - Reelin cells and sex‐dependent synaptopathology in autism following postnatalFinal published version, 23.9 MBLicence: CC BY-NC-ND

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Ardalan, M., Chumak, T., Quist, A., Hermans, E., H.Rafati, A., Gravina, G., Marziyeh Jabbari Shiadeh, S., Svedin, P., Alabaf, S., Hansen, B., Wegener, G., Westberg, L., & Mallard, C. (2022). Reelin cells and sex-dependent synaptopathology in autism following postnatal immune activation. British Journal of Pharmacology, 179(17), 4400-4422. https://doi.org/10.1111/bph.15859

@article{530de29e5e364226a05249c3cd6a2eab,

title = "Reelin cells and sex-dependent synaptopathology in autism following postnatal immune activation",

abstract = "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.",

keywords = "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",

author = "Maryam Ardalan and Tetyana Chumak and Alexandra Quist and Eva Hermans and Ali H.Rafati and Giacomo Gravina and {Marziyeh Jabbari Shiadeh}, Seyedeh and Pernilla Svedin and Setareh Alabaf and Brian Hansen and Gregers Wegener and Lars Westberg and Carina Mallard",

year = "2022",

month = sep,

doi = "10.1111/bph.15859",

language = "English",

volume = "179",

pages = "4400--4422",

journal = "British Journal of Pharmacology",

issn = "0007-1188",

publisher = "John/Wiley & Sons Ltd.",

number = "17",

}

Ardalan, M, Chumak, T, Quist, A, Hermans, E, H.Rafati, A, Gravina, G, Marziyeh Jabbari Shiadeh, S, Svedin, P, Alabaf, S, Hansen, B , Wegener, G, Westberg, L & Mallard, C 2022, 'Reelin cells and sex-dependent synaptopathology in autism following postnatal immune activation', British Journal of Pharmacology, vol. 179, no. 17, pp. 4400-4422. https://doi.org/10.1111/bph.15859

Reelin cells and sex-dependent synaptopathology in autism following postnatal immune activation. / Ardalan, Maryam; Chumak, Tetyana ; Quist, Alexandra et al.
In: British Journal of Pharmacology, Vol. 179, No. 17, 09.2022, p. 4400-4422.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Reelin cells and sex-dependent synaptopathology in autism following postnatal immune activation

AU - Ardalan, Maryam

AU - Chumak, Tetyana

AU - Quist, Alexandra

AU - Hermans, Eva

AU - H.Rafati, Ali

AU - Gravina, Giacomo

AU - Marziyeh Jabbari Shiadeh, Seyedeh

AU - Svedin, Pernilla

AU - Alabaf, Setareh

AU - Hansen, Brian

AU - Wegener, Gregers

AU - Westberg, Lars

AU - Mallard, Carina

PY - 2022/9

Y1 - 2022/9

N2 - 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.

AB - 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.

KW - MRI diffusion kurtosis

KW - Reelin

KW - autism

KW - neonatal infection

KW - preterm

KW - synaptogenesis

KW - SPECTRUM DISORDER

KW - MOUSE

KW - BRAIN-DEVELOPMENT

KW - NEUROLIGINS

KW - CHILDREN

KW - HIPPOCAMPUS

KW - CONCISE GUIDE

KW - INFLAMMATION

KW - GENE ALLELES

KW - PLASTICITY

KW - Humans

KW - Male

KW - Extracellular Matrix Proteins/genetics

KW - Lipopolysaccharides

KW - Female

KW - Serine Endopeptidases/genetics

KW - Autistic Disorder

KW - Reelin Protein

KW - Animals

KW - Nerve Tissue Proteins/genetics

KW - Hippocampus/metabolism

KW - Mice

U2 - 10.1111/bph.15859

DO - 10.1111/bph.15859

M3 - Journal article

C2 - 35474185

SN - 0007-1188

VL - 179

SP - 4400

EP - 4422

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 17

ER -

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

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