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(R)-ketamine attenuates neurodevelopmental disease-related phenotypes in a mouse model of maternal immune activation

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Abstract

Infections during pregnancy are associated with an increased risk of neuropsychiatric disorders with developmental etiologies, such as schizophrenia and autism spectrum disorders (ASD). Studies have shown that the animal model of maternal immune activation (MIA) reproduces a wide range of phenotypes relevant to the study of neurodevelopmental disorders. Emerging evidence shows that (R)-ketamine attenuates behavioral, cellular, and molecular changes observed in animal models of neuropsychiatric disorders. Here, we investigate whether (R)-ketamine administration during adolescence attenuates some of the phenotypes related to neurodevelopmental disorders in an animal model of MIA. For MIA, pregnant Swiss mice received intraperitoneally (i.p.) lipopolysaccharide (LPS; 100 µg/kg/day) or saline on gestational days 15 and 16. The two MIA-based groups of male offspring received (R)-ketamine (20 mg/kg/day; i.p.) or saline from postnatal day (PND) 36 to 50. At PND 62, the animals were examined for anxiety-like behavior and locomotor activity in the open-field test (OFT), as well as in the social interaction test (SIT). At PND 63, the prefrontal cortex (PFC) was collected for analysis of oxidative balance and gene expression of the cytokines IL-1β, IL-6, and TGF-β1. We show that (R)-ketamine abolishes anxiety-related behavior and social interaction deficits induced by MIA. Additionally, (R)-ketamine attenuated the increase in lipid peroxidation and the cytokines in the PFC of the offspring exposed to MIA. The present work suggests that (R)-ketamine administration may have a long-lasting attenuation in deficits in emotional behavior induced by MIA, and that these effects may be attributed to its antioxidant and anti-inflammatory activity in the PFC.

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Acknowledgements

The authors are grateful for the fellowship granted to Elifrances Galdino de Oliveira by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; Finance Code 001) and the Science and Technology Support Foundation of the State of Pernambuco (FACEPE, process BCT-0327-4.01/21).

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Authors and Affiliations

  1. Laboratory of Neuroendocrinology and Metabolism, Department of Physiology and Pharmacology, Bioscience Center, Federal University of Pernambuco, Av. Prof. Moraes Rego, 1235 Cidade Universitária, Recife, PE, 50670-901, Brazil

    Elifrances Galdino de Oliveira, Diógenes Afonso de Lima, José Carlos da Silva Júnior, Mayara Victória de Souza Barbosa, Eduardo Carvalho Lira, Filipe Silveira Duarte & Dayane Aparecida Gomes

  2. Graduate Program of Neuropsychiatry and Behavioral Sciences, Federal University of Pernambuco, Recife, PE, Brazil

    Elifrances Galdino de Oliveira, Severina Cassia de Andrade Silva, Jonata Henrique de Santana, Osmar Henrique dos Santos Junior, Claudia Jacques Lagranha & Dayane Aparecida Gomes

  3. Laboratory of Biochemistry and Exercise Biochemistry, Department of Physical Education and Sports Science, Federal University of Pernambuco, Vitória de Santo Antão, PE, Brazil

    Severina Cassia de Andrade Silva, Jonata Henrique de Santana, Osmar Henrique dos Santos Junior & Claudia Jacques Lagranha

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Contributions

EGO: conceptualization, data curation, formal analysis, investigation, methodology, roles/writing—original draft, writing—review & editing. DAL: investigation, methodology. JCSJ: investigation, methodology. MVSB: investigation, methodology. SCAS: methodology, data curation, investigation. JHS: methodology, data curation, investigation. OHSJ: methodology, data curation, investigation. ECL: validation, visualization, funding acquisition, resources. CJL: conceptualization, methodology, data curation, investigation, writing—review & editing. FSD: conceptualization, funding acquisition, methodology, project administration, resources, supervision, validation, visualization, roles/writing—original draft, writing—review & editing. DAG: conceptualization, funding acquisition, methodology, project administration, resources, supervision, validation, visualization, roles/writing—original draft, writing—review & editing.

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Correspondence to Elifrances Galdino de Oliveira.

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de Oliveira, E.G., de Lima, D.A., da Silva Júnior, J.C. et al. (R)-ketamine attenuates neurodevelopmental disease-related phenotypes in a mouse model of maternal immune activation. Eur Arch Psychiatry Clin Neurosci 273, 1501–1512 (2023). https://doi.org/10.1007/s00406-023-01629-3

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