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

• Published in: European archives of psychiatry and clinical neuroscience Vol. 273; no. 7; pp. 1501 - 1512
• Main Authors: de Oliveira, Elifrances Galdino, de Lima, Diógenes Afonso, da Silva Júnior, José Carlos, de Souza Barbosa, Mayara Victória, de Andrade Silva, Severina Cassia, de Santana, Jonata Henrique, dos Santos Junior, Osmar Henrique, Lira, Eduardo Carvalho, Lagranha, Claudia Jacques, Duarte, Filipe Silveira, Gomes, Dayane Aparecida
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2023; Springer; Springer Nature B.V
• Subjects: Analysis; Animal models; Anti-inflammatory agents; Anxiety; Autism; Cytokines; Emotional behavior; Gene expression; Genetic aspects; Health aspects; Immune response; Inflammation; Interleukin 6; Ketamine; Lipid peroxidation; Lipopolysaccharides; Locomotor activity; Medical research; Medicine; Medicine & Public Health; Medicine, Experimental; Mental disorders; Missing in action; Nervous system diseases; Neurodevelopmental disorders; Neurosciences; Offspring; Open-field behavior; Original Paper; Phenotype; Phenotypes; Prefrontal cortex; Pregnant women; Psychiatry; Schizophrenia; Social aspects; Social behavior; Social interaction; Transforming growth factor-b1; Emotional behavior; Inflammation; Maternal immune activation; Prefrontal cortex; Oxidative imbalance; (R)-ketamine
• ISSN: 0940-1334; 1433-8491; 1433-8491
• DOI: 10.1007/s00406-023-01629-3

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.