Neonatal Immune Challenge with Lipopolysaccharide Triggers Long-lasting Sex- and Age-related Behavioral and Immune/Neurotrophic Alterations in Mice: Relevance to Autism Spectrum Disorders

• Published in: Molecular neurobiology Vol. 55; no. 5; pp. 3775 - 3788
• Main Authors: Custódio, Charllyany Sabino, Mello, Bruna Stefânia Ferreira, Filho, Adriano José Maia Chaves, de Carvalho Lima, Camila Nayane, Cordeiro, Rafaela Carneiro, Miyajima, Fábio, Réus, Gislaine Z., Vasconcelos, Silvânia Maria Mendes, Barichello, Tatiana, Quevedo, João, de Oliveira, Antônio Carlos, de Lucena, David Freitas, Macedo, Danielle S.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.05.2018; Springer Nature B.V
• Subjects: Age; Age Factors; Animals; Anxiety; Autism; Autism Spectrum Disorder - immunology; Autism Spectrum Disorder - metabolism; Behavior, Animal - drug effects; Behavior, Animal - physiology; Biomedical and Life Sciences; Biomedicine; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Cell Biology; Disease Models, Animal; Female; Females; Hippocampus - drug effects; Hippocampus - metabolism; Hypothalamus; Hypothalamus - drug effects; Hypothalamus - metabolism; Immune system; Innate immunity; Interleukin 4; Interleukin 6; Lipid Peroxidation; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Male; Males; Maze Learning - drug effects; Memory, Short-Term - drug effects; Mental disorders; Mice; Neonates; Neurobiology; Neurodevelopmental disorders; Neurology; Neurosciences; Parvalbumin; Peroxidase; Prefrontal cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Rodents; Schizophrenia; Sex differences; Sex Factors; Sexes; Short term memory; γ-Interferon; Lipopolysaccharide; Sex differences; Immune activation; Immune-inflammatory alterations; Autism spectrum disorder; Age
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-017-0616-1

Early-life challenges, particularly infections and stress, are related to neuropsychiatric disorders such as autism and schizophrenia. Here, we conducted a wide range of behavioral tests in periadolescent (postnatal day (PN) 35) and adult (PN70) Swiss mice neonatally challenged with LPS on PN5 and -7, to unveil behavioral alterations triggered by LPS exposure. Immune and neurotrophic (brain-derived neurotrophic factor—BDNF) alterations were determined in the prefrontal cortex (PFC), hippocampus (HC), and hypothalamus (HT). Since the incidence and clinical manifestations of neurodevelopmental disorders present significant sex-related differences, we sought to distinctly evaluate male and female mice. While on PN35, LPS-challenged male mice presented depressive, anxiety-like, repetitive behavior, and working memory deficits; on PN70, only depressive- and anxiety-like behaviors were observed. Conversely, females presented prepulse inhibition (PPI) deficits in both ages studied. Behavioral changes in periadolescence and adulthood were accompanied, in both sexes, by increased levels of interleukin (IL-4) (PFC, HC, and HT) and decreased levels of IL-6 (PFC, HC, and HT). BDNF levels increased in both sexes on PN70. LPS-challenged male mice presented, in both ages evaluated, increased HC myeloperoxidase activity (MPO); while when adult increased levels of interferon gamma (IFNγ), nitrite and decreased parvalbumin were observed. Alterations in innate immunity and parvalbumin were the main LPS-induced remarks between males and females in our study. We concluded that neonatal LPS challenge triggers sex-specific behavioral and neurochemical alterations that resemble autism spectrum disorder, constituting in a relevant model for the mechanistic investigation of sex bias associated with the development of this disorder.