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Mol Neurobiol. 2018 May;55(5):3775-3788. doi: 10.1007/s12035-017-0616-1. Epub 2017 May 23.

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

Author information

1
Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Universidade Federal do Ceará, Rua Cel. Nunes de Melo 1000, Fortaleza, CE, 60430-270, Brazil.
2
Medical Microbiology Postgraduate Program, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil.
3
University of Liverpool Institute of Translational Medicine, Wolfson Centre, Block A: Waterhouse Building, 1-5 Brownlow Street, Liverpool, L69 3GL, UK.
4
Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil.
5
Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.
6
Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.
7
Neuroscience Graduate Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
8
Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
9
Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Universidade Federal do Ceará, Rua Cel. Nunes de Melo 1000, Fortaleza, CE, 60430-270, Brazil. daniellesilmacedo@gmail.com.
10
Medical Microbiology Postgraduate Program, Faculty of Medicine, Universidade Federal do Ceará, Fortaleza, CE, Brazil. daniellesilmacedo@gmail.com.
11
National Science and Technology Institute for Translational Medicine (INCT-TM), Houston, Brazil. daniellesilmacedo@gmail.com.

Abstract

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.

KEYWORDS:

Age; Autism spectrum disorder; Immune activation; Immune-inflammatory alterations; Lipopolysaccharide; Sex differences

PMID:
28536974
DOI:
10.1007/s12035-017-0616-1
[Indexed for MEDLINE]

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