Molecular Neurobiology

, Volume 55, Issue 5, pp 3775–3788 | Cite as

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

  • Charllyany Sabino Custódio
  • Bruna Stefânia Ferreira Mello
  • Adriano José Maia Chaves Filho
  • Camila Nayane de Carvalho Lima
  • Rafaela Carneiro Cordeiro
  • Fábio Miyajima
  • Gislaine Z. Réus
  • Silvânia Maria Mendes Vasconcelos
  • Tatiana Barichello
  • João Quevedo
  • Antônio Carlos de Oliveira
  • David Freitas de Lucena
  • Danielle S. Macedo


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.


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



The authors acknowledge the Brazilian Governmental Institutions CAPES, CNPq, and FUNCAP for the financial support of this study (scholarships and research grant).


Authors DSM, CSC, and DFL contributed to the design of the study. CSC, BSFM, AJMCF, and RCC performed the behavioral experiments. Authors DFL, ACO, and DSM analyzed behavioral data. Authors DSM, TB, JQ, GZR, and FM analyzed the biochemical data and wrote the first draft of the paper. Authors CNCL, RCC, SMMV, and CSC performed neurochemical analyses.


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Charllyany Sabino Custódio
    • 1
    • 2
  • Bruna Stefânia Ferreira Mello
    • 1
    • 2
  • Adriano José Maia Chaves Filho
    • 1
  • Camila Nayane de Carvalho Lima
    • 1
  • Rafaela Carneiro Cordeiro
    • 1
    • 2
  • Fábio Miyajima
    • 1
    • 3
  • Gislaine Z. Réus
    • 4
  • Silvânia Maria Mendes Vasconcelos
    • 1
  • Tatiana Barichello
    • 5
    • 6
    • 7
  • João Quevedo
    • 5
    • 6
    • 7
  • Antônio Carlos de Oliveira
    • 8
  • David Freitas de Lucena
    • 1
  • Danielle S. Macedo
    • 1
    • 2
    • 9
  1. 1.Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of MedicineUniversidade Federal do CearáFortalezaBrazil
  2. 2.Medical Microbiology Postgraduate Program, Faculty of MedicineUniversidade Federal do CearáFortalezaBrazil
  3. 3.University of Liverpool Institute of Translational Medicine, Wolfson CentreLiverpoolUK
  4. 4.Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences UnitUniversity of Southern Santa Catarina (UNESC)CriciúmaBrazil
  5. 5.Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical SchoolThe University of Texas Health Science Center at Houston (UTHealth)HoustonUSA
  6. 6.Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical SchoolThe University of Texas Health Science Center at Houston (UTHealth)HoustonUSA
  7. 7.Neuroscience Graduate ProgramThe University of Texas Graduate School of Biomedical Sciences at HoustonHoustonUSA
  8. 8.Department of PharmacologyInstitute of Biological Sciences, Universidade Federal de Minas GeraisBelo HorizonteBrazil
  9. 9.National Science and Technology Institute for Translational Medicine (INCT-TM)HoustonBrazil

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