title: The risk for behavioural deficits is determined by the maternal immune response to prenatal immune challenge in a neurodevelopmental model.
abstract: BACKGROUND
  Schizophrenia is a highly disabling psychiatric disorder with a proposed neurodevelopmental basis. One mechanism through which genetic and environmental risk factors might act is by triggering persistent brain inflammation, as evidenced by long-lasting neuro-immunological disturbances in patients. Our goal was to investigate whether microglia activation is a neurobiological correlate to the altered behaviour in the maternal immune activation (MIA) model, a well-validated animal model with relevance to schizophrenia. A recent observation in the MIA model is the differential maternal body weight response to the immune stimulus, correlated with a different behavioural outcome in the offspring. Although it is generally assumed that the differences in maternal weight response reflect differences in cytokine response, this has not been investigated so far. Our aim was to investigate whether (i) the maternal weight response to MIA reflects differences in the maternal cytokine response, (ii) the differential behavioural phenotype of the offspring extends to depressive symptoms such as anhedonia and (iii) there are changes in chronic microglia activation dependent on the behavioural phenotype.
  
  
  METHODS
  Based on a dose-response study, MIA was induced in pregnant rats by injecting 4mg/kg Poly I:C at gestational day 15. Serum samples were collected to assess the amount of TNF-α in the maternal blood following MIA. MIA offspring were divided into weight loss (WL; n=14) and weight gain (WG; n=10) groups, depending on the maternal body weight response to Poly I:C. Adult offspring were behaviourally phenotyped for prepulse inhibition, locomotor activity with and without amphetamine and MK-801 challenge, and sucrose preference. Finally, microglia activation was scored on CD11b- and Iba1-immunohistochemically stained sections.
  
  
  RESULTS
  Pregnant dams that lost weight following MIA showed increased levels of TNF-α compared to controls, unlike dams that gained weight following MIA. Poly I:C WL offspring showed the most severe behavioural outcome. Poly I:C WG offspring, on the other hand, did not show clear behavioural deficits. Most interestingly a reduced sucrose preference indicative of anhedonia was found in Poly I:C WL but not Poly I:C WG offspring compared to controls. Finally, there were no significant differences in microglia activation scores between any of the investigated groups.
  
  
  CONCLUSIONS
  The individual maternal immune response to MIA is an important determinant of the behavioural outcome in offspring, including negative symptoms such as anhedonia. We failed to find any significant difference in the level of microglia activation between Poly I:C WL, Poly I:C WG and control offspring.
authors: Experimental Laboratory of Translational Neuroscience and Otolaryngology, Faculty of Medicine and Health Sciences, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors: S
authors: S
authors: Missault
authors: Experimental Laboratory of Translational Neuroscience and Otolaryngology, Faculty of Medicine and Health Sciences, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors: K
authors: K
authors: Van den Eynde
authors: Laboratory of Protein Science, Proteomics & Epigenetic Signaling, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, 2610 Wilrijk, Belgium.
authors: W
authors: W
authors: Vanden Berghe
authors: StatUA, University of Antwerp, Campus Drie Eiken, Prins Boudewijnlaan 43, 2650 Edegem, Belgium.
authors: E
authors: E
authors: Fransen
authors: StatUA, University of Antwerp, City Campus, Prinsstraat 13, 2000 Antwerpen, Belgium.
authors: A
authors: A
authors: Weeren
authors: Laboratory of Cell Biology & Histology, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium.
authors: J P
authors: JP
authors: Timmermans
authors: Laboratory of Cell Biology & Histology, Faculty of Medicine and Health Sciences, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium.
authors: S
authors: S
authors: Kumar-Singh
authors: Experimental Laboratory of Translational Neuroscience and Otolaryngology, Faculty of Medicine and Health Sciences, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, 2610 Wilrijk, Belgium. Electronic address: Stefanie.Dedeurwaerdere@hotmail.com.
authors: S
authors: S
authors: Dedeurwaerdere
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D007107:Immune System / Q000187:drug effects / Q000276:immunology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000276:immunology*; D051381:Rats; D013216:Reflex, Startle / Q000187:drug effects / Q000276:immunology; D012559:Schizophrenia / Q000276:immunology*; D015430:Weight Gain / Q000187:drug effects / Q000276:immunology; D015431:Weight Loss / Q000187:drug effects / Q000276:immunology
chemical_list: D011070:Poly I-C
keywords: Autism; Locomotion; Maternal immune activation; Neuroinflammation; Poly I:C; Schizophrenia