title: Maternal immune activation induces changes in myelin and metabolic proteins, some of which can be prevented with risperidone in adolescence.
abstract: BACKGROUND
  Maternal infection is a risk factor for schizophrenia but the molecular and cellular mechanisms are not fully known. Myelin abnormalities are amongst the most robust neuropathological changes observed in schizophrenia, and preliminary evidence suggests that prenatal inflammation may play a role.
  
  
  METHODS
  Label-free liquid chromatography-mass spectrometry was performed on the prefrontal cortex (PFC) of adult rat offspring born to dams that were exposed on gestational day 15 to the viral mimic polyinosinic:polycytidylic acid [poly(I:C), 4 mg/kg] or saline and treated with the atypical antipsychotic drug risperidone (0.045 mg/kg) or saline in adolescence. Western blotting was employed to validate protein changes.
  
  
  RESULTS
  Over 1,000 proteins were quantified in the PFC with pathway analyses implicating changes in core metabolic pathways, following prenatal poly(I:C) exposure. Some of these protein changes were absent in the PFC of poly(I:C)-treated offspring that subsequently received risperidone treatment in adolescence. Particularly interesting reductions in the expression of the myelin-related proteins myelin basic protein isoform 3 (MBP1) and rhombex 29 were observed, which were reversed by risperidone treatment. Validation by Western blotting confirmed changes in MBP1 and mitogen-activated kinase 1 (MAPK1). Western blotting was extended to assess the MAPK signalling proteins due to their roles in inflammation, namely phosphorylated MAPK1 and phosphorylated MAPK-activated protein kinase 2. Both were upregulated by poly(I:C) treatment and reversed by risperidone treatment.
  
  
  CONCLUSIONS
  Overall, our data suggest that maternal inflammation may contribute to an increased risk for schizophrenia through mechanisms involving metabolic function and myelin formation and that risperidone in adolescence may prevent or reverse such changes.
authors.affiliation: Department of Psychiatry, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.
authors.forename: Lorna
authors.initials: L
authors.lastname: Farrelly
authors.forename: Melanie
authors.initials: M
authors.lastname: Föcking
authors.forename: Yael
authors.initials: Y
authors.lastname: Piontkewitz
authors.forename: Patrick
authors.initials: P
authors.lastname: Dicker
authors.forename: Jane
authors.initials: J
authors.lastname: English
authors.forename: Kieran
authors.initials: K
authors.lastname: Wynne
authors.forename: Mary
authors.initials: M
authors.lastname: Cannon
authors.forename: Gerard
authors.initials: G
authors.lastname: Cagney
authors.forename: David R
authors.initials: DR
authors.lastname: Cotter
mesh_terms: D000375:Aging; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D009186:Myelin Sheath / Q000187:drug effects*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D017208:Rats, Wistar; D018967:Risperidone / Q000494:pharmacology*; D012559:Schizophrenia / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D018967:Risperidone