Behavioral alterations in rat offspring following maternal immune activation and CXC chemokine receptor antagonism
Schizophrenia patients typically exhibit cognitive impairments that directly affect their daily functioning, but are not effectively treated by current antipsychotics. Maternal immune activation (MIA) during pregnancy, which can be triggered by a variety of infectious agents, has been associated with the development of schizophrenia in adult offspring. Epidemiological evidence indicates that elevated maternal levels of the chemokine interleukin- 8 (IL-8) during MIA contribute to the neurodevelopmental alterations underlying the disorder. The present experiments used an animal model of neurodevelopmental disorders to study the effects of MIA and chemokine receptor antagonism on the behavior of rat offspring, with behavioral tests chosen to examine cognitive functions that are typically impaired in human schizophrenia patients. The viral mimetic polyinosinic-polycytidylic acid (polyI:C) (4.0 mg/kg, i.v.) was injected into pregnant Long-Evans (LE) dams on gestational day (GD) 15. Dams were also treated with the three injections of CXCL8(3–72)K11R/G31P (G31P) (500 µg/kg, i.p.), a chemokine receptor antagonist that binds CXCR1 and CXCR2 with high affinity. PolyI:C treatment significantly increased maternal levels of the chemokine CXCL1, the rodent analogue of IL-8 that binds CXCR1 and CXCR2. The offspring of polyI:C-treated dams showed impaired associative recognition memory and multisensory integration, as well as subtle impairments in prepulse inhibition (PPI). G31P administration did not reverse any of the behavioral deficits caused by polyI:C, although G31P did alter PPI during adolescence. Although the present experiments included replications and novel findings for the polyI:C model, the effects of polyI:C were smaller than in other published research. Utilizing animal models that include both genetic and environmental components, as well as more widely targeted anti-inflammatory therapies will likely result in more promising findings in future research.
DegreeMaster of Science (M.Sc.)
CommitteeMulligan, Sean; Cayabyab, Francisco
Copyright DateSeptember 2014