Behavioral alterations in rat offspring following maternal immune activation and ELR-CXC chemokine receptor antagonism during pregnancy: Implications for neurodevelopmental psychiatric disorders

Dec 3, 2014Progress in neuro-psychopharmacology & biological psychiatry

Behavior changes in rat offspring after maternal immune activation and blocking specific immune signals during pregnancy: implications for brain development disorders

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Abstract

Polyinosinic-polycytidylic acid (polyI:C) treatment significantly increased maternal serum concentrations of interleukin-1β, tumor necrosis factor, and CXCL1 3 hours after administration.

Maternal immune activation during pregnancy is linked to a higher risk of neurodevelopmental disorders in offspring.
Elevated levels of maternal interleukin-8 (IL-8) are associated with increased risk of schizophrenia in children.
Male offspring from mothers treated with polyI:C exhibited subtle impairments in prepulse inhibition, memory, and behavioral flexibility.
The administration of a CXCR1/CXCR2 antagonist partially improved some behavioral deficits in offspring but did not fully reverse the effects.
Increased maternal CXCL1 may contribute to behavioral changes, but it is not the sole factor responsible for the outcomes observed.

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Research suggests that maternal immune activation (MIA) during pregnancy increases the risk of neurodevelopmental disorders including schizophrenia and autism in the offspring. Current theories suggest that inflammatory mediators including cytokines and chemokines may underlie the increased risk of these disorders in humans. For example, elevated maternal interleukin-8 (IL-8) during pregnancy is associated with increased risk of schizophrenia in the offspring. Given this association, the present experiments examined ELR-CXC chemokines CXCL1 and CXCL2, rodent homologues of human IL-8, and activation of their receptors (CXCR1 and CXCR2) in an established rodent model of MIA. Pregnant Long Evans rats were treated with the viral mimetic polyinosinic-polycytidylic acid (polyI:C; 4 mg/kg, i.v.) on gestational day 15. Protein analysis using multiplex assays and ELISA showed that polyI:C significantly increased maternal serum concentrations of interleukin-1β, tumor necrosis factor, and CXCL1 3h after administration. Subsequent experiments tested the role of elevated maternal CXCL1 on behavior of the offspring by administering a CXCR1/CXCR2 antagonist (G31P; 500 μg/kg, i.p.; 1h before, 48 and 96 h after polyI:C treatment). The male offspring of dams treated with polyI:C demonstrated subtle impairments in prepulse inhibition (PPI), impaired associative and crossmodal recognition memory, and altered behavioral flexibility in an operant test battery. While G31P did not completely reverse the behavioral impairments caused by polyI:C, it enhanced PPI during adolescence and strategy set-shifting and reversal learning during young adulthood. These results suggest that while polyI:C treatment significantly increases maternal CXCL1, elevations of this chemokine are not solely responsible for the effects of polyI:C on the behavior of the offspring.

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Behavioral alterations in rat offspring following maternal immune activation and ELR-CXC chemokine receptor antagonism during pregnancy: Implications for neurodevelopmental psychiatric disorders

Abstract

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