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Effects of Immune Activation during Early or Late Gestation on N-Methyl-ᴅ-Aspartate Receptor Measures in Adult Rat Offspring

Rahman, T, Zavitsanou, K, Purves-Tyson, T, Harms, LR, Meehan, C, Schall, U, Todd, J, Hodgson, DM, Michie, PT and Weickert, CS 2017 , 'Effects of Immune Activation during Early or Late Gestation on N-Methyl-ᴅ-Aspartate Receptor Measures in Adult Rat Offspring' , Frontiers in Psychiatry , pp. 1-12 , doi:

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Background: Glutamatergic receptor [N-methyl-ᴅ-aspartate receptor (NMDAR)] alterationswithin cortex, hippocampus, and striatum are linked to schizophrenia pathology.Maternal immune activation (MIA) is an environmental risk factor for the developmentof schizophrenia in offspring. In rodents, gestational timing of MIA may result in distinctbehavioral outcomes in adulthood, but how timing of MIA may impact the nature andextent of NMDAR-related changes in brain is not known. We hypothesize that NMDARrelatedmolecular changes in rat cortex, striatum, and hippocampus are induced by MIAand are dependent on the timing of gestational inflammation and sex of the offspring.Methods: Wistar dams were treated the with viral mimic, polyriboinosinic:polyribocytidylicacid (polyI:C), or vehicle on either gestational day 10 or 19. Fresh-frozen coronal brainsections were collected from offspring between postnatal day 63–91. Autoradiographicbinding was used to infer levels of the NMDAR channel, and NR2A and NR2B subunitsin cortex [cingulate (Cg), motor, auditory], hippocampus (dentate gyrus, cornu ammonisarea 3, cornu ammonis area 1), and striatum [dorsal striatum, nucleus accumbens core,and nucleus accumbens shell (AS)]. NR1 and NR2A mRNA levels were measured byin situ hybridization in cortex, hippocampus, and striatum in male offspring only.Results: In the total sample, NMDAR channel binding was elevated in the Cg of polyI:Coffspring. NR2A binding was elevated, while NR2B binding was unchanged, in all brainregions of polyI:C offspring overall. Male, but not female, polyI:C offspring exhibitedincreased NMDAR channel and NR2A binding in the striatum overall, and increased NR2A binding in the cortex overall. Male polyI:C offspring exhibited increased NR1 mRNAin the AS, and increased NR2A mRNA in cortex and subregions of the hippocampus.Conclusion: MIA may alter glutamatergic signaling in cortical and hippocampal regionsvia alterations in NMDAR indices; however, this was independent of gestational timing.Male MIA offspring have exaggerated changes in NMDAR compared to females inboth the cortex and striatum. The MIA-induced increase in NR2A may decrease brainplasticity and contribute to the exacerbated behavioral changes reported in males andindicate that the brains of male offspring are more susceptible to long-lasting changes inglutamate neurotransmission induced by developmental inflammation.

Item Type: Article
Authors/Creators:Rahman, T and Zavitsanou, K and Purves-Tyson, T and Harms, LR and Meehan, C and Schall, U and Todd, J and Hodgson, DM and Michie, PT and Weickert, CS
Keywords: NMDA, Rat, poly I:C, Maternal immune activation, Glutamate, Hippocampus, Striatum
Journal or Publication Title: Frontiers in Psychiatry
Publisher: Frontiers Research Foundation
ISSN: 1664-0640
DOI / ID Number:
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© 2017 Rahman, Zavitsanou, Purves-Tyson, Harms, Meehan, Schall, Todd, Hodgson, Michie and Weickert. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0)

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