Evolution of a maternal immune activation (mIA) model in rats: Early developmental effects

Katie N Murray, Michelle E Edye, Maurizio Manca, Anthony C Vernon, Joanna M Oladipo, Victoria Fasolino, Michael K Harte, Varsha Mason, Ben Grayson, Patrick C McHugh, Irene Knuesel, Eric P Prinssen, Reinmar Hager, Joanna C Neill

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Abstract

Maternal immune activation (mIA) in rodents is rapidly emerging as a key model for neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia. Here, we optimise a mIA model in rats, aiming to address certain limitations of current work in this field. Specifically, the lack of clear evidence for methodology chosen, identification of successful induction of mIA in the dams and investigation of male offspring only. We focus on gestational and early juvenile changes in offspring following mIA, as detailed information on these critical early developmental time points is sparse. Following strain (Wistar, Lister Hooded, Sprague Dawley) comparison and selection, and polyriboinosinic-polyribocytidylic acid (poly I:C) dose selection (2.5–15 mg/kg single or once daily for 5 days), mIA was induced in pregnant Wistar rats with 10 mg/kg poly I:C i.p. on gestational day (GD) 15. Early morphometric analysis was conducted in male and female offspring at GD21 and postnatal day (PD) 21, eight dams for each treatment at each time point were used, 32 in total. Subsequent microglia analysis was conducted at PD21 in a small group of offspring. Poly I:C at 10 mg/kg i.p. induced a robust, but variable, plasma IL-6 response 3 h post-injection and reduced body weight at 6 h and 24 h post-injection in two separate cohorts of Wistar rats at GD15. Plasma IL-6 was not elevated at PD21 in offspring or dams. Poly I:C-induced mIA did not affect litter numbers, but resulted in PD21 pup, and GD21 placenta growth restriction. Poly I:C significantly increased microglial activation at PD21 in male hippocampi. We have identified 10 mg/kg poly I:C i.p on GD15 as a robust experimental approach for inducing mIA in Wistar rats and used this to identify early neurodevelopmental changes. This work provides a framework to study the developmental trajectory of disease-relevant, sex-specific phenotypic changes in rats.

LanguageEnglish
Pages48-59
Number of pages12
JournalBrain, Behavior, and Immunity
Volume75
Early online date12 Sep 2018
DOIs
Publication statusPublished - Jan 2019

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Mothers
Poly I-C
Wistar Rats
Interleukin-6
Injections
Acids
Microglia
Placenta
Rodentia
Hippocampus
Schizophrenia
Body Weight
Growth
Therapeutics

Cite this

Murray, Katie N ; Edye, Michelle E ; Manca, Maurizio ; Vernon, Anthony C ; Oladipo, Joanna M ; Fasolino, Victoria ; Harte, Michael K ; Mason, Varsha ; Grayson, Ben ; McHugh, Patrick C ; Knuesel, Irene ; Prinssen, Eric P ; Hager, Reinmar ; Neill, Joanna C. / Evolution of a maternal immune activation (mIA) model in rats : Early developmental effects. In: Brain, Behavior, and Immunity. 2019 ; Vol. 75. pp. 48-59.
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Murray, KN, Edye, ME, Manca, M, Vernon, AC, Oladipo, JM, Fasolino, V, Harte, MK, Mason, V, Grayson, B, McHugh, PC, Knuesel, I, Prinssen, EP, Hager, R & Neill, JC 2019, 'Evolution of a maternal immune activation (mIA) model in rats: Early developmental effects', Brain, Behavior, and Immunity, vol. 75, pp. 48-59. https://doi.org/10.1016/j.bbi.2018.09.005

Evolution of a maternal immune activation (mIA) model in rats : Early developmental effects. / Murray, Katie N; Edye, Michelle E; Manca, Maurizio; Vernon, Anthony C; Oladipo, Joanna M; Fasolino, Victoria; Harte, Michael K; Mason, Varsha; Grayson, Ben; McHugh, Patrick C; Knuesel, Irene; Prinssen, Eric P; Hager, Reinmar; Neill, Joanna C.

In: Brain, Behavior, and Immunity, Vol. 75, 01.2019, p. 48-59.

Research output: Contribution to journalArticle

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T2 - Brain, Behavior, and Immunity

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AU - Manca, Maurizio

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AU - Oladipo, Joanna M

AU - Fasolino, Victoria

AU - Harte, Michael K

AU - Mason, Varsha

AU - Grayson, Ben

AU - McHugh, Patrick C

AU - Knuesel, Irene

AU - Prinssen, Eric P

AU - Hager, Reinmar

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KW - Placenta

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