Prenatal immune challenge in rats: Effects of polyinosinic–polycytidylic acid on spatial learning, prepulse inhibition, conditioned fear, and responses to MK-801 and amphetamine

Abstract

Prenatal maternal immune activation increases risk for schizophrenia and/or autism. Previous data suggest that maternal weight change in response to the immune activator polyinosinic-polycytidylic (Poly IC) in rats influences the severity of effect in the offspring as does the exposure period. We treated gravid Sprague-Dawley rats from E14-18 with 8 mg/kg/day Poly IC or saline. The Poly IC group was divided into those that gained the least weight or lost (Poly IC (L)) and those that gained the most (Poly IC (H)) weight. There were no effects of Poly IC on anxiety (elevated zero-maze, open-field, object burying), or Morris water maze cued learning or working memory or Cincinnati water maze egocentric learning. The Poly IC (H) group males had decreased acoustic startle whereas Poly IC (L) females had reduced startle and increased PPI. Poly IC offspring showed exaggerated hyperactivity in response to amphetamine (primarily in the Poly IC (H) groups) and attenuated hyperactivity in response to MK-801 challenge (primarily in the Poly IC (L) group). Poly IC (L) males showed reduced cued conditioned freezing; both sexes showed less time in the dark in a light-dark test, and the Poly IC groups showed impaired Morris water maze hidden platform acquisition and probe performance. The data demonstrate that offspring from the most affected dams were more affected than those from less reactive dams indicating that, degree of maternal immune activation predicts severity of effects on offspring behavior.

Maternal immune activation during pregnancy in rats impairs working memory capacity of the offspring

“…Notably, the present results show no difference between polyI:C and saline offspring during the initial nonmatching-tosample phase of the OST, which has a working memory component. Thus, our lack of effect with odor stimuli is consistent with the findings of Vorhees et al (2015) using a spatial matching-to-sample task. When the polyI:C-offspring were presented with the more challenging OST, deficits in task acquisition and performance emerged, consistent with impaired working memory capacity.…”

“…PolyI:C offspring are impaired on the OST Some previous studies have shown impaired working memory in the offspring of polyI:C-treated mice (Bitanihirwe et al 2010;Meyer et al 2005;Richetto et al 2013;2014); however, others have failed to see effects in young adult mice tested at short delays (Krstic et al 2012;Meyer et al 2005) and rats (Vorhees et al 2015). Notably, the present results show no difference between polyI:C and saline offspring during the initial nonmatching-tosample phase of the OST, which has a working memory component.…”

“…In general, working memory impairments in the offspring from MIA litters have been observed, particularly with longer delays and in older animals. In rats, no effects on a matching-to-sample working memory task in the water maze were observed in offspring following MIA during pregnancy (Vorhees et al 2015). Importantly, the tasks used in these previous studies require rodents to remember a limited amount of information without manipulating capacity.…”

Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology

“…It should be noted here that male specific effects of poly-I:C on PPI occurred when offspring were exposed at GD9, while femalespecific PPI deficits were found when exposed to poly-I:C at GD14 -therefore the timing of infection may impact the male and female developing brain differently. Vorhees et al also found male specific deficits in fear-potentiated memory (cue conditioned freezing) in the offspring of poly-I:C exposed rats, but only following a repeated dosing regimen of poly-I:C injections from gestational day 14-18, while a single injection at day 14 had no such effect on the offspring (Vorhees et al 2012;Vorhees et al 2015). However, spatial memory, as assessed using a spontaneous alternation paradigm in the Y-maze, was specifically disrupted in female mouse offspring exposed to poly-I:C (5mk/kg i.p., GD9, n=5-8/group) (O'Leary et al 2014).…”

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

“…However, high etiological validity can come at a cost. When measuring cognition, testing may be confounded by differences in learning (Vorhees et al 2012;Vorhees et al 2015). In addition, these models often produce a variety of nonspecific and diverse neurological changes, thus preventing the study of isolated systems (Hadar et al 2015).…”