Prenatal immune challenge in rats: Altered responses to dopaminergic and glutamatergic agents, prepulse inhibition of acoustic startle, and reduced route‐based learning as a function of maternal body weight gain after prenatal exposure to poly IC

Abstract

Prenatal maternal immune activation has been used to test the neurodevelopmental hypothesis of schizophrenia. Most of the data are in mouse models; far less is available for rats. We previously showed that maternal weight change in response to the immune activator polyinosinic-polycytidylic (Poly IC) in rats differentially affects offspring. Therefore, we treated gravid Harlan Sprague-Dawley rats i.p. on embryonic day 14 with 8 mg/kg of Poly IC or Saline. The Poly IC group was divided into those that lost or gained the least weight, Poly IC (L), versus those that gained the most weight, Poly IC (H), following treatment. The study design controlled for litter size, litter sampling, sex distribution, and test experience. We found no effects of Poly IC on elevated zero-maze, open-field activity, object burying, light-dark test, straight channel swimming, Morris water maze spatial acquisition, reversal, or shift navigation or spatial working or reference memory, or conditioned contextual or cued fear or latent inhibition. The Poly IC (H) group showed a significant decrease in the rate of route-based learning when visible cues unavailable in the Cincinnati water maze and reduced prepulse inhibition of acoustic startle in females, but not males. The Poly IC (L) group exhibited altered responses to acute pharmacological challenges: exaggerated hyperactivity in response to (+)-amphetamine and an attenuated hyperactivity in response to MK-801. This model did not exhibit the cognitive, acoustic startle, or latent inhibition deficits reported in Poly IC-treated rats, but showed changes in response to drugs acting on neurotransmitter systems implicated in the pathophysiology of schizophrenia (dopaminergic hyperfunction and glutamatergic hypofunction).

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

“…GD 14) (Vorhees et al 2012). 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.…”

“…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).…”

Different Paths to Core Pathology: The Equifinal Model of the Schizophrenia Syndrome

“…[37][38][39][40] Experimental animal models of maternal immune activation have provided insights into these multifactor relationships. For example, mice exposed to immune activation in utero show schizophrenia syndrome-relevant behavioral abnormalities in adulthood, such as impaired sensorimotor gating [41][42][43] and cognitive ability, 41,[43][44][45][46][47] including working memory. 48,49 Maternal immune activation models also show molecular changes that are identified in the PFC of individuals with schizophrenia, 50 including lower expression of PV, 43 GAD67, 51 and GAD67 in PV axonal boutons.…”