Prenatal Stress Induces Schizophrenia-Like Alterations of Serotonin 2A and Metabotropic Glutamate 2 Receptors in the Adult Offspring: Role of Maternal Immune System

Abstract

It has been suggested that severe adverse life events during pregnancy increase the risk of schizophrenia in the offspring. The serotonin 5-HT2A and the metabotropic glutamate 2 (mGlu2) receptors both have been the target of considerable attention regarding schizophrenia and antipsychotic drug development. We tested the effects of maternal variable stress during pregnancy on expression and behavioral function of these two receptors in mice. Prenatal stress increased 5-HT2A and decreased mGlu2 expression in frontal cortex, a brain region involved in perception, cognition and mood. This pattern of expression of 5-HT2A and mGlu2 receptors was consistent with behavioral alterations, including increased head-twitch response to the hallucinogenic 5-HT2A agonist DOI, and decreased mGlu2-dependent antipsychotic-like effect of the mGlu2/3 agonist LY379268 in adult, but not prepubertal, mice born to stressed mothers during pregnancy. Cross-fostering studies determined that these alterations were not due to effects of prenatal stress on maternal care. Additionally, a similar pattern of biochemical and behavioral changes were observed in mice born to mothers injected with poly-(I:C) during pregnancy as a model of prenatal immune activation. These data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for schizophrenia and other psychiatric disorders.

Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia

“…Compared with controls, MIA offspring display an elevated level of 5-HT2AR in the PFC, which can explain the deficit of sensory gating and greater DOI-induced schizophrenia-like behavior and brain activity in these animals. Increased 5-HT2AR in the PFC was also reported for other rodent models that exhibit high sensitivity to DOI (29)(30)(31). Moreover, similar observations were made in antipsychotic-free schizophrenic subjects (28).…”

“…Here, we combined these two factors, MIA and an acute injection of hallucinogenic drug DOI, and found that MIA offspring display stronger DOI-induced behavioral responses and greater brain activity as measured both by IEG induction and MEMRI. Elevated sensitivity to DOI and up-regulation of egr-1 in the PFC was also reported previously for offspring born to influenzainfected or poly(I:C)-injected pregnant mice (30,31). In addition, these mice also display a decreased density of metabotropic glutamate 2 receptors (mGluR2s) in the PFC.…”

“…Compared with controls, antipsychotic-free human schizophrenic subjects display an increased 5-HT2AR level in the PFC (28). Moreover, rodent models of schizophrenia, including MIA and prenatal or postnatal stress, yield offspring with elevated 5-HT2AR in the PFC, as well as a greater sensitivity to DOI (29)(30)(31). We find that, compared with controls, MIA offspring exhibit a 50% increase in 5-HT2AR mRNA levels in the PFC [t (26) = 2.738, P < 0.05] (Fig.…”

Maternal lipopolysaccharide treatment differentially affects 5-HT2A and mGlu2/3 receptor function in the adult male and female rat offspring

“…Interestingly, both male as well as female rats born to immune-challenged mothers showed a significantly stronger response compared to control animals. Similar findings have also been observed in adult mice exposed to prenatal stress as well as in offspring born to influenza virus infected mothers (Moreno et al, 2011;Holloway et al, 2013). Additionally, prenatally immune-challenged mice displayed an elevated DOI-induced neuronal activity in several brain regions, including the PFC, thalamus and striatum, as revealed by manganese-enhanced magnetic resonance imaging (Malkova et al, 2014).…”

Prenatal glucocorticoid exposure in rats: programming effects on stress reactivity and cognition in adult offspring

“…There is some evidence that prenatal stress alters maternal care, which might influence and further contribute to the alterations in the offspring (Francis et al, 1999;Kuo et al, 2014). Although in this experiment we were unable to dissect any contribution of prenatal and postnatal maternal effects on the programmed phenotypes in offspring, previous studies including in this model suggest that the programming effects induced by prenatal treatment are independent of maternal postnatal behavior (Holloway et al, 2013;Nyirenda et al, 2001). …”