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Schizophrenia Environmental Risk Factors Act Synergistically in Mice

12 March 2013. A new mouse study links two environmental risk factors for schizophrenia and other psychiatric disorders—prenatal maternal infection and early life trauma—and finds a synergistic effect on behavior, neurochemistry, and neuroimmunology. Led by Urs Meyer of the Swiss Federal Institute of Technology and published March 1 in Science, the study supports a “two-hit” model of schizophrenia, which posits that genetic or environmental factors that disrupt early brain development result in vulnerability to a later environmental hit that produces symptom onset (Maynard et al., 2001).

The idea that mothers who develop infections while pregnant are more likely to have offspring with schizophrenia has been around for several decades, first supported by the finding in a Finnish cohort that fetuses in their second trimester during the 1957 Asian influenza epidemic had an elevated risk of developing schizophrenia later in life (Mednick et al., 1988; see SRF related news story). The risk for schizophrenia extends beyond viral infections to include bacteria and parasites as well, suggesting that the mother’s inflammatory response to infection is more critical to the alteration of fetal brain development than the actual infection itself (Brown and Derkits, 2010). Early life trauma, including abuse and death of a parent during childhood or adolescence, has also been associated with risk for schizophrenia and psychosis later in life (see SRF related news story; SRF news story).

The risks of maternal infection and trauma extend beyond schizophrenia, and have also been implicated in other developmental psychiatric illnesses such as bipolar disorder and autism (Tsuchiya et al., 2003; Herbert, 2010). However, the rather small risk that each factor alone contributes to the illnesses suggests that two or more factors may combine to produce symptom onset, with the first factor producing a vulnerability to subsequent hits.

In the current study, first author Sandra Giovanoli and colleagues examined this hypothesis using a mouse model. The researchers investigated the consequences of prenatal immune activation with or without subsequent stress during puberty. To elicit maternal immune activation, they mimicked viral infection with administration of polyriboinosinic-polyribocytidylic acid, or poly(I:C), to pregnant dams. Offspring were then allowed to develop normally, or were exposed to a series of five stressors such as an electric foot shock and water deprivation during puberty (postnatal days 30-40).

Immune activation + stress = behavioral alterations
Behavioral testing of adult animals revealed several separate and combined effects of maternal immune activation and peripubertal stress. Anxiety-like behavior, as assessed using the elevated plus maze, was similarly increased in both groups of stress-exposed animals (with and without prenatal immune activation), suggesting that the prenatal immunological manipulation did not affect anxiety-like behavior. Stress exposure and immune activation also exerted separate effects on a conditioned active avoidance paradigm, with the absence of a significant latent inhibition effect, indicating impaired associative learning, observed in all groups except the control animals not exposed to stress.

In contrast, synergistic effects of prenatal immune activation and peripubertal stress were observed on two schizophrenia-relevant behaviors. Neither immune activation nor stress exposure alone produced a sensorimotor gating deficiency (measured by prepulse inhibition of the acoustic startle reflex) or behavioral hypersensitivity to the psychotomimetic drugs amphetamine and MK-801 (measured by locomotor activity). However, when the two environmental factors were combined, sensorimotor gating impairments and hyperactivity after drug exposure were observed.

In contrast to the findings in adult animals, with the exception of anxiety-like behavior, none of the behaviors were altered during puberty, suggesting that the effects of immune activation and stress are dependent on maturational processes that occur during or after puberty. In addition, when the researchers delayed the application of stress until later in adolescence (postnatal days 5-60), they did not find an interaction with prenatal immune activation, indicating that a precise timing of the stress was necessary to produce the synergistic effects.

Neurochemical correlates
The observed behavioral abnormalities appear to be independent of changes in the hypothalamus-pituitary-adrenal (HPA) stress-response system, since levels of the primary HPA axis hormone corticosterone were unaffected. However, several neurochemical abnormalities were observed after prenatal immune activation and/or peripubertal stress. Giovanoli and colleagues found elevated dopamine levels in the nucleus accumbens after prenatal immune activation, which were not affected by stress exposure. In contrast, stress exposure produced a decrease in the medial prefrontal cortex levels of serotonin that was independent of prenatal history. Dopamine levels in the hippocampus were elevated only after exposure to both environmental factors, pointing to a role for combined exposure in alterations of the classical schizophrenia neurotransmitter.

Interestingly, another recent study has found alterations in the glutamatergic system, another key player in schizophrenia, in mice born to mothers exposed to poly(I:C) (Holloway et al., 2013). A reduction in mGluR2 receptors in frontal cortex was observed, suggesting that the glutamatergic system may be an interesting target to examine in future studies investigating the synergy between maternal immune activation and stress. Holloway and colleagues also observed elevated levels of 5HT2A receptors in offspring of poly(I:C)-exposed mice.

Neuroimmunological correlates
Because prenatal immune activation and chronic stress have both individually been associated with subsequent immune alterations in the brain (Hsiao et al., 2012; Frank et al., 2007), Meyer and colleagues next examined neuroimmunological responses to their maternal immunological activation and peripubertal stress paradigms in two relevant brain regions—the hippocampus and the prefrontal cortex—as well as in a control region, secondary motor cortex, which is insensitive to immunological changes after stress.

Immune activation and stress, singly or in combination, had little impact on microglial cells (key mediators of inflammatory responses in the nervous system) in adult animals, but led to a dramatic increase in peripubertal animals’ vulnerability to stress-induced neuroimmunological changes. CD68 and CD11b, markers of activated microglia, were increased in the hippocampus and prefrontal cortex, but not secondary motor cortex. These changes were also accompanied by increased levels of the proinflammatory cytokines IL-1β and TNF-α, although levels of corticosterone were unchanged. Finally, mRNA levels of CD200, CD200R, and CD47, effectors of neuron-microglia inhibitory signaling, were also altered in the hippocampus and prefrontal cortex after combined exposure to prenatal immune activation and stress.

Future studies are needed to determine how well the findings in mice translate to humans, although the current data are consistent with synergistic interactions between two known environmental risk factors for developmental psychiatric illnesses. The authors write that their findings suggest that “prenatal adversities … can thus function as a ‘disease primer’ that increases the offspring’s vulnerability to the detrimental neuropathological effects of subsequent stress exposure during peripubertal life.”—Allison A. Curley

Giovanoli S, Engler H, Engler A, Richetto J, Voget M, Willi R, Winter C, Riva MA, Mortensen PB, Schedlowski M, Meyer U. Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. Science . 2013 Mar 1 ; 339(6123):1095-9. Abstract

Comments on News and Primary Papers
Primary Papers: Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice.

Comment by:  Patricio O'Donnell, SRF Advisor
Submitted 7 March 2013 Posted 7 March 2013

The “two-hit” hypothesis for neuropsychiatric disorders,...  Read more

View all comments by Patricio O'Donnell

Primary Papers: Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice.

Comment by:  Lindsay HayesAkira Sawa (SRF Advisor)
Submitted 8 March 2013 Posted 8 March 2013

In a time when gene-environment interactions are the hot...  Read more

View all comments by Lindsay Hayes
View all comments by Akira Sawa

Primary Papers: Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice.

Comment by:  John McGrath, SRF Advisor
Submitted 8 March 2013 Posted 12 March 2013
  I recommend this paper

This is a smart paper. It extends the solid body of...  Read more

View all comments by John McGrath
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