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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. PubMed Abstract

Comments on Paper and Primary News
Comment by:  Patricio O'Donnell, SRF Advisor
Submitted 7 March 2013 Posted 7 March 2013

The “two-hit” hypothesis for neuropsychiatric disorders, although popular, has seldom been directly tested using animal models. Giovanoli et al. provide compelling evidence of synergistic interactions among prenatal immune activation and pubertal social stress in driving abnormal adult behaviors. This is a refreshing use of animal models, quite welcome at a time when the field is plagued with useless considerations about “validity” in rodent models of psychiatric disorders. Questioning animal models based on perceived validity issues not only does not advance the field, but also blocks avenues of progress, and animal research related to psychiatric disorders should abandon psychiatry-irrelevant concepts such as “validity.” Animal models are tools, like reagents, that can be used to test specific hypotheses that relate to etiology or pathophysiology of mental disorders (O’Donnell, 2013). The group of Urs Meyer used maternal immune activation in mice as a tool to establish a latent pathological condition that per se produces mild behavioral deficits. Adolescent stress, on the...  Read more

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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 topic, Giovanoli et al. pushed the envelope a little further by providing evidence that multiple environmental hits may be an additional mechanism mediating the neuropathology of some developmental psychiatric disorders—a model for environment-environment interactions. In the current study, the authors used a sub-threshold dose of maternal immune activation (MIA) in combination with juvenile stress to uncover a synergistic effect mediating a worsened behavioral outcome, suggesting MIA and juvenile stress may utilize a common biological pathway. In addition, they revealed that juvenile stress was only effective during a critical period to mediate the compounded effect, thus highlighting the need for a greater understanding of the mechanisms underlying biological susceptibilities in adolescence.

Urs Meyer, and his group, are leading figures in the MIA model used to study developmental psychiatric disorders. MIA at various stages during prenatal development can lead to stereotypic behavioral changes in the offspring (  Read more

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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 research demonstrating the impact of prenatal maternal immune activation (the first hit) on brain development and later brain functioning. The impact of stress (the second hit) compounds or amplifies the resultant phenotype. It is now clear that trauma is associated with an increased risk of schizophrenia, but why do only a small percent of individuals exposed to stressful trauma develop schizophrenia (vs. developing more common disorders such as depression or anxiety)? These new models help us unravel the complex pathways that can disrupt optimal brain function.

Can I also echo Patricio O'Donnell's comment about the need to adopt a modern and pragmatic perspective on the utility of animal models for understanding complex neuropsychiatric disorders? Considering how little we understand about brain development, any animal experiments that uncover pathways between 1) candidate exposures or genes linked to schizophrenia, versus 2) any altered brain outcome (from molecular to behavioral) should be of intense interest to the...  Read more

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