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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 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, 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 other hand, has also been shown to produce mild adult deficits. Combining both approaches results in adult animals with more strongly affected behavior and neurochemistry. The study should be used as an example of how to cast animal models in a useful light.

The article by Giovanoli et al. highlights altered neuroimmune responses in the adolescent brain following the prenatal manipulation. Proinflammatory cytokines are elevated in the hippocampus of young mice, but only in those stressed as adolescents. These data indicate that animals without a predisposition can handle the immune activation induced by stress, but not those with a compromise induced by maternal immune activation. The link to psychiatry is tantalizing. The notion of immune factors and oxidative stress playing a role in major psychiatric disorders has been around for some time; only recently there has been a surge in animal testing of these possibilities. The findings reported in Science open the way to the exploration of novel therapeutics that may target immune factors and/or microglia activation for psychiatric conditions.

References:

O’Donnell P. How can animal models be better utilized? In: Schizophrenia: Evolution and Synthesis. S.M. Silverstein, B. Moghaddam, T. Wykes, Eds. Strungman Forum Reports, vol 13. Cambridge, MA: MIT Press (2013).

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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 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 (Meyer et al., 2009). While there is not a clear mechanism mediating the phenotype of MIA, this paper showed that MIA leaves the offspring vulnerable to any secondary insult, be it genetic or, in this case, environmental.

A mechanism the authors propose to mediate the behavioral changes is through microglia cell number and activation status, including data on normal astrocytes and endothelial cells. Stress caused increased cell numbers of Iba1+ microglia and an increased cell size, suggesting an amoeboid/activated morphology in control and MIA offspring. But the combination of MIA and stress led to increased expression of CD68, a functional marker for activated microglia, and production of proinflammatory cytokines, suggesting that MIA induced susceptibility and, when combined with stress, provoked microglial overactivation. However, these changes were mostly observed in the hippocampus at postnatal day (P) 41-45, before the emergence of the behavioral phenotypes at P70. Together, these data suggest that the MIA made the microglia susceptible to activation, and the addition of juvenile stress reactivated the microglia, causing proliferation in the hippocampus and activation in the hippocampus and prefrontal cortex. This potentially produced a remodeling of the neural circuits mediating the behavioral phenotype observed at P70. The authors also showed changes in dopamine and serotonin levels in the brain; however, it is unclear if microglia play a role in the neurotransmitter regulation. Alternatively, we recently reported that adolescent stress, in combination with genetic susceptibility, showed changes in extracellular dopamine through epigenetic modification of mesocortical dopamine neurons (Niwa et al., 2013). In any case, microglia are long-lived in vivo, and the residual increased numbers of microglia in the hippocampus remained at P70 but returned to a resting state by showing normal size and CD68 expression. The effect on microglia was different based on brain region (hippocampus vs. prefrontal cortex), emphasizing a need for further microglia subcategorization and identification of molecular markers that may cause microglia in different circuits to behave differently to stimulation. These distinctions are critical for future drug design studies to target specific circuits for defined symptoms in disease.

Several questions still remain, such as the mechanisms for how microglia are interacting with the neural circuits and how MIA makes the microglia susceptible to further overactivation. A new trend in uncovering the role of microglia in specific behaviors was observed in several previous studies by further rescuing the behaviors with bone marrow transplantation following lethal irradiation (Chen et al., 2010; Derecki et al., 2012; Hsiao et al., 2012). This strategy is a good next setup to solidify the role of overactivated microglia in these specific behaviors.

References:

Meyer U, Feldon J, Fatemi SH (2009) In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders. Neurosci Biobehav Rev 33:1061-1079. Abstract

Niwa M, Jaaro-Peled H, Tankou S, Seshadri S, Hikida T, Matsumoto Y, Cascella NG, Kano S, Ozaki N, Nabeshima T, Sawa A (2013) Adolescent stress-induced epigenetic control of dopaminergic neurons via glucocorticoids. Science 339:335-339. Abstract

Chen SK, Tvrdik P, Peden E, Cho S, Wu S, Spangrude G, Capecchi MR (2010) Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141:775-785. Abstract

Derecki NC, Cronk JC, Lu Z, Xu E, Abbott SB, Guyenet PG, Kipnis J (2012) Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 484:105-109. Abstract

Hsiao EY, McBride SW, Chow J, Mazmanian SK, Patterson PH (2012) Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci USA 109:12776-12781. Abstract

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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 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 field. This type of research can inform neuroscience discovery, and feed back into more refined research questions. The new paper from Urs Meyer and colleagues is a perfect example of this. Based on clues linking prenatal infection and risk of schizophrenia, animal models using immune activation (like poly(I:C) or LPS) have made crucial discoveries about the crosstalk between biological systems first identified in immune function, and brain development.

The schizophrenia research community should not passively wait for the rest of neuroscience to work out the instructions for building healthy brains. We should take the lead based on the clues that we observe clinically or from epidemiology, and use the tools of modern neuroscience to catalyze discoveries (McGrath and Richards, 2009).

References:

McGrath JJ, Richard LJ. (2009) Why schizophrenia epidemiology needs developmental neurobiology – and vice versa. Schizophrenia Bulletin 35(3):577-81. Abstract

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