Maternal Immune Activation and Neuropsychiatric Illness: A Translational Research Perspective

Abstract

Epidemiologic studies, including prospective birth cohort investigations, have implicated maternal immune activation in the etiology of neuropsychiatric disorders. Maternal infectious pathogens and inflammation are plausible risk factors for these outcomes and have been associated with schizophrenia, autism spectrum disorder, and bipolar disorder. Concurrent with epidemiologic research are animal models of prenatal immune activation, which have documented behavioral, neurochemical, neuroanatomic, and neurophysiologic disruptions that mirror phenotypes observed in these neuropsychiatric disorders. Epidemiologic studies of maternal immune activation offer the advantage of directly evaluating human populations but are limited in their ability to uncover pathogenic mechanisms. Animal models, on the other hand, are limited in their generalizability to psychiatric disorders but have made significant strides toward discovering causal relationships and biological pathways between maternal immune activation and neuropsychiatric phenotypes. Incorporating these risk factors in reverse translational animal models of maternal immune activation has yielded a wealth of data supporting the predictive potential of epidemiologic studies. To further enhance the translatability between epidemiology and basic science, the authors propose a complementary approach that includes deconstructing neuropsychiatric outcomes of maternal immune activation into key pathophysiologically defined phenotypes that are identifiable in humans and animals and that evaluate the interspecies concordance regarding interactions between maternal immune activation and genetic and epigenetic factors, including processes involving intergenerational disease transmission. [AJP AT 175: Remembering Our Past As We Envision Our Future October 1857: The Pathology of Insanity J.C. Bucknill: "In the brain the state of inflammation itself either very quickly ceases or very soon causes death; but when it does cease it leaves behind it consequences which are frequently the causes of insanity, and the conditions of cerebral atrophy." (Am J Psychiatry 1857; 14:172-193 )].

Keywords: Animal Models; Epidemiology; Maternal Immune Activation; Neuropsychiatric Outcomes; Translation.

Figure 1

Contribution of epidemiologic and basic science studies to translational research of maternal immune activation in neuropsychiatric disorders. (a) Schematic illustration of the prevailing research approaches in both disciplines. With a few exceptions, epidemiologic studies of MIA generally aim at establishing associations between infectious, inflammatory, or other immune exposures and risk of certain neuropsychiatric disorders, the latter of which are defined by the current nosologic system. On the other hand, most animal models of MIA are single-factor models in which the isolated effects of MIA-related exposures are investigated with respect to behavioral, cognitive, neuroimaging, and neurophysiologic phenotypes in the offspring. For practical reasons, these models are often implemented in rodent species and are based on artificial immune-activating agents (e.g., synthetic doublestranded RNA) that do not require stringent biosafety precautions. The outcome of these epidemiological and basic science approaches is often a lack of analogy, resulting in a translational gap that can undermine their translational validity. (b) Schematic illustration of epidemiological and basic science approaches that can maximize the bi-directional translational validity through the modification of research concepts and the addition of supplementary research modules. In these alternate approaches, the objective of assessing MIA exposure-disease risk associations in epidemiologic designs is complemented with or even replaced by: 1) attempts to explore the effects of MIA on specific behavioral, cognitive, neuroimaging, and neurophysiologic phenotypes, which are free of nosologic constraints; 2) the concomitant study of genetic and epigenetic factors; 3) the establishment of multifactorial animal models that incorporate genetic/epigenetic risk factors and MIArelated exposures that involve epidemiologically established infectious pathogens and other immune factors such as inflammatory mediators. In addition, cross-species comparisons involving animal species with advanced cortical development will further enhance the bi-directional translatability between epidemiologic and basic science studies.