Prenatal infection, maternal immune activation, and risk for schizophrenia

Abstract

A body of epidemiological literature has suggested an association between prenatal infection, subsequent maternal immune activation (MIA), and later risk of schizophrenia. These epidemiological studies have inspired preclinical research using rodent and primate models of prenatal infection and MIA. The findings from these preclinical studies indicate that severe infection and immune activation during pregnancy can negatively impact offspring brain development and impair adult behavior. This review aims to summarize the major epidemiological and preclinical findings addressing the connection between prenatal infection and immune activation and later risk of developing schizophrenia, as well as the more limited literature addressing the mechanisms by which this gestational insult might affect offspring neurodevelopment. Finally, directions for future research will be discussed.

Abnormal immune system development and function in schizophrenia helps reconcile diverse findings and suggests new treatment and prevention strategies

“…This includes several new lines of research demonstrating that (1) schizophrenia patients exhibit altered immune cell activities, as well as heightened peripheral and central inflammatory responses (e.g., Fillman et al, 2013;Gionovali et al, 2013;Miller et al, 2011;Potvin et al, 2008); (2) the strongest risk alleles associated with schizophrenia also have known effects on immune function and/or infection vulnerability (Jia et al, 2010;McAllister, 2014 Q6 ;Schmitt et al, 2011); (3) most pre-and postnatal environmental risk factors for schizophrenia involve either increased exposure to infectious diseases or increased vulnerability to infection and/or autoimmune disorders (Brown and Derkits, 2010;Canetta and Brown, 2012;Strous and Shoenfeld, 2006); (4) a number of anti-psychotic drugs possess potent antimicrobial effects (Drzyzga et al, 2006;Pollmächer et al, 2000); and (5) some antibiotic and anti-inflammatory drugs reduce psychotic symptoms .…”

“…Schizophrenia's well-established associations with preand perinatal adversity (e.g., Canetta and Brown, 2012;Palmer, 2011), as well as increased vulnerability to infections and immune diseases, are highly suggestive of early immune system programming. Moreover, peak onset of schizophrenia occurs during late adolescence and early adulthood, with onset of most cases occurring between the ages of 18 and 35; this corresponds with a period of time over which the thymus markedly decreases in volume, with initial involution occurring around puberty and a gradual decrease in size occurring over the next two decades, until the thymus reaches roughly 20% of its original volume (Steinmann et al, 1985).…”

LPS alters placental inflammatory and endocrine mediators and inhibits fetal neurite growth in affected offspring during late gestation

“…Many epidemiological studies have now shown that maternal infection increases the risk for neurodevelopmental and neuropsychiatric disorders in affected offspring including schizophrenia [2,3], autism spectrum disorders [4,5] and cerebral palsy [6] (for reviews see Refs. [7,8]). Critical to these outcomes, is the role of the placenta at the maternalefetal interface in regulating fetal growth and development [9].…”

Interaction of BDNF with cytokines in chronic schizophrenia

“…The neurodevelopmental model of schizophrenia suggests a ''2-hit'' model (Keshavan, 1999;Rapoport et al, 2012), in which a first hit may be a prenatal viral or bacterial infection that activates microglia and immuno-inflammatory pathways (Canetta and Brown, 2012;Altamura et al, 2013), followed by secondary inflammatory hits during adolescence with consequent autoimmune responses (Anderson and Maes, 2013). These autoimmune responses in the brain can act through cytokines, and abnormal cytokine levels are associated with various neurological, neurodegenerative, and neurotoxic conditions, including schizophrenia (Altamura et al, 2013;Miller et al, 2013;Na et al, 2014;Müller, 2014;Upthegrove et al, 2014;Zakharyan and Boyajyan, 2014;Sperner-Unterweger and Fuchs, 2015).…”