Maternal immune activation increases neonatal mouse cortex thickness and cell density.

Abstract

Autism is a debilitating neuropsychiatric disorder affecting children and young adults during the most vulnerable points in psychological and social development. With an estimated incidence of one in 88 births, autism spectrum disorder is characterized by impaired social interaction and communication, and restricted interests and stereotyped behaviors that occur before the age of three. Epidemiologic studies have suggested a role for environmental factors in the development of both autism and schizophrenia (Patterson 2009). A well-documented environmental risk factor for developing these neuropsychiatric diseases is maternal infection during pregnancy. Multiple studies have correlated a high prevalence of influenza infection with a high rate of schizophrenic births several months afterwards (Brown 2011; Mednick et al. 1988). The most direct evidence of this relationship comes from prospective studies involving banked serum from women who were pregnant in the 1960s, and follow-up work examined their offspring over 20 years later. Among mothers with serologically-verified influenza infection, schizophrenia risk was increased 3–7 fold in the offspring (Brown and Susser 2002). Similar evidence links other maternal infections, such as rubella, toxoplasma, and genital/reproductive infections, with subsequent schizophrenia in the offspring (Babulas et al. 2006; Brown et al. 2005). A correlation between autism and maternal viral infection was recently established by a large study of the Danish medical records (Atladottir et al. 2010). Autism risk is reportedly increased almost 200-fold with a maternal rubella infection (Chess 1977). Maternal infections including toxoplasmosis, syphilis, varicella, and rubeola during pregnancy are associated with autism in small case studies, summarized in Ciaranello and Ciaranello (1995). These findings suggest a potential role for infection during pregnancy in the etiology of at least some cases of autism. In studies aimed at modeling a viral infection during pregnancy in mice, a non-infectious Toll-like receptor 3 (TLR3) agonist, polyI:C has been injected into the mother during pregnancy and importantly this intervention altered the behavior of the adult offspring in a manner resembling autism (Patterson 2009). The mice show decreased social interaction, abnormal vocalizations, increased anxiety, and poor performance on latent inhibition and prepulse inhibition tests. Concurrent with these behavioral changes, some histologic changes reminiscent of the human disease have been documented such as fewer Purkinje cells in the cerebellum as seen in autism (Shi et al. 2009) and reduced cortical parvalbumin reactivity as seen in schizophrenia (Meyer et al. 2008). The mechanism by which maternal immune activation causes the behavioral changes has also been investigated and implicates the cytokines, particularly interleukin-6, which are produced at the site of immune stimulation but then travel throughout the maternal circulation to interfere with fetal development (Hsiao and Patterson 2011; Smith et al. 2007). Importantly, the abnormal levels of pro-inflammatory cytokines and growth factors present in the maternal immune-exposed fetal brains could potentially alter proliferation or migration of the neural progenitor cells destined to form the cerebral cortex. Studies of the human autism brain are also consistent with the notion that autism might arise from an activation of the immune system to trigger abnormal brain development. Analyses of postmortem brain tissue and CSF from individuals with autism have established that cytokines, chemokines, and growth factors are increased (Vargas et al. 2005). Similarly, transcripts for immunity-related genes are elevated in autism postmortem brain tissues (Voineagu et al. 2011). In addition to the increase of cyto-kines, chemokines, and growth factors, individuals with autism are reported to display an increased head circumference, brain volume, and neuron number in cortex at the onset of symptoms in early childhood (Schumann and Nordahl 2010; Courchesne et al. 2011). Potentially also related to the excess of cortical neurons, minicolumns, a vertically oriented cluster of neurons spanning the cortical layers within the cerebral cortex, are more numerous and display a greater dispersion due to a decreased alignment of pyramidal cells along the core axis (Casanova and Trippe 2009). In aggregate, these studies support a model where maternal immune activity during pregnancy might promote an increase of cytokine, chemokines, and growth factors that promotes the generation of an excess number of cortical neurons in-utero. We directly test the hypothesis that maternal immune activation during pregnancy is sufficient to trigger an expansion of the cortical neuron population by measuring cortical thickness and cell density in the neonatal cortex at postnatal day 0 (P0) following in utero maternal intraperi-toneal polyI:C injections.