Autism spectrum disorder (ASD) and schizophrenia (SZ) are two neurodevelopmental disorders that, despite having distinct diagnostic criteria, share certain clinical and etiological features. The genetic origin of the two disorders is beyond doubt, with evidence for unique and overlapping genetic risk factors. However, lower estimates of heritability have recently been reported for both disorders, lending support to a significant contribution from non-genetic factors. Notably, there is increasing evidence that immune activation during prenatal life may act as a risk factor for ASD and SZ. In this review, evidence supporting the hypothesis that prenatal immune activation (PIA) influences the onset and progression of ASD and SZ is analyzed. Results show that the detrimental effects of PIA on neurodevelopment include morphological changes in various brain regions, with perhaps the most notable being the hippocampus and prefrontal cortex, as well as altered activity of neurotransmitter systems such as the serotonergic system and impairments in working memory and prepulse inhibition. An examination of the risk factor of PIA offers new insight into the pathophysiology of ASD and SZ, and in this way opens up new possibilities for the treatment of these two disorders.
Neurodevelopmental disorders involve disruptions of brain functioning that can negatively affect the processes of learning, memory, and emotion (McCary et al., 2012). Autism spectrum disorder (ASD) and schizophrenia (SZ) are perhaps two of the most significant neurodevelopmental disorders in terms of their relatively high prevalence (Centers for Disease Control and Prevention, 2012 and National Institute of Mental Health, 2009) and negative impact on health-related quality of life (Eack and Newhill, 2007 and Kuhlthau et al., 2010). ASD is characterized by social impairment, communication deficits, and certain stereotyped behavioral patterns (Wing, Gould, & Gillberg, 2011). Impairment in social interaction may present itself as early as infancy or may not develop until later in childhood (Volkmar & Klin, 2005). Due to difficulties understanding social cues such as facial expression, children with ASD may have trouble interpreting others’ thoughts and feelings (Lai, Lombardo, & Baron-Cohen, 2013). SZ typically has its onset in adolescence; however, premorbid symptoms are often seen in earlier years (Fatemi & Folsom, 2009). SZ manifests in negative symptoms – those that cause reductions in a capacity – such as poor social functioning and apathy, and positive symptoms – excesses or distortions of normal functioning – such as hallucinations and delusions (Fatemi & Folsom, 2009). Abnormalities can develop as early as in utero and can lead to the activation of neural circuit pathology during adolescence or early adulthood (Fatemi & Folsom, 2009).
Genetic linkage studies have reported both similar and distinct loci associated with ASD and SZ. While high heritability estimates of at least 80% have been reported for ASD and SZ (Carroll & Owen, 2009), more recent studies have adjusted these estimates downwards. A recent study reported a heritability estimate of 37% for ASD (Hallmayer et al., 2011), while another study on key endophenotypic measures for SZ reported heritability estimates ranging from 24% to 55% (Greenwood et al., 2007). These reduced estimates support the idea that environmental factors may play a significant role in the pathogenesis of ASD and SZ.
The negative impact of early events only started receiving attention relatively recently, when in the early 1990s David J.P. Barker and his colleagues studied the effects of nutrition during the prenatal period on the risk of adulthood diseases such as coronary heart disease (Barker & Martyn, 1992). More recent research has emphasized the role of prenatal immune activation (PIA) in the psychopathology of neurodevelopmental disorders. Prenatal immune activation describes the response of a pregnant woman's immune system to infection, and, crucially, the impact her immune response may have on normal fetal brain development, including the risk of neurodevelopmental disorders in offspring (Smith, Li, Garbett, Mirnics, & Patterson, 2007). The purpose of this article is to (a) provide an overview of neuroanatomical, neurochemical, neuropsychological, and behavioral changes that can result from PIA, (b) discuss potential mechanisms by which these changes can occur, (c) describe the role of the timing of infection in PIA-induced changes in the offspring, (d) explain how PIA is implicated in ASD and SZ, and (e) suggest directions for future research in this field. The idea that PIA can lead to various psychopathologies warrants further exploration, especially seeing that the field of developmental origins of health and disease is relatively contemporary.
This review is based upon our own search of the literature, and thus may have inadvertently excluded certain studies if these were not identified by our search methods or selected for inclusion in the review. Compounding this is the publication bias, such that positive findings are more likely to be published than negative findings. However, results from various studies suggest that PIA may be a significant risk factor for the pathogenesis of ASD and SZ. Studying the role of environmental factors in the onset and progression of ASD and SZ is important because it provides one explanation for the “missing etiology” of these disorders. Importantly, PIA is associated with a variety of structural and functional abnormalities in the brain, which are associated with neuropsychological and behavioral deficits that are commonly observed in ASD and SZ. It is clear that various factors associated with PIA, such as timing, dosage, and type of infection, may differentially affect neurodevelopmental processes involved in the pathogenesis of neurodevelopmental disorders. Understanding PIA models of ASD and SZ can open up new possibilities for treatments for these disorders; however, further research is needed to gain a more definitive understanding of the exact impact of the aforementioned factors associated with PIA on multiple outcomes associated with neurodevelopment in affected offspring.
