Prenatal exposure to infection and subsequent inflammatory responses have been implicated in the etiology of schizophrenia and autism. In this review, we summarize current evidence from human and animal studies supporting the hypothesis that the pathogenesis of these two disorders is linked via exposure to inflammation at early stages of development. Moreover, we propose a hypothetical model in which inflammatory mechanisms may account for multiple shared and disorder-specific pathological characteristics of both entities. In essence, our model suggests that acute neuroinflammation during early fetal development may be relevant for the induction of psychopathological and neuropathological features shared by schizophrenia and autism, whereas postacute latent and persistent inflammation may contribute to schizophrenia- and autism-specific phenotypes, respectively.
Neuroimmune factors are now being recognized to play important roles in the etiology of neurological and neuropsychiatric disorders, including those with an onset of pathogenesis during early brain development. Indeed, the brain is highly vulnerable to environmental insults during early development (1). Therefore, immunological processes targeting the developing brain can be expected to have long-lasting impact on brain and behavioral functions throughout the life span (2,3).
Over the past 3 decades, one line of research has focused on the impact of prenatal maternal infection on the development of childhood and adult neuropsychiatric disorders, particularly schizophrenia and autism (4,5). In addition to their suggested etiopathogenetic contribution to chronic mental illness, intrauterine infection and subsequent maternal/fetal inflammatory responses have also been associated with neonatal white matter damage and cerebral palsy (6–9). In particular, the fetal inflammatory response to intrauterine infection seems to contribute to neonatal brain injury and subsequent neurological disability (6–9). In this article, we focus on the link between prenatal infection and neuropsychiatric disease, especially schizophrenia and autism.
Schizophrenia is a chronic psychotic disorder that affects ∼1% of the population worldwide (10). The disease onset is typically in late adolescence or early adulthood and includes psychotic symptoms, which are commonly referred to as positive, negative, and cognitive symptoms (10). Positive symptoms are features that are not present in healthy individuals but appear as a result of the disease process. These include visual and/or auditory hallucinations, delusions, paranoia, and major thought disorders. Negative symptoms refer to features that are normally present but are reduced or absent as a result of the disease process, including social withdrawal, apathy, anhedonia, alogia, and behavioral perseveration. Cognitive symptoms of schizophrenia involve disturbances in executive functions, working memory impairment, and inability to sustain attention.
The main psychopathological features of autism are severe deficiencies in social interaction and communication, and restricted and repetitive behaviors (11). Autism is one of three disorders collectively called autism spectrum disorders (ASDs), the other two being Asperger syndrome and pervasive developmental disorder-not otherwise specified (PDD-NOS). In contrast to autism, individuals with Asperger syndrome generally lack delays in cognitive development and communication, whereas PDD-NOS is diagnosed when the full set of criteria for autism or Asperger's syndrome are not met (11). Overt symptoms of autism often begin by the age of 6 mo, become established by 2 or 3 y, and tend to persist throughout life (11). The current prevalence of ASD is estimated to be ∼0.5–1%, and this rate seems to increase by ∼15% annually (12). It remains a matter of debate whether this is a genuine increase in disease incidence or related to changes in diagnostic practice (12).
In what follows, we first outline some of the major commonalities between schizophrenia and autism, followed by a summary of epidemiologic and laboratory evidence supporting a causal relationship between prenatal infection and both schizophrenia and autism. We focus on key neuroimmunological factors that seem to shape the “neuropsychiatric vulnerability” of infants born to mothers with intrauterine infection. We then propose and discuss a hypothetical model in which inflammatory processes may simultaneously account for both disorder-specific and shared pathological features of schizophrenia and autism.
Schizophrenia and Autism: Separate Entities or Pieces of the Same Puzzle?
Schizophrenia and autism seem to overlap at multiple levels. Therefore, it is not surprising that autism was initially believed to be an early manifestation of schizophrenia, and as such it was often referred to as “childhood psychosis” or “schizophrenic syndrome of childhood” (13,14). In 1971, ASD was finally separated conceptually from schizophrenia based on a delineation of symptomatic differences (including age of onset), family histories, and differential treatment responses in individuals with suspected adult schizophrenia versus infantile autism (13,14).
At the behavioral level, deficits in social interaction and cognition, disruption of emotional processing and sensorimotor gating, and impairments in executive functions are psychopathological features commonly observed in both disorders (11,15). Moreover, at least a subset of individuals with autism frequently experience psychotic phases involving auditory and visual hallucinations, similarly to acutely ill patients with schizophrenia (16). Based on this, it has been suggested that individuals with autism are at increased risk of developing psychosis and that the presence of neurodevelopmental deficits typically associated with autism may represent an alternative “entry-point” into a common final pathway of psychosis (16).
Schizophrenia and autism also seem to share multiple features at the brain morphological level. For example, structural and functional abnormalities in the cerebellum, insular cortex, and fusiform gyrus are present in both disorders (15–18). Patients with schizophrenia and autism also display a similar pattern of deficient neuronal activation during a social cognition task, with both patient groups showing reduced activation in the right amygdala, fusiform gyrus, and ventrolateral prefrontal cortex (19). The impression of overlapping brain abnormalities between schizophrenia and autism has also been supported by a recent meta-analytic anatomical likelihood estimation consolidating multiple imaging datasets, revealing appreciable brain structural concordance between the two disorders, especially in the right parahippocampal gyrus, posterior cingulate, putamen, claustrum, and left thalamus (15).
At the cellular level, one of the best established neuronal markers known to be altered in both schizophrenia and autism is Reelin (20). Because Reelin has crucial neurodevelopmental functions such as providing a detachment signal for migrating cells, it has been suggested that reduced Reelin signaling may contribute the early neurodevelopmental pathology involved in schizophrenia and autism (20).
It seems that schizophrenia and autism also share specific abnormalities at the neurochemical level, which seem to relate primarily to abnormalities in the serotonergic system. For example, similar to a subset of schizophrenia patients, some individuals with autism display abnormal serotonin synthesis capacity and serotonin receptor dysfunctions (21,22).
Finally, schizophrenia and autism seem to share several genetic and environmental risk factors (15), with prenatal exposure to infection being one of them. The role of prenatal infection in alerting neurodevelopmental trajectories relevant to schizophrenia and autism is discussed in the subsequent section.
Maternal Infection and the “Cytokine Hypothesis” of Neurodevelopmental Disorders
Epidemiologic studies suggest that the risk of schizophrenia is increased after prenatal maternal viral infections such as influenza, rubella, measles, and polio, as well as infections with bacterial pathogens and genital and/or reproductive infections (4). Thus, the association between maternal infection during pregnancy and schizophrenia in the offspring does not seem to be pathogen specific. Similarly, prenatal/perinatal exposure to numerous pathogens including rubella, measles, and cytomegalovirus has been implicated in the etiology of autism (5,23), suggesting that the infection-associated risk of autism may also not be pathogen specific. This notion finds support from a recent nationwide study in Denmark on >20,000 children born to mothers who required hospitalization because of infection during pregnancy (24). Hospital admission due to maternal exposure to various viral or bacterial infections significantly increased the offspring's risk of ASD, an effect that seemed unrelated to hospitalization per se (24).
These findings suggest that factors common to the immune response to a variety of pathogens are candidate mediators of the association between prenatal/perinatal infection and neurodevelopmental disorders. One hypothesis suggests that enhanced expression of proinflammatory cytokines and other mediators of inflammation in the maternal, fetal, and neonatal compartments may interfere with brain development, thereby increasing the risk for long-term brain dysfunction later in life (25,26). Cytokines are low-molecular weight proteins secreted by immune cells and other cell types in response to a number of environmental stimuli, particularly infections (27). They have wide-ranging roles in the innate and adaptive immune systems, where they help to regulate the recruitment and activation of lymphocytes and immune cell differentiation and homeostasis. In addition, some cytokines possess direct effector mechanisms, including induction of cell apoptosis and inhibition of protein synthesis. Furthermore, proinflammatory cytokines such as IL-1β, IL-6, and TNF-α are essential to the inflammatory response by mediating febrile reactions, activating phagocytotic cells such as macrophages or dendritic cells, facilitating vascular permeability, and promoting the release of plasma-derived inflammatory mediators such as bradykinin and components of the complement system (27). In the adult CNS, cytokines and their receptors are expressed by glial and neuronal cell types and are important mediators of the neuroimmune crosstalk in various brain and behavioral functions (28). In addition, many cytokines and cytokine receptors are constitutively expressed during fetal brain development (29,30), implying essential roles for these molecules in the regulation and modulation of normal brain development. Indeed, cytokines in general, and proinflammatory cytokines in particular, seem to have appreciable effects on various neurodevelopmental processes, neuronal plasticity, and neuronal survival (31). Therefore, it can be expected that abnormal levels of these molecules during critical periods of early brain development may adversely affect neurodevelopmental trajectories, thereby contributing to an increased susceptibility for complex brain disorders of developmental origin such as schizophrenia and autism.
Two major lines of evidence support the hypothesis that cytokine-mediated aberrance of early brain development might be relevant for autism and schizophrenia. First, epidemiological studies demonstrate a significant association between high maternal levels of the proinflammatory cytokines TNF-α (32) and IL-8 (33) during pregnancy and elevated risk of schizophrenia spectrum disorder (SSD) in the offspring. Second, experimental animal work shows that prenatal exposure to proinflammatory agents in the absence of viral or bacterial infection is sufficient to cause long-lasting brain and behavioral dysfunction relevant to schizophrenia and autism (26,34,35). Subsequent to the establishment of a mouse model of prenatal human influenza infection, which mimics various brain and behavioral abnormalities with potential relevance to both schizophrenia and autism, several research groups have used cytokine-releasing agents or specific proinflammatory cytokines when modeling the neurodevelopmental consequences of prenatal immune challenge (26,34,35). This includes maternal exposure to the bacterial endotoxin, lipopolysaccharide (LPS), or the synthetic double-stranded RNA analog, polyriboinosinic-polyribocytidilic acid (PolyI:C). Both immunogens trigger the production and release of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α (36). PolyI:C is also a potent inducer of the type I interferons IFN-α and IFN-β (36). In essence, LPS administration mimics infection with Gram-negative bacteria, whereas administration of PolyI:C mimics the acute-phase inflammatory response to viral infection (36). Importantly, maternal exposure to LPS or PolyI:C during pregnancy is capable of enhancing proinflammatory cytokine levels in the three maternal-fetal compartments, namely, the placenta, the amniotic fluid, and the fetus, including the fetal brain (37,38). The efficacy of prenatal exposure to cytokine-releasing agents to induce fetal brain inflammation, together with its long-term impact on brain and behavioral abnormalities relevant to schizophrenia and autism, underscores the essential role of prenatal cytokine-associated inflammation in mediating the effects of maternal infection on the offspring. The concept is further supported by the findings that blocking the actions of the proinflammatory cytokine IL-6 in the pregnant maternal host by genetic or pharmacological interventions prevents the long-term brain and behavioral consequences of prenatal PolyI:C treatment (39) and that over-expression of the anti-inflammatory cytokine IL-10 prevents the emergence of multiple behavioral and pharmacological abnormalities typically seen after prenatal PolyI:C-induced immune challenge (40).
Prenatal infection and inflammatory responses seem to play a significant role in the etiology of both schizophrenia and autism. This suggests that the pathogenesis of schizophrenia and autism may be fundamentally linked via prenatal inflammation. According to our proposed model, acute neuroinflammation during early fetal development may be relevant for the induction of psychopathological and neuropathological phenotypes shared by schizophrenia and autism, whereas subsequent latent versus persistent inflammation may lead to phenotypic characteristics of schizophrenia versus autism, respectively. The precise mechanisms whereby latent or persistent inflammation negatively affects neurobiological and neurochemical abnormalities relevant to schizophrenia and/or autism are currently the subject of extensive experimental studies. The further elucidation of such mechanisms might lead to the establishment of novel immunomodulatory interventions that could help prevent abnormal brain development and long-term mental illness in subjects with prenatal infectious/inflammatory histories. The identification of preventive strategies is particularly important for chronic mental illnesses such as schizophrenia and autism with little hope for complete functional recovery once the disorder has developed. We hope that the model presented here will help achieving this goal.
autism spectrum disorders