Schizophrenia and autism: both shared and disorder-specific pathogenesis via perinatal inflammation?

“In support of this, several cytokines seem to modulate processes of learning and memory, anxiety-related behaviors, and social interaction (3,78,79).”

“This idea of multiple hits with either sensitizing or preconditioning effects is also central to several theories of prenatal immune priming, which have been put forward by others in the context of peripheral immunity, CNS inflammation, perinatal brain damage, retinopathy, and various forms of learning and memory (68–…”

“One example is that autism has generally been associated with excessive brain growth (macrocephaly) involving thickening of cortex, increased gray and white matter, and lack of gray matter loss (41), whereas schizophrenia seems to be associated with microcephaly involving thinner cortical areas, reduced gray and white…”

“For example, a nearly 50-fold increase in TNF- level was found in the cerebrospinal fluid (CSF) of autistic children (47), and severe inflammation is present in the brains of autistic patients from a broad range of ages (48), characterized by prominent activation of microglia and astroglia cells and enhanced proinflam…”

“Such genetic components seem highly essential because both autism and schizophrenia exhibit strong patterns of heritability (83,84).”

“In contrast to the delayed onset of schizophrenia, overt symptoms of autism often begin as early as by the age of 6 mo and become established by age 2 or 3 y (11,12).”

“In the CNS, microglia and astrocytes are the major immunocompetent cells, which regulate both the induction and limitation of inflammatory processes (45).”

“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 antiinfla…”

“On the other hand, chronic or exaggerated microglial activation has been linked to multiple neuroinflammatory and neurodegenerative diseases, including Parkinson’s disease, multiple sclerosis, Alzheimer’s disease, and Huntington’s disease (46).”

“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).”

“Indeed, even though peripheral proinflammatory markers such as IL-6 seem to be elevated in at least a subgroup of schizophrenic patients, the reported increases are relatively modest (55).”

“Several recent studies corroborate the presence of ongoing systemic inflammation and neuroinflammation in autistic individuals (49,50).”

“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).”

“One example is that autism has generally been associated with excessive brain growth (macrocephaly) involving thickening of cortex, increased gray and white matter, and lack of gray matter loss (41), whereas schizophrenia seems to be associated with microcephaly involving thinner cortical areas, reduced gray and white…”

“Glutamate is a potent activator of microglia cells (45,61), and the presence of increased CNS glutamate levels (21) together with upregulation of specific glutamate receptor subtypes (62) on microglia cells may facilitate the persistence of neuroinflammation subsequent to the induction of acute fetal inflammation (Fig.”

“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).”

“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…”

“In support of this, several cytokines seem to modulate processes of learning and memory, anxiety-related behaviors, and social interaction (3,78,79).”

“The fact that cerebellar pathology seems to be more pronounced in autism than in schizophrenia (81,82) lends further support to our model of persistent neuroinflammation in autism versus latent neuroinflammation in schizophrenia.”

“The fact that cerebellar pathology seems to be more pronounced in autism than in schizophrenia (81,82) lends further support to our model of persistent neuroinflammation in autism versus latent neuroinflammation in schizophrenia.”

“Consistent with this suggestion, exposure to environmental insults such as stress and drugs of abuse, which are believed to facilitate or even trigger the onset of full-blown psychosis in individuals at high risk for schizophrenia (73), are also known to exert direct influences on the immune system (74,75).”

“As reviewed in detail elsewhere (3), numerous experimental studies in rodents show that immunological exposure in early (prenatal or neonatal) life can cause the organism to respond differently (and often more vigorously) to subsequent immunological or nonimmunological challenges.”

“In view of the two apparently mutually exclusive positions that schizophrenia and autism are either related (15,16) or remote (42), our proposal that the two are fundamentally linked via prenatal inflammation may seem counter intuitive.”

“HMGB1 is a highly conserved, ubiquitous protein that activates inflammation-associated immune responses (59).”

“Glutamate is a potent activator of microglia cells (45,61), and the presence of increased CNS glutamate levels (21) together with upregulation of specific glutamate receptor subtypes (62) on microglia cells may facilitate the persistence of neuroinflammation subsequent to the induction of acute fetal inflammation (Fig.”

“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.”

“developmental processes, neuronal plasticity, and neuronal survival (31).”

“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).”

“Several recent studies corroborate the presence of ongoing systemic inflammation and neuroinflammation in autistic individuals (49,50).”

“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).”

“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).”

“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…”

“Glutamate is a potent activator of microglia cells (45,61), and the presence of increased CNS glutamate levels (21) together with upregulation of specific glutamate receptor subtypes (62) on microglia cells may facilitate the persistence of neuroinflammation subsequent to the induction of acute fetal inflammation (Fig.”

“For example, a nearly 50-fold increase in TNF- level was found in the cerebrospinal fluid (CSF) of autistic children (47), and severe inflammation is present in the brains of autistic patients from a broad range of ages (48), characterized by prominent activation of microglia and astroglia cells and enhanced proinflam…”

“A common feature of these molecules is that they can effectively antagonize the biological activities and/or production of multiple proinflammatory molecules, thereby regulating inflammation in both acute and chronic conditions (27).”

“Furthermore, proinflammatory cytokines such as IL-1 , IL-6, and TNF- 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 su…”

“after chronic (51,52) or subchronic (53) maternal inflammation.”

“The presence of altered peripheral levels of IL-10 and related cytokines has often been explained by an imbalance between T helper 1 (Th1) and 2 (Th2) cytokines in patients with schizophrenia (65).”

“In contrast to the delayed onset of schizophrenia, overt symptoms of autism often begin as early as by the age of 6 mo and become established by age 2 or 3 y (11,12).”

“Consistent with this suggestion, exposure to environmental insults such as stress and drugs of abuse, which are believed to facilitate or even trigger the onset of full-blown psychosis in individuals at high risk for schizophrenia (73), are also known to exert direct influences on the immune system (74,75).”

“These human data are consistent with the experimental results discussed above suggesting that schizophrenia-related brain and behavioral abnormalities induced by acute prenatal immune challenge can occur in the absence of overt neuroinflammation and/or astrogliosis (40,54).”

“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.”

“Against this background, it is highly interesting to note that the addition of antiinflammatory treatment to standard antipsychotic medication for schizophrenia seems to be superior to antipsychotic treatment alone especially when such anti-inflammatory therapy is initiated in the early phases of the disease (76).”

“These prenatal inflammation-induced behavioral manifestations are accompanied by neuroanatomical and neurochemical abnormalities seen in both schizophrenia and autism, including neuromorphological alterations in cerebellum, basal ganglia, and amygdala; deficient Reelin expression in hippocampus and prefrontal cortex;…”

“For example, similar to a subset of schizophrenia patients, some individuals with autism display abnormal serotonin synthesis capacity and serotonin receptor dysfunctions (21,22).”

“In line with previous theoretical accounts (25,26), maternal infection during critical stages of pregnancy leads to acute cytokine-associated inflammation in the fetal system, including the fetal brain.”

“Furthermore, despite considerable research efforts, imaging and postmortem immunohistochemical studies provide mixed evidence for over activation of microglia and astrocytes in the brains of schizophrenic patients (56).”

“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 parahippoc…”

“For example, multiple molecules with potent anti-inflammatory and immunosuppressive properties seem to be increased in subjects diagnosed with schizophrenia, including IL-10, TGF- , soluble IL-1 receptor antagonist (sIL-1RA), and soluble TNF receptor (sTNF-R) (55,63,64).”

“However, we would like to emphasize that enhanced anti-inflammatory and immunosuppressive actions may increase the sensitivity to infections (77), and this may act in concert with the presence of latent immune abnormalities (induced by perinatal immune priming) in the development of altered inflammatory responses in p…”

“after chronic (51,52) or subchronic (53) maternal inflammation.”

“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.”

“These human data are consistent with the experimental results discussed above suggesting that schizophrenia-related brain and behavioral abnormalities induced by acute prenatal immune challenge can occur in the absence of overt neuroinflammation and/or astrogliosis (40,54).”

“after chronic (51,52) or subchronic (53) maternal inflammation.”

“Furthermore, proinflammatory cytokines such as IL-1 , IL-6, and TNF- 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 su…”

“Consistent with this suggestion, exposure to environmental insults such as stress and drugs of abuse, which are believed to facilitate or even trigger the onset of full-blown psychosis in individuals at high risk for schizophrenia (73), are also known to exert direct influences on the immune system (74,75).”

“Such early immune priming may provide an environmental basis for the findings that production of proinflammatory cytokines such as IL-6 and TNF- after stimulation with phytohemagglutinin and LPS is significantly higher in schizophrenic patients relative to controls (55,72).”

“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).”

“For example, in contrast to other brain structures, the development of the cerebellum reaches peak levels only in late fetal and neonatal periods (80).”

“Similarly, converging evidence suggests a role for the IL-1 gene complex (involving sIL-1RA) in schizophrenia (67).”

“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.”

“For example, autistic patients have reduced serum levels of the immunosuppressive cytokine TGF- 1 (57) and increased serum levels of the high-mobility group box 1 (HMGB1) protein (58).”

“For example, multiple molecules with potent anti-inflammatory and immunosuppressive properties seem to be increased in subjects diagnosed with schizophrenia, including IL-10, TGF- , soluble IL-1 receptor antagonist (sIL-1RA), and soluble TNF receptor (sTNF-R) (55,63,64).”

“These include some shared behavioral abnormalities as well as neuropathological features (29).”

“…changes in common with both SZ and ASD reinforces the construct validity of the model, given that these disorders share the risk factor of maternal infection and that their psychiatric and anatomical pathologies significantly overlap (Lord et al., 2000; Meyer et al., 2011; Rapoport et al., 2009).”

“The emerging consensus among leaders in the field is that prenatal infection may be relevant to a number of CNS diseases and restricting interpretation to a specific human disorder may limit the utility and relevance of the MIA model (38, 39).”

“2010, Brown & Derkits 2010, Meyer et al .”

“, using RNA poly(I:C) to stimulate an antiviral inflammatory response or lipopolysaccharide to stimulate a bacterial inflammatory response) (Brown and Derkits, 2010; Deverman and Patterson, 2009; Meyer et al., 2011; Miller et al., 2013; Patterson, 2011).”

“This is particularly true between child onset schizophrenia and autism (Meyer et al., 2011; Rapoport et al., 2009).”

“Exposure to acute fetal inflammation may further induce latent neuroinflammatory abnormalities that can be unmasked by exposure to certain environmental stimuli throughout postnatal life (Meyer et al., 2011a).”

“Recent work suggests that persistent inflammation is responsible for phenotypic abnormalities observed in autism, whereas a latent inflammatory process in utero appears responsible for schizophrenia-specific brain and behavioural abnormalities [112].”

“hit").(15, 53) An adaptive, evolutionary perspective further suggests potential survival advantages of the observed brain phenotypes.”

“…and cellularmechanisms remain to be identified, it has been suggested that enhanced pro-inflammatory activity in general, andmicroglia over-activation in particular, may play a role in precipitating such progressive brain changes in schizophrenia (van Berckel et al., 2008; Meyer et al., 2011).”

“Although MIA models have been used most often to model ASD or SZ, the emerging consensus among leaders in the field is that prenatal infection may be relevant to a number of CNS diseases and restricting interpretation to any given human disorder may limit the utility and relevance of the MIA model [46, 47].”

“(79) Similarly inflammation during pregnancy, from any cause, increases the risk of autism and schizophrenia in the child.((80)) It is hypothesized that diminished immunoregulation can increase this risk further.”

“Had space permitted there are other psychiatric conditions that could have been included in the discussion because of evidence for inflammatory components: attention deficit hyperactivity disorder, and PTSD [142, 143], schizophrenia and autism [144, 145].”

“Both can involve auditory and visual hallucinations (Meyer et al., 2011; Barneveld et al., 2011), abnormalities of serotonergic, dopaminergic and glutamatergic systems (Brown et al., 2013; Shimmura et al., 2013; Sodhi and Sanders-Bush., 2004) and shared genetic causes (de Lacy and King, 2013;…”

“…risk factors in the pathogenesis of mental diseases, reduction in ancient and habitual human infections, disruption of the commensal microbes and diminished contact with environmental microbes may also increase the vulnerability to inflammatory as well as mental diseases (Meyer et al., 2011).”

“Since immune functions of glia are much better known than those of neurons [4,5,9], we will emphasize more on the latter ones in this review.”

“Epidemiological findings have consistently associated maternal infection in pregnancy with suboptimal offspring cognitive and socioemotional development and increased risk for schizophrenia and autism (Khandaker et al., 2013; Brown et al., 2004; Brown and Patterson, 2011; Brown and Derkits, 2010; Buka et al., 2001; Fa…”

“linked to prenatal stress [122,123].”

“IL-6, however, is a member of pro-infl ammatory cytokines involved in MIA and the development of neurodevelopmental disorders (Meyer et al. 2011).”

“An early example is the use of improved phenotyping in 1971 to recognize that autism spectrum disorder was a different disease than schizophrenia 2 .”

“This approach has proved fruitful given there are significant similarities between the disorders, with a recent article even suggesting that it may be neuroinflammatory events during early fetal development which result in this shared pathogenesis (Meyer et al., 2011).”

“Cytokines such as TNF-α released during intrauterine inflammation are a possible cause of brain damage observed in animal studies linking preterm birth and periventricular white matter damage (61,85,94).”

“Cognitive deficits often precede the onset of other symptoms and are associated with poor medication compliance and a higher tendency for relapse in first episode psychosis (Meyer et al, 2011b).”

“…in the brain that predisposes an individual, perhaps already at risk due to genetic and environmental influences, to develop the neuropathology and behavioral and cognitive impairments observed in major disorders such as schizophrenia and autism (Rehn and Rees, 2005; Meyer et al., 2011).”

“, 2013; Patterson, 2011), schizophrenia (Meyer et al., 2011; Miller et al., 2013; Patterson, 2009), and cerebral palsy (Yoon et al.”

“This is relevant as there are both clinical and biological links between autism and schizophrenia (Meyer et al., 2011).”

“ism spectrum disorders (ASD), and epilepsy [7, 22, 27].”

“More speculatively, perinatal inflammation is suggested to play a critical role in the pathogenesis of autism and schizophrenia [157–159].”

“There has been increasing interested in and evidence for an important contribution of prenatal exposure to infection and/or inflammation in the etiology of developmental brain disorders (Brown and Derkits, 2010; Meyer et al., 2011; Patterson, 2011).”

“Although there is a wide range of environmental risk factors linked to SZ, the most compelling risk factor to date is maternal infection (4, 26, 95, 96), which has been estimated to account for up to one-third of cases (25).”

“Also, increased levels of a neutrophil attractant chemokine (IL-8) were reported to be associated with other neurodevelopmental disorder, namely schizophrenia (Brown et al., 2004), which is hypothesized to share a common etiologic pathway with autism during pregnancy (Meyer et al., 2011).”

“has accumulated to suggest that prenatal infection also is a risk factor for autism spectrum disorder (ASD) [3, 4].”

“In view of the significant epidemiological association with familial allergic disorder, where the birth order effect is clear, this is of great interest (discussed in Meyer et al., 2011; Onore et al., 2012).”

“Autism spectrum disorder (ASD) is characterized by symptoms in the domains of social interaction, communication, and restricted and repetitive interests and behaviors (Meyer et al., 2011; Noterdaeme, 2011; Ratajczak, 2011).”

“[4-7].”

“…infection, either through direct exposure of preganant mice to viruses, or via activation of maternal immune response in the absence of an infectious agent, led to atypical behaviors in the resulting pups (Brown and Derkits, 2010; Meyer et al., 2011; Patterson, 2011; Miller V. M. et al., 2013).”

“This is not surprising when considering the similarities between schizophrenia and autismrelated disorders, which might also share a neuroinflammatory pathogenesis during early fetal development (Meyer et al., 2011).”

“It has been hypothesized that prenatal exposure to infection, including the subsequent maternal proinflammatory response, can alter the development of the fetal brain (Fineberg and Ellman, 2013; Meyer et al., 2009, 2011; Michel et al., 2012; Onore et al., 2012; Patterson, 2009).”

“An additional case group, OCPD, was introduced, comprising the subset of controls who had at least one childhood psychiatric disorder other than ASD.”

“Social cognitive impairments are hallmark behavioral deficits in both, ASD and SCH (Couture et al., 2006; Meyer et al., 2011).”

“Because MIA is a risk factor for both ASD and SZ (Atladóttir et al., 2010, 2012; Meyer et al., 2011; Brown, 2012), the MHCIMEF2 signaling pathway identified here may be critical for the pathogenesis of these disorders.”

“Developmental neuroinflammation caused by maternal prenatal infections is pathophysiologically relevant and may contribute to progressive brain changes and thus progression of schizophrenia (Meyer et al. 2011).”

“Mounting evidence indicates that in other neuropsychiatric conditions such as schizophrenia, inflammatory cytokines such as IL-1β and IL-6 have a role in onset and progress of neuropsychiatric symptoms [27-31].”

“This "second hit" due to stress, immune re-exposure or even peripubertal sex hormonal changes might potentially unmask and exacerbate the hitherto latent inflammatory processes with resultant onset of clinical symptoms (Meyer et al., 2011; Knickmeyer et al., 2010) .”

“Several studies have been performed to mimic viral infections during pregnancy by giving TLR3 ligands as models for developmentally induced psychiatric disorders [141, 142].”

“Moreover, dysregulation of immune-related genes has been shown in the brains of patients with neuropsychiatric disorders such as schizophrenia [244], raising the possibility that immune-induced inflammation increases vulnerability of the brain that already is at risk due to genetic influences [245,246].”

“…changes occurring in the placenta Inflammation, particularly during the prenatal period, has been associated with increased incidence of disorders such as autism (Patterson, 2011) and schizophrenia (reviewed in Green and Nolan, 2014; Meyer et al., 2011; Miller et al., 2013) in the offspring.”