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).”

“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…”

“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).”

“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).”

“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).”

“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).”

“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).”

“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).”

“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).”

“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).”