Neurodevelopment and inflammatory patterns in schizophrenia in relation to pathophysiology

Progress in Neuro-Psychopharmacology & Biological Psychiatry 42 (2013) 63–70

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Neurodevelopment and inflammatory patterns in schizophrenia in relation to pathophysiology A. Carlo Altamura ⁎, Sara Pozzoli, Alessio Fiorentini, Bernardo Dell'Osso Department of Psychiatry, University of Milan, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milano, Italy

a r t i c l e

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Article history: Received 20 December 2011 Received in revised form 23 August 2012 Accepted 25 August 2012 Available online 25 September 2012 Keywords: Schizophrenia Inflammation Neurodevelopmental hypothesis Cytokines

a b s t r a c t As for other major psychoses, the etiology of schizophrenia still remains poorly understood, involving genetic and epigenetic mechanisms, as well as environmental contributions. In addition, immune alterations have been widely reported in schizophrenic patients, involving both the unspecific and specific pathways of the immune system, and suggesting that infectious/autoimmune processes play an important role in the etiopathogenesis of the disorder. Cytokines, in particular, are supposed to play a critical role in infectious and inflammatory processes, mediating the cross-talk between the brain and the immune system. In this perspective, even though mixed results have been reported, it seems that schizophrenia is associated with an imbalance in inflammatory cytokines. Alterations in the inflammatory and immune systems, moreover, seem to be already present in the early stages of schizophrenia and connected to the neurodevelopmental hypothesis of the disorder, identifying its roots in brain development abnormalities that do not manifest themselves until adolescence or early adulthood. At the same time, neuropathological and longitudinal studies in schizophrenia also support a neurodegenerative hypothesis and, more recently, a novel mixed hypothesis, integrating neurodevelopmental and neurodegenerative models, has been put forward. The present review aims to provide an updated overview of the connections between the immune and inflammatory alterations and the aforementioned hypotheses in schizophrenia. © 2012 Published by Elsevier Inc.

1. Introduction Schizophrenia is a highly disabling, multidimensional syndrome, that has, most commonly, its onset in the first half of adult life. Kraepelin and Bleuler both recognized that a significant part of schizophrenic subjects had previously shown differences of character and behavior, over childhood (Jones and Buckley, 2006). Subsequent genetic studies documented subtle differences in neurological development in high-risk children (Fish, 1977; Fish et al., 1992; Walker and Lewine, 1990). Indeed, neurodevelopmental abnormalities, occurring throughout childhood, have been reported in up to one-half of high-risk children, born from schizophrenic mothers (Fish, 1977; Fish et al., 1992; Marcus et al., 1993; Walker and Lewine, 1990). These comprise, among others, Abbreviations: CNS, Central Nervous System; ILs, Interleukins; INFs, Interferons; TNFs, Tumor Necrosis Factors; TNFs, Tumor Necrosis Factors; TGFs, Transforming Growth Factors; IL-6, Interleukin 6; IL-8, Interleukin 8; IL-10, Interleukin 10; MCP-1, Monocyte Chemotactic Protein-1; IL-1, Interleukin 1; IL-2, Interleukin 2; INF-alpha, Interferon-alpha; INF-gamma, Interferon-gamma; Th-1, T helper-1; Th-2, T helper-2; M1, Macrophage 1; IL-1beta, Interleukin 1beta; TGF-beta, Transforming Growth Factors- beta; IL-12, Interleukin 12; sIL2R, Interleukin 2 soluble Receptor; MIA, Maternal Immune Activation; FAs, Fatty Acids; PGEs, Prostaglandines; NMDA, N-Methyl-D-Aspartate; IDO, Indoleamine-2,3-Dioxygenase; HPA, Hypothalamic-Pituitary-Adrenal. ⁎ Corresponding author at: Department of Psychiatry, University of Milan, Director, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122, Milan, Italy. Tel.: + 39 02 55035982; fax: + 39 02 50320310. E-mail address: [email protected] (A.C. Altamura). 0278-5846/$ – see front matter © 2012 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.pnpbp.2012.08.015

hypoactivity, hypotonia, soft neurological signs – poor motor coordination, in particular – and deficits in attention and information processing in late childhood. Taken as a whole, these data support the hypothesis that at least part of the genetic vulnerability to schizophrenia involves abnormal neurodevelopment (Jones and Buckley, 2006). Actually, many environmental risk-factors seem to operate before, around or immediately after birth. These include: pregnancy and birth complications, perinatal and early childhood brain damage, altered fetal development, season of birth and heavy cannabis intake (Jones and Buckley, 2006), suggesting that up to one third of the variance in liability to schizophrenia may be attributable to non-genetic factors. Despite consistent evidence supporting the presence of neurodevelopmental alterations in schizophrenia, many authors have put more emphasis on the neurodegenerative processes that occur over the course of the illness (Csernansky, 2007). Currently, however, the traditional neurodegenerative hypothesis has been largely questioned and, at least to some extent, revisited (Lieberman, 1999; Rund, 2009; Woods, 1998), indicating that the debate, as to whether there is a developmental or degenerative process, likely stems from a spurious dichotomy and depends on the stage at which its observation begins (Jones and Buckley, 2006). Over the last two decades, moreover, within the pathophysiological process of schizophrenia – either of neurodevelopmental and/or neurodegenerative nature – a dysregulation of the inflammatory response system has been largely documented (Altamura et al., 1999; Boin et

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al., 2001; Lin et al., 1998; Maes et al., 2002). For instance, evidence of immune activation has been derived from the detection of abnormal levels of proinflammatory cytokines and their receptors in peripheral blood and cerebrospinal fluid from schizophrenic patients. Cytokines, in particular, are involved in normal central nervous system (CNS) development, as well as in the pathogenesis of many neuropsychiatric disorders, acting directly on neural cells or modulating neurotransmitter and peptidergic pathways. In this perspective, neurobiological hypotheses linking the neurodevelopmental alterations occurring in schizophrenia with the inflammatory processes, largely documented over the course of the illness, have been put forward. The present review article is aimed to provide a comprehensive and updated overview of the main acquisitions in the field of neurodevelopmental and inflammatory evidence found in schizophrenia. 2. Material and methods Literature for this narrative overview was identified by searching Medline and Cochrane Libraries in two steps. First, a search was carried out identifying articles published in English and related to the neurodevelopmental and inflammatory processes in schizophrenia. Specifically, the keyword “schizophrenia” was variably combined with the terms “neurodevelopment”, “immune alterations”, “immune abnormalities”, “immune system”, “neurodegeneration” and “inflammation”. Furthermore, a hand search for relevant articles was conducted examining the reference list of the publications retrieved in the primary search. 3. Results Results of the retrieved publications are presented in two main sections: a first one concerning the neurodevelopmental hypothesis in schizophrenia and a second one dealing with the inflammatory alterations and cytokine role in schizophrenia, in relation to neurodevelopment. 3.1. The neurodevelopmental hypothesis of schizophrenia Several lines of evidence strongly indicate that schizophrenia is a disorder of neurodevelopmental origin (Gourion et al., 2004). The “neurodevelopmental model” of schizophrenia, in its simplest form, postulates that the disorder could be the correlate of an aberration in neurodevelopmental process starting much earlier than the onset of clinical symptoms, caused by a combination of genetic and environmental factors (Cardno et al., 1999; Rapoport et al., 2005;Singh et al., 2004). 3.1.1. Arguments supporting the neurodevelopmental hypothesis of schizophrenia The neurodevelopmental hypothesis of schizophrenia assumes that the cerebral damage characteristic of the disorder, which becomes more evident in the long-tem run, has, actually, begun early in life (Buckley, 1998; Keshavan and Murray, 1997; Murray and Lewis, 1987; Waddington and Buckley, 1996; Weinberger, 1987). In particular, several investigators believe that the damage occurs during brain development, over the intrauterine period and the first few years after birth (Gilmore et al., 1998; Weinberger, 1987). Related observations of reduced neuronal size and arborization (Selemon and Goldman-Rakic, 1999), combined with evidence from longitudinal imaging studies (Gur et al., 1998; Thompson et al., 2001), would suggest, however, that additional factors, active during adolescence, may play a role in the etiology and pathophysiology of the disorder as well. Interactions between early brain damage and abnormal development in adolescence are well explained in the “2-hit” model, proposed by Keshavan (Keshavan, 1999; Keshavan and Hogarty,

1999), according to which the occurrence of abnormal development, during 2 critical time points (i.e., early brain development and adolescence), eventually produces the symptoms peculiar to schizophrenia. According to this model, moreover, early developmental insults may lead to dysfunction of specific neural networks that would account for the premorbid signs and symptoms observed in individuals, who later develop a full-blown schizophrenic disorder (Keshavan, 1999). In fact, at adolescence, excessive elimination of synapses, during the physiological pruning process, along with loss of plasticity may account for the emergence of symptoms (Fatemi and Folsom, 2009; Keshavan, 1999; Keshavan and Hogarty, 1999). Therefore, the “neurodevelopmental model” seems to be based on reports of an excess of adverse events occurring during the pre- and perinatal periods, which would lead to the presence of cognitive and behavioral signs, particularly in adolescence and childhood. Another element supporting this hypothesis is represented by the lack of clear-cut neurodegenerative patterns in many schizophrenics (Lewis and Levitt, 2002). Furthermore, multiple markers of congenital anomalies, indicative of neurodevelopmental insults, have been indicated as supportive for the neurodevelopmental model of schizophrenia (Lloyd et al., 2008; Meltzer and Fatemi, 2000), including: agenesis of corpus callosum, stenosis of Sylvian aqueduct, cerebral hamartomas, and cavum septum pellucidum. Presence of low-set ears, epicanthal eye folds, wide spaces between the first and second toes and abnormal dermatoglyphics are, in turn, suggestive of both first and second trimester abnormalities (Fatemi and Folsom, 2009). Multiple records, moreover, indicate the presence of premorbid neurological soft signs in children who later develop schizophrenia (Barkus et al., 2006; Fish et al., 1992). In a pivotal study, for instance, pre-schizophrenic children were found to have abnormal upper limb movements in home movies (Walker et al., 1994). Additionally, children at high risk for schizophrenia were found to show a broad range of abnormalities, the most prominent of which seemed to occur in attention, motor function, coordination, sensory integration, mood and social behaviors (Niemi et al., 2003). Indeed, these abnormalities may have predictive value in determining which children will later keep on showing overt signs of either schizophrenia spectrum disorders or schizophrenia itself (Fish et al., 1992). Taken as a whole, all the aforementioned findings are consistent with the hypothesis of schizophrenia as a disorder due to abnormal brain development. Genetic data and findings from studies examining the interactions between genes and pre/perinatal environmental factors provide additional evidence in this regard. 3.1.2. Genetic data and gene-environment interaction in the etiology of schizophrenia Several studies have established an important role for genetic factors in the pathophysiology of schizophrenia, with polygenic model effects of multiple-risk genes, acting additively or multiplicatively, likely providing the best explanation for the disorder. Linkage and association studies (Lewis et al., 2003; Sullivan et al., 2001, 2006) have shown 12 chromosomal regions, containing 2181 known genes (Lewis et al., 2003), and 9 specific genes, involved in the possible etiology of the disorder (Sullivan et al., 2006). On the other hand, environmental factors play an active role in the pathogenesis of schizophrenia, including pre- and perinatal complications, as well as maternal infections occurring during pregnancy. A meta-analysis of population-based data (Cannon et al., 2002a, 2002b) found significant estimates for 3 main categories of pre- and perinatal complications: 1) complications of pregnancy (e.g., bleeding, preeclampsia, diabetes), 2) abnormal fetal growth and development (e.g., low birth weight, congenital malformations, small head circumference), and 3) complications of delivery (e.g., asphyxia, uterine atony, emergency cesarean section). The increase in the overall risk for schizophrenia conferred by such events is small but appreciable. The pooled odds ratio of the effect of exposure to obstetric

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complications on the subsequent development of schizophrenia, in fact, has been estimated to be about 2.0 (95% confidence interval 1.6–2.4) (Geddes and Lawrie, 1995; Geddes et al., 1999). Obstetric complications, in turn, are supposed to increase the risk of developing schizophrenia in two main ways: acting alone and/or interacting with genetic risk factors (Boog, 2004; Cannon et al., 2002a, 2002b; Preti et al., 2000). In fact, it has been suggested that specific susceptibility genes for schizophrenia may be regulated by hypoxia/ischemia (Schmidt-Kastner et al., 2006) occurring during birth. In a study of schizophrenia candidate genes, Schmidt-Kastner and colleagues found that at least 50% of them were regulated by hypoxia (Schmidt-Kastner et al., 2006). The authors suggested that the interaction between genes and environmental factors, such as hypoxia, can result in developmental perturbations leading to a predisposition to the disorder in adolescence. Other environmental factors, potentially causing abnormal neurodevelopment, include the infective processes occurring during pregnancy. A large body of evidence, in fact, indicates that environmental factors, such as maternal infections, can increase the risk of the offspring to develop schizophrenia at adulthood (Karlsson et al., 2001; Lewis, 2001). The first observations of an association between maternal infections and schizophrenia were reported by Hare and collaborators (Hare et al., 1972) and Machon's group (Machon et al., 1983). They found an excess of schizophrenic patients, born during late winter and spring, as indicator of potential influenza infections being responsible for such cases. These initial findings were followed by mixed and negative replications (Altamura et al., 2003; Brown et al., 2000a, 2000b). As such, the available body of research in the field suggests that pre/perinatal infections and other environmental insults, that adversely affect infant brain development, may increase the likelihood to develop schizophrenia in later life, particularly in genetically susceptible individuals (Jones and Cannon, 1998; Weinberger, 1995; Wright et al., 1993). Such increased risk has been associated with maternal infections with viruses, including influenza (Mednick et al., 1988), measles (Torrey et al., 1988), polio (Suvisaari et al., 1999), herpes simplex type 2 (Buka et al., 2001), as well as specific bacterial infections, such as diphtheria and pneumonia (O'Callaghan et al., 1994; Watson et al., 1984). Association studies regarding the influenza A virus showed that the maximum risk for the embryonic brain to be hit is represented by the exposure to the infective agent during the 4th and 7th month of gestation (Brown et al., 2004). Subsequent studies have shown that other viruses, such as rubella, may increase the risk for development of schizophrenia in the progeny of exposed mothers (Brown et al., 2000a, 2000b; Susser et al., 1999). Prenatal exposure to rubella, in particular, was found to increase 10- to 20-fold the risk of developing schizophrenia (Brown, 2006); prenatal exposure to influenza in the first trimester increased risk 7-fold, and infection in early to mid gestation increased risk 3-fold. Also presence of maternal antibodies against Toxoplasma gondii lead to 2.5-fold increased risk. There are at least two mechanisms that may be responsible for transmission of viral effects from mother to the fetus: 1) via direct viral infection or 2) through the induction of cytochine production. Studies supporting the direct viral infection are mostly experimental and related to animal models. Only one study, in fact, showed that human influenza A viral infection of a pregnant mother might have caused transplacental passage of viral load to the fetus (Nakai et al., 2003). On the other hand, several of the aforementioned studies found that a variety of maternal infections, occurring during pregnancy, was associated with an increased incidence of schizophrenia in the offspring. Thus, it is likely that the association between in utero or early postnatal exposure to infections and schizophrenia is a more general phenomenon related to infection, rather than limited to a single etiologic viral agent such as influenza. Of note, several reports showed that human influenza virus and other infective agents can induce production of systemic cytokines by the maternal immune

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system, the placenta, or even the fetus itself (Fidel et al., 1994; Fortunado et al., 1996; Hillier et al., 1993; Urkabo et al., 2001; Yoon et al., 2003). Therefore, some authors hypothesized that proinflammatory cytokines, generated by the immune system, may be important mediators of the association between maternal infection, abnormal brain development and increased risk for schizophrenia and other neurodevelopmental disorders (Gilmore and Jarskog, 1997). 3.2. Alterations of inflammatory pathways in schizophrenia Dysregulation of the inflammatory response system appears to be a major piece of evidence in the pathophysiology of schizophrenia, along with genetic and environmental factors, ultimately affecting the neurodevelopmental process (Altamura et al., 1999; Jablensky, 2000; Muller et al., 1999; Mundo et al., 2005; Smith and Maes, 1995). Recently, there has been growing interest on the interface between immunology and chronic mental illness, including areas such as stress, neuroplasticity, genetics and cytokines. The latter ones, in particular, playing a pivotal role in infectious and inflammatory processes and mediating of the cross-talk between the brain and the immune system, are supposed to be the main actors of the immune and inflammatory abnormalities, documented in schizophrenia. Cytokine role in both physiological and neuropathological processes related to neurodevelopment and schizophrenia is, herein, presented in detail. 3.2.1. Cytokine expression and main actions Cytokines are a family of polypeptides that are essential to the immune system: they are systemic mediators of host response to infection, representing a reliable marker of infectious and inflammatory conditions (Braun and Derkits, 2010; Weizman and Bessler, 1999). Cytokines are synthesized and secreted by both immune and nonimmune cells and their effects are mediated by specific receptors, expressed on the surface of target cells. Cytokine receptors are available also in soluble forms and their activity can either enhance or inhibit itself. Moreover, endogenous cytokine receptor antagonists compete with cytokines for membrane receptors. The action of cytokines is exerted by activation and recruitment of immune cells, increased vascular permeability and blood supply to inflamed tissues. Cytokines include interleukins (ILs), interferons (IFNs), tumor necrosis factors (TNFs), transforming growth factors (TGFs) and chemokines. These molecules and their receptors are expressed physiologically in CNS cells. However, in normal conditions, only low-level expression of cytokines in blood vessels can be detected (Licinio et al., 1998). Because cytokines are large hydrophilic polypeptides, their ability to cross the brain–blood barrier is reduced, at least under physiologic conditions. Therefore, it has been argued that cytokines may communicate with the CNS through different pathways, including: (i) passive transport through leaky areas, such as the circumventricular organs; (ii) increased permeability of brain–blood-barrier; (iii) binding to specific transporters on cerebral vascular endothelium, thereby inducing generation of secondary messengers, such as prostaglandin and nitric oxide; and (iv) activation of peripheral vagal fibers, which could transmit the signal to deep brain nuclei (Licinio and Wong, 1997; Watkins et al., 1995a, 1995b). Such mechanisms, moreover, do not seem to be mutually exclusive. The only one that does not imply blood-borne pathways is the activation of afferent neurons via paracrine action. A target candidate for locally induced cytokines is the vagus nerve, whose branches are associated with lymph nodes that drain regions in which immune activation occurs. Moreover, the vagus is formed by high percentage of afferent fibers which terminate in a region of brainstem (nucleus of the solitary tract), that is activated by immune challenges (Goehler et al., 1995; Wan et al., 1994). The nucleus of the solitary tract represents a relay station to other brain nuclei (Maier et al., 1998; Schaefer et al., 2002). In support of this specific function, several studies showed that vagotomy induces a striking blockade of responses to peripheral

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cytokines, suggesting that signal from cytokines to brain is carried by this peripheral nerve (Fleshner et al., 1995; Watkins et al., 1999 and 1995a, 1995b). 3.2.2. Evidence of cytokine dysregulation in schizophrenia The presence of abnormal circulating levels of proinflammatory cytokines and their receptors is well established in peripheral blood and cerebrospinal fluid of schizophrenic patients (Garver et al., 2003; Kaminska et al., 2001; Maes et al., 1994; Miller et al., 2011; Potvin et al., 2008; Van Kammen et al., 1998) and their first-degree relatives (Miller et al., 2011; Nunes et al., 2006), thus confirming the presence of immune abnormalities in schizophrenia (Ganguli et al., 1994a, 1994b; Lin et al., 1998; Mundo et al., 2005; Naudin et al., 1996, 1997; Van Kammen et al., 1998). There is also some evidence that alterations in levels of proinflammatory cytokines, such as IL-6 (Lin et al., 1998), IL8 and IL10 (Maes et al., 2002), are more pronounced in treatmentresistant schizophrenic patients, likely indicating an increased monocytic function. Recently, moreover, clinical studies on augmentation with non steroidal anti-inflammatory compounds to antipsychotics have suggested that cytokines, and their receptors, may be key markers of illness relapse or response to augmentation, at least for a subgroup of schizophrenic patients (Akhondzadeh et al., 2006; Laan et al., 2010; Muller et al., 2002, 2010). Furthermore, schizophrenic patients carrying a polymorphism of the chemokine MCP-1 gene were found to be resistant to antipsychotic treatment, when compared with non-carriers, possibly representing a more severe subtype of patients (Mundo et al., 2005). This suggests that inflammatory response could play a role in the response to treatment and in the overall outcome of schizophrenia. All these data are part of a growing body of evidence of an immune-inflammatory dysfunction in schizophrenic patients (Miller et al., 2011). 3.2.3. Hypotheses for cytokine-mediated basis for schizophrenia In the last two decades, different hypotheses in relation to the cytokine-mediated development of schizophrenia have been proposed. The “macrophage T-lymphocyte” hypothesis suggests that chronically activated macrophages produce cytokines, such as IL-1, IL-2, TNF, IFN-alpha and IFN-gamma, which are supposed to be the key mediators for the disorder (Smith and Maes, 1995). The “T helper (Th) 2 hypothesis” postulates a shift away from Th-1 cytotoxic cell immune function toward Th-2 like humoral immune reactivity (Muller et al., 1999, 2002; Schwarz et al., 2001). This specific hypothesis, however, has been somehow questioned by two recent meta-analyses (Miller et al., 2011; Potvin et al., 2008): the former not supporting the Th2 shift in schizophrenia and the latter showing, actually, a Th1 shift. Taken as a whole, indeed, both meta-analyses support the presence of inflammation or M1 activation. The “microglial hypothesis” argues that proinflammatory cytokines and free radicals are released by activated CNS microglia, thus causing abnormal neurogenesis, neural degradation and white matter abnormalities, which play a role in the pathogenesis of schizophrenia (Monji et al., 2009). In a recent meta-analysis, Brian and co-workers collected a significant body of evidence indicating that cytokine alterations in schizophrenia may vary according to clinical status, as in other nonpsychotic disorders, such as systemic lupus erythematosus and celiac disease (Miller et al., 2011). They found that studies with acutely relapsed inpatients and first episode patients shared the same effects size, suggesting that the association between cytokine abnormalities and acute exacerbations is independent of antipsychotic medications. On this basis, they suggested that some cytokines (IL-1beta, IL-6 and TGF-beta, in particular) may be state markers for acute relapse, while some others (e.g., IL-12, IFN-gamma, TNF-alpha and sIL2R) could represent trait markers for schizophrenia.

3.2.4. Cytokine interaction with environmental factors over the neurodevelopment in schizophrenia Cytokines play an important role during neurodevelopment and in CNS functions at all stages, starting with the induction of neuroepithelium (Gaulden and Reiter, 2008). Later on, cytokines monitor the renewal of neuroepithelial cells, which act as precursors for all neurons, microglia and adult progenitors, as well as framework for radially migrating neurons (Pinto and Gotz, 2007). These processes are orchestrated by cytokines and related responses of their target cells (Lee et al., 2010). As general rule, there is an overproduction of neurons and glia and cytokines are crucial to either promote survival of cells, properly connected in neural network, as well as to induce apoptosis of cells with impaired connections (Deverman and Patterson, 2009). Therefore, even minimal variation on cytokine levels could result in subsequent functional impairment (Chklovskii, 2004). Given that cytokines are important for development and function of the brain, they may represent a link between the immune system, the neurotransmission and the neurodevelopmental hypothesis of schizophrenia. In recent years, a proliferation of studies focussed on infection and subsequent activation of inflammatory pathways in schizophrenia has emerged. Two major hypotheses have been put forward: the first argues that individual infections increase risk of developing schizophrenia through peculiar effects, the second suggests that different infections act through common pathways, which may ultimately alter fetal brain development and increase risk of schizophrenia. Cytokines have been proposed as key mediators of such processes (Braun and Derkits, 2010; Gilmore and Jarskog, 1997), based on clinical and preclinical findings. As mentioned above, an increase of cytokines, following maternal infection, may alter the immune status of the brain, causing abnormal cells development with subsequent brain damage (Braun and Derkits, 2010; Dammann and Leviton, 1997). It is clear that maternal immune activation (MIA) induces increase of cytokines in the placenta (IL-1beta, IL-6, TNF-alpha) and amniotic fluid (IL-6, TNF-alpha) (Jonakait, 2007; Patterson, 2009). The action of cytokines on the placenta might alter transfer of cells, nutrient, oxygen, growth factors and maternal antibodies, each of which with potential crucial effect on fetal development (Patterson, 2009). However, it is not clear whether cytokines are altered in the fetal brain, even though animal model investigation suggests that there could be a significant increase of IL-1beta, IL-6, and INF-gamma (Elovitz et al., 2006). This increase suggests that cytokines may act directly on developing neurons, likely causing disrupted maturation of oligodendroglia, as well as white matter abnormalities (Bauer et al., 2007). Cytokines, moreover, might activate other potential processes, such as stimulation of astroglia and microglia, to produce excitatory amino acid and nitric oxide, which lead to disrupted maturation of oligodendrocytes (Davis et al., 2003). In any case, the overall increase of cytokines, including IL-8 and TNF-alpha, has been correlated with several infections and has been associated with schizophrenia, as already reported. Moreover, maternal and fetal levels of IL-8 have been correlated to each others. IL-8 appears to be a key factor for neutrophil attraction, as well as release of lysosomal enzymes from neutrophils, leading to discharge of oxygen free radicals. TNF-alpha has been associated with chorioamnionitis (Saji et al., 2000) and fetal infections (Baud et al., 1999). Along with maternal infections, other risk factors have been considered important in altering MIA. For instance, nutritional deficits and stress have been linked with increase of inflammatory cytokines. In particular, chronic and acute stress have been associated with increased production of proinflammatory cytokines (Leonard and Song, 1999; Watkins et al., 1999) and decreased levels of anti-inflammatory ones (Deinzer et al., 2004; Goebel et al., 2000; Maes et al., 1998). Along with stress, another important factor influencing inflammatory patterns is food consumption (Hansen et al., 1997). In postprandial blood samples, in fact, several inflammatory markers have been

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retrieved, such as IL-6 and C-reactive protein, even though the inflammatory response varies with different kind of food. The most important factors eliciting the inflammatory system are caloric intake, glycemic index and lipid profile (Margioris, 2009). In particular, a critical role is played by omega 3 and 6 fatty acids (FAs), which modulate immune function with adverse effects. Omega-3 FAs suppress inflammation, by attenuating prostaglandines (PGEs) synthesis and production of proinflammatory cytokines, such as IL-1, IL-6, TNF-alpha and INF-gamma (Maes et al., 1999). On the other side, omega-6 FAs, which are precursors of PGE2, promote inflammation by increasing production of cytokines, such as IL-1, TNF-alpha and IL-6 (Maes et al., 1999, 2000). In support of this, a comparison between subjects with low and high omega-3 FAs revealed a higher-stress-induced production of proinflammatory cytokines in the first group (Maes et al., 2000). It is also worth mentioning that development in urban areas and birth in winter–spring can enhance the risk of maternal infections with subsequent inflammatory response (Coe and Lubach, 2005; Merlot et al., 2008; Shen et al., 2008). Finally, the observation that MIA can change the balance of cytokines in the fetal brain is supposed to be of particular relevance in the context of the immune dysregulation described in schizophrenia. However, it has not been clarified yet whether cytokine fetal imbalance is able to induce per se an immune dysregulation in the adult brain (Fig. 1). Besides affecting neurodevelopment, some cytokines (i.e., IL-2 and IL-6) appear to have a role in the progression of schizophrenic illness. For instance, IL-2 stimulates the proliferation of T lymphocytes and its inhibition contributes to humoral immunity enhancement (Bresee and Rapaport, 2009). Kim and colleagues found lower IL-2 serum levels in patients with long duration of illness (Kim et al., 2000), while other studies showed antipsychotic treatment responsible for a decrease of IL-2 serum levels (Mahendran et al., 2004). Moreover, IL 2 serum levels have been recently associated with severity of negative symptoms and tardive dyskinesia (Liu et al., 2012). These findings suggest that IL-2 may be a key modulator of dopaminergic metabolism and psychotic symptoms in schizophrenia (Kim et al., 2000). Another contribution to the progression of the illness might be due to an increase of humoral immunity, which has been observed in schizophrenia. The hyper-activation of humoral immunity, in fact,

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stimulates the tryptophan 2,3-dioxygenase enzyme, with an increased transformation of the amino acid tryptophan in kynurenic acid that acts as a NMDA antagonist (Muller and Schwarz, 2006). Other authors, however, have questioned this theory, stressing that the enzyme indoleamine-2,3-dioxygenase (IDO) – catalyzing the degradation of L-tryptophan to N-formylkynurenine – is induced by Th1 and M1 cytokines, highlighting that, actually, oxidative stress would be related to cell mediated immune activation (Th1-like response). Among cytokines, IL-6 potentiates B lymphocyte proliferation and it seems to play a key role in the immunological abnormalities observed in schizophrenic patients (Naudin et al., 1997). It is also worthwhile to highlight that several studies showed that a long duration of illness in schizophrenia is associated with higher serum levels of IL-6 (Ganguli et al., 1994a, 1994b; Naudin et al., 1997). Moreover, elevated IL-6 serum concentrations have been proposed as key factors, responsible for cerebral atrophy observed in schizophrenics with long duration of illness (Akiyama, 1999; Waddington, 1993). This hypothesis is consistent with results of a recent study showing that IL-6 excessive signaling is related to the state of illness and not to a genetic predisposition (Sasayama et al., 2011). 3.3. Reconciling neurodevelopmental and neurodegenerative hypotheses in schizophrenia: current perspectives The present review attempted to present the most intriguing patterns linking abnormalities in the neurodevelopment with altered immune/inflammatory mechanisms in the CNS of schizophrenic patients. However, such perspective does not exclude the possibility to consider also the presence of progressive neurodegeneration as prominent biological feature of the disorder. In fact, it seems likely that what we currently diagnose as a unitary disorder includes, actually, highly heterogeneous schizophrenic entities, in terms of pathophysiology (Altamura, 1993). These would include forms predominantly characterized by neurodevelopmental alterations (e.g., inflammatory features), as well as others with minor or absent neurodevelopmental aspects, but marked and progressive neurodegeneration, starting from the early adolescence, as main biological feature. A different genetic predisposition could account for these two pathophysiological patterns. In the first case, a disorder with

Fig. 1. Interactions between cytokines, maternal immune activation (MIA), neurodevelopment and neuroprogression.

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more pronounced environmental implications (e.g., birth complications, early infections, etc.) would initiate the clinical picture upon a genetic predisposition. In the second case, a main progressive neurodegeneration, likely starting in the adolescence (as for other neurological disorders, such as Huntington's disease or muscular dystrophy) (Werry, 1996), and less frequently characterized by environmental factors, might be prevalent. In the second case, moreover, the occurrence of the disorder might have a different and more robust genetic loading, which includes a late dysregulation of the immuneinflammatory, often without an environmental trigger. Therefore, the attempt to solve the question whether schizophrenia is or is not a neurodevelopmental disorder or a progressive neurodegenerative seems to be outdated (Jones and Buckley, 2006). Differences in the genetic background could give account of these two different timing and patterns of presentation. In any case, all the abovementioned data seem to qualify schizophrenia as a neurodegenerative disorder, characterized by an immune-inflammatory peculiar pattern, which interferes with normal brain functions. Among the markers of these dysfunctions it should not be forgotten the HPA axis dysregulation which, in turn, could be responsible for the cascade of neurochemical events leading to the “classical” symptoms of schizophrenia (Altamura, 1993). In conclusion, all the reviewed inflammatory and neurodevelopmental data represent the most robust evidence (besides cerebral visualization abnormalities) confuting the conceptualization of schizophrenia as a “functional psychosis”. Indeed, they encourage to consider it as a pure “brain disease”, as Kraepelin correctly defined it, as a dementing process occurring in the frontal part of the brain, regardless of how and when these deep dysregulations of neural mechanisms, leading to neuronal death in specific brain areas, occur. Neuronal loss seems, likely, to be due to the neurodevelopmental/inflammatory abnormalities reported in this review. Conflict of interest Prof. Altamura has been consultant for: Roche, Merck, Astra Zeneca, Bristol Myers Squibb, Janssen-Cilag; and in the Speakers Bureau of: Eli Lilly and Pfizer. Other authors declare no conflict of interest with the contents of the present article. Dr Dell'Osso has been in the Speaker Bureau of Astra Zeneca, Bristol Myers Squibb, Janssen-Cilag, Eli Lilly, Pfizer, Glaxo Smith Kline, Lundbeck, Cyberonics and Italfarmaco. Acknowledgments Dr Michela Cigliobianco, M.D., Dept. of Psychiatry, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano. References Akhondzadeh S, Tatabase M, Amini H, Ahmadi Abhari SA, Abbasi SH, Behnam B, et al. Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial. Schizophr Res 2006;84:180–2. Akiyama K. Serum levels of soluble IL-2 receptor alpha, IL-6 and IL-1 receptor antagonist in schizophrenia before and during neuroleptic administration. Schizophr Res 1999;37:97-106. Altamura AC. A multidimensional (pharmacokinetic and clinical–biological) approach to neuroleptic response in schizophrenia. With particular reference to drug resistance. Schizophr Res 1993;8(3):187–98. Altamura AC, Boin F, Maes M. HPA axis and cytokines dysregulation in schizophrenia: potential implications for the antipsychotics treatment. Eur Neuropsychopharmacol 1999;10:1–4. Altamura AC, Bassetti R, Bocchio L, Santini A, Mundo E. Season of birth and inflammatory response system in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2003;27(5):879–80. Barkus E, Stirling J, Hopkins R, Lewis S. The presence of neurological soft signs along the psychosis proneness continuum. Schizophr Bull 2006;32:573–7. Baud O, Emilie D, Pelletier E, Lacaze-Masmonteil T, Zupan V, Fernandez H, et al. Amniotic fluid concentrations of interleukin-1beta, interleukin-6, and TNF-alpha in

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