Brain maturational processes and delayed onset in schizophrenia.

The central feature of schizophrenia is its onset in adolescence. Although this clinical observation is consistent with the view that schizophrenia may be a neurodevelopmental disorder, debate has focused on when the proposed brain maturational deviations may begin and what might be the nature of such defective development. Conflicting models of this illness (e.g., the early and late neurodevelopmental models) have been proposed. In this paper, we will first review concepts from basic developmental neurobiology pertinent to these issues; we then summarize aspects of the neurobiology of schizophrenia that have a particular bearing on the adolescent onset of this illness. We propose that the schizophrenic syndrome may result from early brain adversity and late maturational processes of brain development interacting with adverse humoral, biochemical, and psychosocial factors during adolescence and early adulthood. The onset of schizophrenia in adolescence may be related to the "plasticity switch" secondary to the peripubertal brain maturational changes, perhaps involving an alteration in glutamate receptor function. This loss of plasticity could result in social and nonsocial cognitive deficits that are central to the pathophysiology of schizophrenia; the vulnerable person may therefore utilize prepubertal processing styles that are insufficient to the adaptive and "gistful" abstraction requirements of adult cognition. Schizophrenia onset might occur in the context of psychosocial developmental challenges to a delayed social cognitive capacity among neurodevelopmentally compromised individuals. We review therapeutic implications as well as testable predictions generated by this model, and discuss research strategies that might further our understanding of the brain maturational abnormalities in schizophrenia.     

Schizophrenia is not associated with the functional candidate gene ERBB3: results from a case-control study.

Increasing evidence has supported the hypothesis of a neurodevelopmental component in the etiology of schizophrenia. Recently, several independent microarray gene expression studies have revealed downregulated expression of myelin-related genes in the postmortem brains of schizophrenia patients. Complete myelination of the cortex has been observed to occur in late adolescence and early adulthood, which is typically the age of onset of schizophrenia. ERBB3 is a gene which has not only been found to be downregulated in schizophrenia simultaneously in three microarray studies, but also is a strong candidate because of its potential role in neurodevelopment as a receptor of NRG1. Therefore, we performed association analysis of seven nonsynonymous SNPs in this gene. Two SNPs in ERBB3 (rs773123 and rs2271188) were polymorphic in our samples, neither of which showed significant evidence of association with the illness (P = 0.639 and 0.561, respectively). Because replication across such studies is notoriously difficult, the microarray evidence implicating ERBB3 still strongly supports some role of this gene in schizophrenia. However, our failure to find genetic association suggests that the differential expression of ERBB3 in schizophrenia may be environmentally driven, or involve cis- or trans-acting genetic factors beyond the boundaries of the gene itself.     

Histamine and prostaglandins in schizophrenia: revisited.

It has long been accepted that schizophrenia is primarily a physical illness resulting from a chemical imbalance in the brain. This paper will review evidence supporting the hypothesis that histamine and prostaglandins are both linked and primary in the etiology of schizophrenia. Furthermore, their etiological significance supersedes the role of dopamine as a primary causative factor.     

Schizophrenia: a genetic perspective (review)

Schizophrenia is a complex neurodevelopmental disorder characterized by mental dysfunction across multiple domains of the brain. It affects 1% of world's general population and the nature of neurobiological lesions in the schizophrenic brain are not known. Although the exact etiology of the disorder is not understood, twin, family and adoption studies have provided consistent evidence that genetic factors play a major role in the pathogenesis. A genome-wide genetic linkage screen identified loci on chromosomes 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 13, 15, 18, 22 and the X with positive lod scores, thus excluding a single major locus for schizophrenia. Association studies have generated disappointing results in identifying the susceptible DNA sequence variants and the anticipation hypothesis on trinucleotide repeat expansion provided equivocal results or lack of enthusiasm. Although there are no biological markers at present, the recent finding that human endogenous retrovirus is activated in cerebrospinal fluid as well as in the postmortem schizophrenic brain may change our understanding of the etiopathogenesis of this disease. Meanwhile, treatment with newly developed anti-psychotic drugs combined with educational and cognitive rehabilitation procedure may help the patients to cope with the illness.     

Epidemiology-driven neurodevelopmental animal models of schizophrenia

Human epidemiological studies have provided compelling evidence that the risk of developing schizophrenia is significantly enhanced following prenatal and/or perinatal exposure to various environmental insults, including maternal exposure to stress, infection and/or immune activation, nutritional deficiencies and obstetric complications. Based on these associations, a great deal of interest has been centered upon the establishment of neurodevelopmental animal models which are based on prenatal and/or perinatal exposure to such environmental stimuli. In the present review, we describe this relatively novel class of epidemiology-based animal models in relation to the etiology, neurobiology and psychopharmacology of schizophrenia. Thereby, we discuss the general design and practical implementation of these models, and we provide an integrative summary of experimental findings derived from diverse epidemiology-based models, including models of maternal exposure to psychological stress, glucocorticoid treatment, viral infection, immune activating agents, protein deprivation, vitamin D deficiency, as well as models of obstetric complications in the form of birth by Caesarian section and perinatal/postnatal hypoxia. We highlight that the long-term consequences of prenatal exposure to these environmental challenges in animals successfully capture a broad spectrum of structural and functional brain abnormalities implicated in schizophrenia, some of which can be normalized by acute and/or chronic antipsychotic drug treatment. We thus conclude that epidemiology-driven neurodevelopmental models of schizophrenia are characterized by a high level of face, construct and predictive validity, including intrinsic etiological significance to the disorder. They also fulfill the expectation of the neurodevelopmental theory, such that the effects of prenatal environmental insults often only emerge after puberty. Epidemiologically based animal models not only provide indispensable experimental tools to test the hypothesis of causality in human epidemiological associations, but they also offer important new avenues for the elucidation of neurobiological, neuroendocrine and neuroimmunological mechanisms involved in the etiopathogenesis of schizophrenia and related disorders.     

Structural brain alterations in individuals at ultra-high risk for psychosis: a review of magnetic resonance imaging studies and future directions

Individuals at ultra-high-risk (UHR) for psychosis have become a major focus for research designed to explore markers for early detection of and clinical intervention in schizophrenia. In particular, structural magnetic resonance imaging studies in UHR individuals have provided important insight into the neurobiological basis of psychosis and have shown the brain changes associated with clinical risk factors. In this review, we describe the structural brain abnormalities in magnetic resonance images in UHR individuals. The current accumulated data demonstrate that abnormalities in the prefrontal and temporal cortex and anterior cingulate cortex occur before illness onset. These regions are compatible with the regions of structural deficits found in schizophrenia and first-episode patients. In addition, the burgeoning evidence suggests that such structural abnormalities are potential markers for the transition to psychosis. However, most findings to date are limited because they are from cross-sectional rather than longitudinal studies. Recently, researchers have emphasized neurodevelopmental considerations with respect to brain structural alterations in UHR individuals. Future studies should be conducted to characterize the differences in the brain developmental trajectory between UHR individuals and healthy controls using a longitudinal design. These new studies should contribute to early detection and management as well as provide more predictive markers of later psychosis.     

Is schizophrenia developmental adaptation to environmental menaces?

Schizophrenia is a devastating mental disorder, with its symptoms typically emerging during late adolescence to young adulthood. In contrast, accumulating evidence suggests that schizophrenia is a developmental disorder in which brain abnormalities may occur even before birth. This has brought the major challenge to explain such discrepancy of brain deficits occurring during prenatal period and emergence of symptoms during adulthood. A number of ideas have been proposed to explain delayed emergence of symptoms at adulthood in relation to maturational processes of various brain systems during adolescence. However, these still lack clear relationship to prenatal deficits. Thus, a key to better understand the pathology of schizophrenia is to unveil a theory or model that can explain the relationship between prenatal deficits and post-pubertal onset of symptoms. Here we propose a novel hypothesis, along with discussion of several lines of evidences supporting it, that schizophrenia may not be a disorder in a strict sense, but rather be understood as the biological state occurring as consequence of adaptation to severe environmental conditions during the prenatal periods, which explains the relationship between prenatal developmental deficits and the postnatal maturational process for onset of symptoms.     

Sleep Dysfunction Prior to the Onset of Schizophrenia: A Review and Neurodevelopmental Diathesis–Stress Conceptualization

Sleep dysfunction is a pervasive symptom in schizophrenia, yet little is known regarding the extent to which problematic sleep is present prior to illness onset. Results from an online database search targeting genetic high‐risk, clinical high‐risk, and retrospective studies of patients with schizophrenia prior to onset suggest that abnormalities in sleep dysfunction precede schizophrenia onset. Further, a host of proximal factors such as neural structures, endocrine function, and cognitive performance holds promise for improving our conceptualization of sleep dysfunction. However, support is preliminary, and extensive new research in this area is essential. Drawing from this review, a neurodevelopmental diathesis–stress model is posited to highlight potential research targets and mechanisms through which vulnerability, biological/psychosocial stress, and adolescent neuromaturational factors may contribute to both sleep dysfunction and development of psychosis in at‐risk youth.     

Neuropathology of schizophrenia--a review

Despite clinical evidence of brain dysfunction in schizophrenia, little progress was made for most of the last century in determining its organic parameters. Neuropathology, over the past few decades, has made a substantial contribution to the understanding of cellular and molecular mechanisms of schizophrenia. During the last 10-15 years the concept of schizophrenia as a 'functional' psychosis has changed to the current paradigm of schizophrenia as a neurodevelopmental disorder. Much still has to be unravelled and learnt. This review gives a brief account of the relevant neuroanatomy, viral hypotheses of schizophrenia etiology, pathologic findings reported, concept of neurodevelopmental model and avenues for the future.     

The role of HLA-G in cytokine homeostasis during early pregnancy complicated with maternal infections: a novel etiopathological approach to the neurodevelopmental understanding of schizophrenia

Schizophrenia is perhaps the most enigmatic and tragic psychotic disorder with remarkable mortality and morbidity. Schizophrenia is complex and clinically a heterogeneous disorder. The etiological basis of schizophrenia ranges from autoimmune to neurodevelopmental hypothesis in one hand and involvement of different major gene segment with susceptibility loci on the other. Recently, neurodevelopmental hypothesis gained much impetus over the other domain. To support the neurodevelopmental basis, a number of investigations have shown that maternal infections during pregnancy increases the risk of the offspring developing schizophrenia and other neurodevelopmental disorders. The pathological mechanisms underlying this phenomenon is largely unknown. Many have suggested the involvement of different immune markers and shown that cytokines generated in response to maternal infection alter early brain development through their inflammatory activity. However, these findings have escaped discussion on various important issues related to cytokine homeostasis which depends on a large number of immune parameters including non-classical HLA-G molecules. Infections during early stages of pregnancy may alter cytokine regulation by disturbing the whole uterine immune milieu. To elucidate this issue, authors have tried to correlate the possible relationships between maternal infections and aberration of immune networking at the feto-maternal interface and their subsequent influence on the structural and functional abnormalities of the developing brain. The authors hypothesize that there exists a counter regulatory interaction among proinflammatory cytokines like TNF-alpha, HLA-G molecules and different immune cells like NK cells. We emphasize that HLA-G molecules are the novel immune players which maintain the immune homeostasis during early pregnancy in a manner that it can protect developing fetus from maternal immune attack. However, maternal infections may lead to the disturbance of HLA-G expression which in turn may fail to maintain its otherwise inhibitory potential to down regulate the detrimental inflammatory cytokines. Investigation on such interaction may unravel novel molecular mechanisms of neurodevelopmental basis of schizophrenia. Testing of our proposed hypothesis on animal models and on in vitro derived extravillous trophoblast cell lines holds promise of great insights to usher a new dimension of schizophrenia research and for developing new therapeutic strategies for better treatment and to adopt genetic prediction in schizophrenia management paradigm.     

GABAergic neuronal subtypes in the human frontal cortex--development and deficits in schizophrenia

Recent studies have provided evidence for a deficit of GABA-containing interneurons in the frontal cortex in schizophrenia. That this deficit might be brought about during early foetal or neonatal life is a hypothesis consistent with the substantial indications for a neurodevelopmental aetiology of the disease. GABAergic neurons can be defined by the presence of one of three types of calcium binding proteins, which are thought to have neuroprotective properties. We have undertaken an investigation into the postnatal ontology of these neuronal subtypes and find that calretinin expression is relatively constant and present from before birth, calbindin expression is also present early but redistributes in the cortex over the first months of life, while parvalbumin-immunoreactivity is not observed until between 3 and 6 months of age. Investigation of frontal cortical tissue taken post mortem from a series of schizophrenic patients and matched control subjects revealed that parvalbumin-, but not calretinin-immunoreactive cells are significantly diminished in schizophrenia. These observations support the hypothesis that GABAergic deficits in schizophrenia may stem from toxic events occurring during cortical development which selectively target immature neurons before protection by parvalbumin is conferred.     

GABAergic neuronal subtypes in the human frontal cortex — development and deficits in schizophrenia

Recent studies have provided evidence for a deficit of GABA-containing interneurons in the frontal cortex in schizophrenia. That this deficit might be brought about during early foetal or neonatal life is a hypothesis consistent with the substantial indications for a neurodevelopmental aetiology of the disease. GABAergic neurons can be defined by the presence of one of three types of calcium binding proteins, which are thought to have neuroprotective properties. We have undertaken an investigation into the postnatal ontology of these neuronal subtypes and find that calretinin expression is relatively constant and present from before birth, calbindin expression is also present early but redistributes in the cortex over the first months of life, while parvalbumin-immunoreactivity is not observed until between 3 and 6 months of age. Investigation of frontal cortical tissue taken post mortem from a series of schizophrenic patients and matched control subjects revealed that parvalbumin-, but not calretinin-immunoreactive cells are significantly diminished in schizophrenia. These observations support the hypothesis that GABAergic deficits in schizophrenia may stem from toxic events occurring during cortical development which selectively target immature neurons before protection by parvalbumin is conferred.     

Recent progress in animal modeling of immune inflammatory processes in schizophrenia: implication of specific cytokines

Epidemiologic studies demonstrate significant environmental impact of maternal viral infection and obstetric complications on the risk of schizophrenia and indicate their detrimental influences on brain development in this disorder. Based on these findings, animal models for schizophrenia have been established using double stranded RNA, bacterial lipopolysaccharides, hippocampal lesion, or prenatal/perinatal ischemia. Key molecules regulating such immune/inflammatory reactions are cytokines, which are also involved in brain development, regulating dopaminergic and GABAergic differentiation, and synaptic maturation. Specific members of the cytokine family, such as interleukin-1, epidermal growth factor, and neuregulin-1, are induced after infection and brain injury; therefore, certain cytokines are postulated to have a central role in the neurodevelopmental defects of schizophrenia. Recently, to test this hypothesis, a variety of cytokines were administered to rodent pups. Cytokines administered in the periphery penetrated the immature blood-brain barrier and perturbed phenotypic neural development. Among the many cytokines examined, epidermal growth factor (or potentially other ErbB1 ligands) and interleukin-1 specifically induced the most severe and persistent behavioral and cognitive abnormalities, most of which were ameliorated by antipsychotics. These animal experiments illustrate that, during early development, these cytokine activities in the periphery perturbs normal brain development and impairs later psychobehavioral and/or cognitive traits. The neurodevelopmental and behavioral consequences of prenatal/perinatal cytokine activity are compared with those of other schizophrenia models and cytokine interactions with genes are also discussed in this review.     

Urbanization and risk for schizophrenia: does the effect operate before or around the time of illness onset?

BACKGROUND: Higher level of urbanicity of place of birth and of place of residence at the time of illness onset has been shown to increase the risk for adult schizophrenia. However, because urban birth and urban residence are strongly correlated, no conclusions can be drawn about the timing of the risk-increasing effect. The current study discriminated between any effect of urbanization before and around the time of illness onset. METHODS: All individuals born between 1972 and 1978 were followed up through the Dutch National Psychiatric Case Register for first admission for schizophrenia until 1995 (maximum age 23 years). Exposure status was defined by a combination of place of birth and place of residence at the time of illness onset in the three most densely populated provinces of the Netherlands (the 'Randstad', exposed) or in all other areas (the 'non-Randstad', non-exposed). The risk for schizophrenia was examined in four different exposure groups: non-exposed born and non-exposed resident (NbNr, reference category), non-exposed born and exposed resident (NbEr), exposed born and non-exposed resident (EbNr) and exposed born and exposed resident (EbEr). RESULTS: The greatest risk for schizophrenia was found in the EbNR group, without evidence for any additive effect of urban residence (rate ratio (RR) for narrow schizophrenia in EbNr group, 2.05 (95 % CI 1.18-3-57); in EbEr group, 1.96 (95% CI, 1.55-2.46)). Individuals who were not exposed at birth, but became so later in life, were not at increased risk of developing schizophrenia (RR for narrow schizophrenia in NbEr group, 0.79 (0.46-1.36)). CONCLUSION: The results suggest that environmental factors associated with urbanization increase the risk for schizophrenia before rather than around the time of illness onset.     

Linking oligodendrocyte and myelin dysfunction to neurocircuitry abnormalities in schizophrenia

Multiple lines of evidence in schizophrenia, from brain imaging, studies in postmortem brains, and genetic association studies, have implicated oligodendrocyte and myelin dysfunction in this disease. Recent studies suggest that oligodendrocyte and myelin dysfunction leads to changes in synaptic formation and function, which could lead to cognitive dysfunction, a core symptom of schizophrenia. Furthermore, there is accumulating data linking oligodendrocyte and myelin dysfunction with dopamine and glutamate abnormalities, both of which are found in schizophrenia. These findings implicate oligodendrocyte and myelin dysfunction as a primary change in schizophrenia, not only as secondary consequences of the illness or treatment. Strategies targeting oligodendrocyte and myelin abnormalities could therefore provide therapeutic opportunities for patients suffering from schizophrenia.     

Microglia dysfunction in schizophrenia: an integrative theory

Schizophrenia is a devastating illness of unknown etiology. It is characterized by increased brain ventricular volume, suggesting a progressive neurodevelopmental condition. There is evidence suggesting a correlation between in utero viral exposure and subsequent occurrence of schizophrenia. Many neurotransmitter systems have been implicated as being dysfunctional in schizophrenia. There are also data suggesting immune system dysfunction in schizophrenia, and a negative correlation between schizophrenia and rheumatoid arthritis. Microglia are phagocytic immune cells in the central nervous system (CNS) derived from peripheral blood monocytes. They are involved in brain development, neuroproliferative and neurodegenerative activities, several CNS illnesses, and CNS viral immunity. They may also be involved in neurotransmitter regulation. The current theory postulates microglial dysfunction initiated by early CNS viral exposure results in the abnormal neural development and neurotransmitter dysfunction seen in schizophrenia.     

Paternal age and sporadic schizophrenia: evidence for de novo mutations

Schizophrenia is an etiologically heterogeneous syndrome. It has a strong genetic component and exists in clinically indistinguishable familial and nonfamilial (sporadic) forms. A significant role for de novo genetic mutations in genetic schizophrenia vulnerability is suggested by a strong monotonic increase in schizophrenia risk with advancing paternal age. However, an alternative explanation for the paternal age effect in schizophrenia is that childbearing is delayed in fathers who themselves have genetic schizophrenia vulnerability. In this study, we compared paternal birth ages between patient groups with familial (n = 35) and sporadic (n = 68) patients with DSM-IV schizophrenia from an inpatient schizophrenia research unit. If later age of fathering children is related to having some genetic schizophrenia vulnerability, then paternal birth age should be later in familial schizophrenia cases than in sporadic cases, and any association of father's age and schizophrenia risk in offspring would be a spurious finding, unrelated to etiology. However, if de novo mutations cause sporadic schizophrenia, then patients without a family history of schizophrenia would have older fathers than familial patients. We found that patients without a family history of schizophrenia had significantly older fathers (4.7 years) than familial patients; so later childbirth was not attributable to parental psychiatric illness. These findings support the hypothesis that de novo mutations contribute to the risk for sporadic schizophrenia.     

Neuroanatomical Markers of Neurological Soft Signs in Recent-Onset Schizophrenia and Asperger-Syndrome

Neurological soft signs (NSS) are frequently found in psychiatric disorders of significant neurodevelopmental origin. Previous MRI studies in schizophrenia have shown that NSS are associated with abnormal cortical, thalamic and cerebellar structure and function. So far, however, no neuroimaging studies investigated brain correlates of NSS in individuals with Asperger-Syndrome (AS) and the question whether the two disorders exhibit common or disease-specific cortical correlates of NSS remains unresolved. High-resolution MRI data at 3 T were obtained from 48 demographically matched individuals (16 schizophrenia patients, 16 subjects with AS and 16 healthy individuals). The surface-based analysis via Freesurfer enabled calculation of cortical thickness, area and folding (local gyrification index, LGI). NSS were examined on the Heidelberg Scale and related to cortical measures. In schizophrenia, higher NSS were associated with reduced cortical thickness and LGI in fronto-temporo-parietal brain areas. In AS, higher NSS were associated with increased frontotemporal cortical thickness. This study lends further support to the hypothesis that disorder-specific mechanisms contribute to NSS expression in schizophrenia and AS. Pointing towards dissociable neural patterns may help deconstruct the complex processes underlying NSS in these neurodevelopmental disorders.     

Heritability of BDNF alleles and their effect on brain morphology in schizophrenia

Accumulating evidence suggests that disturbed brain development may play a role in the etiology of schizophrenia, and that the illness is, to a significant degree, heritable. We therefore investigated brain derived neurotrophic factor (BDNF), a neurotrophin expressed in fetal brain, as a candidate disease gene for schizophrenia. We also investigated the effect of BDNF on adult brain morphology. All subjects were diagnosed by DSM-IIIR or DSM-IV criteria with schizophrenia spectrum disorders. Association of a BDNF polymorphism was examined in 48 proband-parent trios using the haplotype based haplotype relative risk method of case control. In a related group of 63 subjects, relationships between the presence or absence of allele 1 and the volumes of the major cerebral lobes, the ventricles, and the cerebellum were assessed using logistic regression. No association was found between this polymorphism and schizophrenia. Subjects who had at least one copy of allele 1, however, had larger parietal lobes than those who did not when controlling for overall cortical volume and age at the time of magnetic resonance. We did not find support for BDNF as a disease gene for schizophrenia. Allelic variability of the gene may, however, influence brain morphology in these same subjects. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:724-728, 1999.     

Genetic analysis of the TrkB gene and schizophrenia in the Japanese population: Juntendo University Schizophrenia Projects (JUSP)

The presence of cognitive and social impairments during childhood and adolescence in patients with schizophrenia has lead to the widespread hypothesis that schizophrenia may be a neurodevelopmental disorder, which suggests that risk genes for schizophrenia may act through the disruption of normal neurodevelopmental processes. Moreover, recent studies indicate that TrkB, which is receptor of neurotrophins including BDNF, might be involved in schizophrenia. The aim of this study is to evaluate the role of sequence variation at the TrkB locus on schizophrenia. We genotyped 12 single nucleotide polymorphisms (SNPs) across TrkB in 276 subjects with schizophrenia and 274 control subjects from the Japanese population and assessed whether TrkB SNPs are associated with a diagnosis of schizophrenia. In addition, we also investigated if any association exists between the TrkB SNPs and the premorbid functioning as measured by M-PAS using 62 subjects with schizophrenia. The TrkB SNPs were not significantly associated with a diagnosis of schizophrenia. Although one TrkB SNP (rs920776) showed weak association with premorbid functioning (p = 0.025), the significance did not remain after Bonferroni correction. Thus, these results do not support a significant role for TrkB sequence variation in the etiology of schizophrenia.