Schizophrenia as a disorder of neurodevelopment.

A combination of genetic susceptibility and environmental perturbations appear to be necessary for the expression of schizophrenia. In addition, the pathogenesis of the disease is hypothesized to be neurodevelopmental in nature based on reports of an excess of adverse events during the pre- and perinatal periods, the presence of cognitive and behavioral signs during childhood and adolescence, and the lack of evidence of a neurodegenerative process in most individuals with schizophrenia. Recent studies of neurodevelopmental mechanisms strongly suggest that no single gene or factor is responsible for driving a highly complex biological process. Together, these findings suggest that combinatorial genetic and environmental factors, which disturb a normal developmental course early in life, result in molecular and histogenic responses that cumulatively lead to different developmental trajectories and the clinical phenotype recognized as schizophrenia.

[1]  S. Anderson,et al.  Mutation of the Emx-1 homeobox gene disrupts the corpus callosum. , 1996, Developmental biology.

[2]  P. Huttenlocher Synaptic density in human frontal cortex - developmental changes and effects of aging. , 1979, Brain research.

[3]  R. McCarley,et al.  A review of MRI findings in schizophrenia , 2001, Schizophrenia Research.

[4]  V. Bolivar,et al.  Mapping of quantitative trait loci with knockout/congenic strains. , 2001, Genome research.

[5]  P. Mortensen,et al.  Evidence of a dose-response relationship between urbanicity during upbringing and schizophrenia risk. , 2001, Archives of general psychiatry.

[6]  A. Jablensky,et al.  Influenza epidemics and incidence of schizophrenia, affective disorders and mental retardation in Western Australia: no evidence of a major effect , 1997, Schizophrenia Research.

[7]  P. Rakic From spontaneous to induced neurological mutations: a personal witness of the ascent of the mouse model. , 2000, Results and problems in cell differentiation.

[8]  Tyrone D. Cannon On the nature and mechanisms of obstetric influences in schizophrenia: a review and synthesis of epidemiologic studies , 1997 .

[9]  B. Woods Is schizophrenia a progressive neurodevelopmental disorder? Toward a unitary pathogenetic mechanism. , 1998, The American journal of psychiatry.

[10]  S. Hans,et al.  Children at risk for schizophrenia: the Jerusalem Infant Development Study. II. Neurobehavioral deficits at school age. , 1993, Archives of general psychiatry.

[11]  D. Weinberger,et al.  Cell biology of the hippocampal formation in schizophrenia , 1999, Biological Psychiatry.

[12]  P. Satz,et al.  Minor physical anomalies in schizophrenia patients, bipolar patients, and their siblings. , 1994, Schizophrenia bulletin.

[13]  M. Isohanni,et al.  Schizophrenia as a long-term outcome of pregnancy, delivery, and perinatal complications: a 28-year follow-up of the 1966 north Finland general population birth cohort. , 1998, The American journal of psychiatry.

[14]  R. Murray,et al.  Maternal exposure to influenza and paranoid schizophrenia , 1997, Schizophrenia Research.

[15]  D. Bonett,et al.  Adult schizophrenia following prenatal exposure to an influenza epidemic. , 1988, Archives of general psychiatry.

[16]  T. Jessell Neuronal specification in the spinal cord: inductive signals and transcriptional codes , 2000, Nature Reviews Genetics.

[17]  J. Pierri,et al.  Altered GABA neurotransmission and prefrontal cortical dysfunction in schizophrenia , 1999, Biological Psychiatry.

[18]  C A Sandman,et al.  Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development. , 1993, Archives of general psychiatry.

[19]  Keisuke Kuida,et al.  Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice , 1996, Nature.

[20]  E. G. Jones,et al.  Maldistribution of interstitial neurons in prefrontal white matter of the brains of schizophrenic patients. , 1996, Archives of general psychiatry.

[21]  T. Crow,et al.  Complications of pregnancy and delivery in relation to psychosis in adult life: data from the British perinatal mortality survey sample. , 1991, BMJ.

[22]  P. Levitt,et al.  Response Diversity and the Timing of Progenitor Cell Maturation Are Regulated by Developmental Changes in EGFR Expression in the Cortex , 1997, Neuron.

[23]  M. Tsuang,et al.  Pregnancy/delivery complications and psychiatric diagnosis. A prospective study. , 1993, Archives of general psychiatry.

[24]  C. Walsh,et al.  Protein–Protein interactions, cytoskeletal regulation and neuronal migration , 2001, Nature Reviews Neuroscience.

[25]  D. Lewis,et al.  Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia , 2001, Molecular Psychiatry.

[26]  S. Fatemi,et al.  Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression , 2000, Molecular Psychiatry.

[27]  J. Trojanowski,et al.  Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. , 1998, Archives of general psychiatry.

[28]  J. Meador-Woodruff,et al.  Glutamate receptor expression in schizophrenic brain , 2000, Brain Research Reviews.

[29]  K. Mirnics,et al.  Genes and subtypes of schizophrenia. , 2001, Trends in molecular medicine.

[30]  M Marmot,et al.  Child developmental risk factors for adult schizophrenia in the British 1946 birth cohort , 1994, The Lancet.

[31]  David A. Lewis,et al.  Is There a Neuropathology of Schizophrenia? Recent Findings Converge on Altered Thalamic-Prefrontal Cortical Connectivity , 2000 .

[32]  R. Murray,et al.  Obstetric complications and age at onset in schizophrenia: an international collaborative meta-analysis of individual patient data. , 1997, The American journal of psychiatry.

[33]  A Sacker,et al.  Childhood antecedents of schizophrenia and affective illness: social adjustment at ages 7 and 11 , 1994, BMJ.

[34]  L. Lillien Changes in retinal cell fate induced by overexpression of EGF receptor , 1995, Nature.

[35]  T. Shors,et al.  Postnatal decrease in transforming growth factor α is associated with enlarged ventricles, deficient amygdaloid vasculature and performance deficits , 2000, Neuroscience.

[36]  S. Hans,et al.  Infants at risk for schizophrenia: sequelae of a genetic neurointegrative defect. A review and replication analysis of pandysmaturation in the Jerusalem Infant Development Study. , 1992, Archives of general psychiatry.

[37]  F. Zindy,et al.  Postnatal neuronal proliferation in mice lacking Ink4d and Kip1 inhibitors of cyclin-dependent kinases. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[38]  S. Kety,et al.  Adoption studies of schizophrenia. , 2000, American journal of medical genetics.

[39]  Alessandro Bertolino,et al.  Regionally Specific Neuronal Pathology in Untreated Patients with Schizophrenia: A Proton Magnetic Resonance Spectroscopic Imaging Study , 1998, Biological Psychiatry.

[40]  E. Grove,et al.  Neocortex Patterning by the Secreted Signaling Molecule FGF8 , 2001, Science.

[41]  B. Ismail,et al.  Obstetric complications and congenital malformation in schizophrenia , 2000, Brain Research Reviews.

[42]  D. Volk,et al.  Increased density of microtubule associated protein 2-immunoreactive neurons in the prefrontal white matter of schizophrenic subjects , 1996, Schizophrenia Research.

[43]  I. Feinberg,et al.  Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? , 1982, Journal of psychiatric research.

[44]  Flavio Keller,et al.  Reelin Is a Serine Protease of the Extracellular Matrix* , 2002, The Journal of Biological Chemistry.

[45]  B. Devlin,et al.  Association and linkage analyses of RGS4 polymorphisms in schizophrenia. , 2002, Human molecular genetics.

[46]  R. Murray,et al.  Obstetric complications and schizophrenia: prenatal underdevelopment and subsequent neurodevelopmental impairment. , 2001, The British journal of psychiatry. Supplement.

[47]  E. Susser,et al.  Schizophrenia after prenatal famine. Further evidence. , 1996, Archives of general psychiatry.

[48]  R. Yolken,et al.  Seasonality of births in schizophrenia and bipolar disorder: a review of the literature , 1997, Schizophrenia Research.

[49]  L. Erlenmeyer‐Kimling,et al.  The New York high-risk project: social and general intelligence in children at risk for schizophrenia , 1998, Schizophrenia Research.

[50]  N. Risch,et al.  Segregation analysis of schizophrenia and related disorders. , 1984, American journal of human genetics.

[51]  P. Levitt,et al.  Brain macrophages and microglia respond differently to lesions of the developing and adult visual system , 1991, The Journal of comparative neurology.

[52]  J. Pierri,et al.  Gene Expression Profiling Reveals Alterations of Specific Metabolic Pathways in Schizophrenia , 2002, The Journal of Neuroscience.

[53]  G. Bartzokis,et al.  Age-related changes in frontal and temporal lobe volumes in men: a magnetic resonance imaging study. , 2001, Archives of general psychiatry.

[54]  A Reichenberg,et al.  Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents. , 1999, The American journal of psychiatry.

[55]  D. Castle,et al.  Does Influenza Cause Schizophrenia? A Five Year Review , 1995, The Australian and New Zealand journal of psychiatry.

[56]  E. Walker Developmentally moderated expressions of the neuropathology underlying schizophrenia. , 1994, Schizophrenia bulletin.

[57]  P. Levitt,et al.  Regulation of regional differences in the differentiation of cerebral cortical neurons by EGF family-matrix interactions. , 1995, Development.

[58]  S. Faraone,et al.  Genes, environment and schizophrenia. , 2001, The British journal of psychiatry. Supplement.

[59]  P. Goldman-Rakic,et al.  Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex. , 1986, Science.

[60]  Pat Levitt,et al.  Analysis of complex brain disorders with gene expression microarrays: schizophrenia as a disease of the synapse , 2001, Trends in Neurosciences.

[61]  David A Lewis,et al.  Catching Up on Schizophrenia Natural History and Neurobiology , 2000, Neuron.

[62]  R. Murray,et al.  Urbanization and psychosis: a study of 1942–1978 birth cohorts in The Netherlands , 1998, Psychological Medicine.

[63]  E. Walker,et al.  Neuromotor precursors of schizophrenia. , 1994, Schizophrenia bulletin.

[64]  S. Mednick,et al.  Risk factors of psychosis: identifying vulnerable populations premorbidly. , 1996, Schizophrenia bulletin.

[65]  R. Hoffman,et al.  Schizophrenia as a disorder of developmentally reduced synaptic connectivity. , 2000, Archives of general psychiatry.

[66]  J. Crawley Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests 1 Published on the World Wide Web on 2 December 1998. 1 , 1999, Brain Research.

[67]  D. Weinberger Implications of normal brain development for the pathogenesis of schizophrenia. , 1987, Archives of general psychiatry.

[68]  I. Gottesman Schizophrenia Genesis: The Origins of Madness , 1990 .

[69]  J. Stengård,et al.  Utility of the predictors of coronary heart disease mortality in a longitudinal study of elderly Finnish men aged 65 to 84 years is dependent on context defined by Apo E genotype and area of residence , 1999, Clinical genetics.

[70]  R. Radcliffe,et al.  Quantitative genetics and mouse behavior. , 2001, Annual review of neuroscience.

[71]  R. Murray,et al.  Premorbid Social Underachievement in Schizophrenia , 1993, British Journal of Psychiatry.

[72]  B T Hyman,et al.  Some cytoarchitectural abnormalities of the entorhinal cortex in schizophrenia. , 1991, Archives of general psychiatry.

[73]  I. Gottesman,et al.  Family and twin strategies as a head start in defining prodromes and endophenotypes for hypothetical early-interventions in schizophrenia , 2001, Schizophrenia Research.

[74]  M. Akil,et al.  Cytoarchitecture of the entorhinal cortex in schizophrenia. , 1997, The American journal of psychiatry.

[75]  M. Tsuang,et al.  IQ decline during childhood and adult psychotic symptoms in a community sample: a 19-year longitudinal study. , 1998, The American journal of psychiatry.

[76]  R. Murray,et al.  A neurodevelopmental approach to the classification of schizophrenia. , 1992, Schizophrenia bulletin.

[77]  D. Ledbetter,et al.  LIS1: from cortical malformation to essential protein of cellular dynamics , 2001, Trends in Neurosciences.

[78]  P. Andersen,et al.  Effects of family history and place and season of birth on the risk of schizophrenia. , 1999, The New England journal of medicine.

[79]  A. David,et al.  IQ and risk for schizophrenia: a population-based cohort study , 1997, Psychological Medicine.

[80]  R. Yolken,et al.  Maternal infections and subsequent psychosis among offspring. , 2001, Archives of general psychiatry.

[81]  S. Lawrie,et al.  Obstetric complications and schizophrenia: A meta-analysis , 1995, Schizophrenia Research.

[82]  Philip D. Harvey,et al.  Cognitive impairment and negative symptoms in geriatric chronic schizophrenic patients: a follow-up study , 1996, Schizophrenia Research.

[83]  D. Ledbetter,et al.  Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality , 1998, Nature Genetics.

[84]  N. Risch Searching for genetic determinants in the new millennium , 2000, Nature.

[85]  R. Murray,et al.  The neurodevelopmental theory of schizophrenia: evidence concerning structure and neuropsychology. , 1996, Annals of medicine.

[86]  S Marenco,et al.  The neurodevelopmental hypothesis of schizophrenia: Following a trail of evidence from cradle to grave , 2000, Development and Psychopathology.

[87]  A. Bertelsen,et al.  Confirming unexpressed genotypes for schizophrenia. Risks in the offspring of Fischer's Danish identical and fraternal discordant twins. , 1989, Archives of general psychiatry.

[88]  Yogesh K. Dwivedi,et al.  Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. , 2000, Archives of general psychiatry.

[89]  E. Walker,et al.  Childhood behavioral characteristics and adult brain morphology in schizophrenia , 1996, Schizophrenia Research.

[90]  L. Lillien,et al.  EGFRs mediate chemotactic migration in the developing telencephalon. , 2001, Development.

[91]  U. Rüb,et al.  Variability in the human entorhinal region may confound neuropsychiatric diagnoses. , 1996, Acta anatomica.

[92]  Pat Levitt,et al.  Molecular Characterization of Schizophrenia Viewed by Microarray Analysis of Gene Expression in Prefrontal Cortex , 2000, Neuron.

[93]  A. David,et al.  Premorbid adjustment and personality in people with schizophrenia† , 1998, British Journal of Psychiatry.

[94]  M. Surani,et al.  Adult phenotype in the mouse can be affected by epigenetic events in the early embryo. , 1993, Development.

[95]  E. Susser,et al.  Nonaffective psychosis after prenatal exposure to rubella. , 2000, The American journal of psychiatry.

[96]  W. Honer,et al.  Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22. , 2000, Science.

[97]  W. Doerfler,et al.  Epigenetic and Genotype-specific Effects on the Stability ofde Novo Imposed Methylation Patterns in Transgenic Mice* , 2000, The Journal of Biological Chemistry.

[98]  C. Weickert,et al.  Striatal TGF-alpha: postnatal developmental expression and evidence for a role in the proliferation of subependymal cells. , 1995, Brain research. Developmental brain research.

[99]  D. Weinberger,et al.  Relationship of obstetric complications and differences in size of brain structures in monozygotic twin pairs discordant for schizophrenia. , 2000, The American journal of psychiatry.

[100]  Daniel R Weinberger,et al.  To Model a Psychiatric Disorder in Animals: Schizophrenia As a Reality Test , 2000, Neuropsychopharmacology.

[101]  T. Crow Prenatal Exposure to Influenza as a Cause of Schizophrenia , 1994, British Journal of Psychiatry.

[102]  C. Goodman,et al.  The Molecular Biology of Axon Guidance , 1996, Science.

[103]  J. Rapoport,et al.  Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[104]  Robin M. Murray,et al.  Schizophrenia: A Neurodevelopmental Perspective , 1993, Neuropsychopharmacology.

[105]  A. Jablensky Epidemiology of schizophrenia: the global burden of disease and disability , 2000, European Archives of Psychiatry and Clinical Neuroscience.

[106]  R. Kahn,et al.  Prenatal exposure to influenza and schizophrenia in surinamese and Dutch Antillean immigrants to The Netherlands , 1998, Schizophrenia Research.

[107]  H. Lester,et al.  RGS proteins reconstitute the rapid gating kinetics of Gβγ-activated inwardly rectifying K+ channels , 1997 .

[108]  S. Kety,et al.  Mental illness in the biological and adoptive families of adpoted schizophrenics. , 1971, The American journal of psychiatry.

[109]  B. Lipska,et al.  Behavioral changes in rats with early ventral hippocampal damage vary with age at damage. , 1997, Brain research. Developmental brain research.

[110]  Allan Collins,et al.  Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies , 1997, Psychopharmacology.

[111]  R. Murray,et al.  Prenatal Exposure to the 1957 Influenza Epidemic and Adult Schizophrenia: A Follow-Up Study , 1996, British Journal of Psychiatry.

[112]  R. Saunders,et al.  A qualitative and quantitative analysis of the entorhinal cortex in schizophrenia. , 1997, Cerebral cortex.

[113]  M. Casanova,et al.  Is there a neuropathology of schizophrenia? , 1988, Biological Psychiatry.

[114]  J. Schiffman,et al.  Minor physical anomalies and schizophrenia spectrum disorders: a prospective investigation. , 2002, The American journal of psychiatry.

[115]  M. Järvelin,et al.  School performance as a predictor of psychiatric hospitalization in adult life. A 28-year follow-up in the Northern Finland 1966 Birth Cohort , 1998, Psychological Medicine.

[116]  A. Pulver Search for schizophrenia susceptibility genes , 2000, Biological Psychiatry.