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Schizophrenia Susceptibility Genes and Neurodevelopment

      There is diverse and largely circumstantial but cumulatively compelling evidence that schizophrenia is a neurodevelopmental disorder (Table 1;
      • Lewis D.A.
      • Levitt P.
      Schizophrenia as a disorder of neurodevelopment.
      ). Similarly, family, twin, and adoption studies show clearly that schizophrenia is primarily genetic in etiology (
      • Harrison P.J.
      • Weinberger D.R.
      Schizophrenia genes, gene expression and neuropathology: On the matter of their convergence.
      ). Undoubtedly, many uncertainties and controversies surround both statements, but few would argue that either proposition is fundamentally false. As such, genetics, neurodevelopment, and schizophrenia are inextricably linked (
      • Arnold S.E.
      • Talbot K.
      • Hahn C.-G.
      Neurodevelopment, neuroplasticity, and new genes for schizophrenia.
      ;
      • Jones P.
      • Murray R.M.
      The genetics of schizophrenia is the genetics of neurodevelopment.
      ), and it would be perverse to postulate that the genes conferring susceptibility to schizophrenia have nothing to do with neurodevelopment. To do so would imply either that the genes operate after neurodevelopment has finished (something that, at least in the neocortex, continues long after the age when symptoms usually begin) or that the genes affect development but not of the brain. Hence the issue is significantly more nuanced than the simplistic question sometimes posed, “Do schizophrenia genes work by affecting neurodevelopment?” First, the catchall term “neurodevelopment” needs to be refined; we need to specify which of the many facets of brain maturation (ranging from neurogenesis and neuronal migration to myelination and sculpting of synaptic circuitry) are involved. Answering this question goes hand in hand with establishing when in neurodevelopment, from the first trimester in utero to adolescence and beyond, are the genes operating. Second, how do the genes—individually, epistatically, and in conjunction with epigenetic and environmental factors—interfere with the critical neurodevelopmental events? Third, how much of the genetic predisposition is not mediated through neurodevelopment but is better viewed as acting in other ways (e.g., by modulating subsequent neural plasticity)? There are as yet no definitive answers to any of these questions, but progress is being made in terms of experimental approaches and emerging findings.
      Table 1Main Domains of Evidence Adduced in Favor of a Neurodevelopmental Basis of Schizophrenia
      • Usual age of onset in late adolescence or early adulthood
      • Most known environmental risk factors operate prenatally or in early childhood
      • Neuromotor, intellectual, and behavioral differences in children many years before onset
      • Structural brain changes and cognitive impairments present at and before onset
      • Neuropathological findings—lack of gliosis or neurodegeneration, plus cytoarchitectural disturbances (e.g., altered cell positioning, packing density, and size)
      • Minor physical anomalies (e.g., craniofacial dysmorphology) (Hennessy et al., pages 1187–1194, in this issue)
      • Animal models—early lesions lead to delayed “schizophrenia-like” phenotypes
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