There is diverse and largely circumstantial but cumulatively compelling evidence that
schizophrenia is a neurodevelopmental disorder (Table 1;
Lewis and Levitt 2002
). Similarly, family, twin, and adoption studies show clearly that schizophrenia is
primarily genetic in etiology (
Harrison and Weinberger 2005
). 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 et al 2005
;
Jones and Murray 1991
), 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
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