The adolescent brain: implications for the understanding, pathophysiology, and treatment of schizophrenia.

The typical onset of schizophrenia during the transition from late adolescence to adulthood is one its central features. However, the neurodevelopmental hypothesis of schizophrenia has largely focused on the contribution of early development events. In this issue, we summarize data from a range of perspectives that emphasize the profound modifications occurring in anatomy, physiology, and functional properties of cortical networks during adolescence that may be important for the emergence of psychosis, enduring cognitive, and physiological deficits as well as for the treatment and prevention of the disorder. The contributions by Hoftman and Lewis and O’Donnell show major modifications in GABAergic, glutamatergic, and dopaminergic neurotransmission and their interactions during the adolescent period that may be abnormal in schizophrenia. Gogtay et al. highlight data from longitudinal anatomical imaging studies that have examined the trajectory of brain maturation in childhood-onset schizophrenia (COS) and in subjects at ultrahigh risk (UHR). Their findings converge on the possibility that in schizophrenia, there is an excess pruning of synaptic contacts during adolescence that leads to reductions in gray matter (GM) volume. The consequences of the co-occurring changes in anatomy and transmitter systems for properties of large-scale cortical networks are discussed byUhlhaas and Singer. They highlight that precisely synchronized neural oscillations emerge only during late adolescence. Accordingly, in schizophrenia, there may be a failure to express important neural synchrony parameters during adolescence, causing the emergence of psychosis as well as contributing to cognitive deficits. The commentary by McGorry discusses the implications of these findings from the perspective of treatment and prevention. There is little doubt today that schizophrenia is a disorder of brain development. Yet, the nature and timing of developmental disturbances are a matter of debate. The neurodevelopmental hypothesis of schizophrenia was proposed in the late 1980s to highlight the fact that the disorder is the end product of an abnormal trajectory in the maturation of cortical circuits that possibly begins already in utero. The association with several prenatal and perinatal risk factors, the presence of cognitive deficits in childhood, as well as the success of certain animal models with circumscribed brain defects during early brain development in modeling the clinical phenotype in adulthood all point to the important role of early adverse events in the pathophysiology of schizophrenia. However, this perspective leaves another central questions unanswered, namely the late manifestation of the disorder and the contribution of aberrant maturational processes during adolescence (see ref. for a recent perspective). Indeed, 1 central question for schizophrenia research is: Why does schizophrenia emerge during late adolescence? This fact has been known since the initial descriptions of Dementia Praecox by Emil Kraepelin, yet remains one of the unsolved mysteries of the disorder. Neurodevelopmental theories have taken different perspectives toward this problem. Weinberger proposed that an insult in the second trimester interacts with the molecular and anatomical changes during adolescence. One particularly important event for the manifestation of psychosis during adolescence according toWeinberger is the functional integration of the frontal cortex into extended cortical networks. Other investigators have emphasized the active contribution of adolescent brain maturation toward the pathophysiology of schizophrenia. According to the late neurodevelopmental model, brain developmental during adolescence does not only server as a trigger for the expression of psychosis but also is itself abnormal. Feinberg in the 1980s suggested on the basis of the groundbreaking work of Huttenlocher that in schizophrenia, the pruning of synaptic contacts is increased. The late manifestation of schizophrenia would therefore be ‘‘caused’’ by excessive synaptic elimination during adolescence. Schizophrenia Bulletin vol. 37 no. 3 pp. 480–483, 2011 doi:10.1093/schbul/sbr025