The neurodevelopmental model of schizophrenia provides a framework for understanding how OCs interact with the developing brain to increase the likelihood of schizophrenia in late adolescence and early adulthood. In normal development, connections in the brain (referred to as synaptic density) increase until an individual is approximately 2 years of age, which slowly decline during childhood, then decline steeply during late childhood and early adolescence. Many of these connections are unnecessary and will be eliminated in the mature brain.

During adolescence, a sharp increase in a process called synaptic pruning, which involves the elimination of superfluous connections, coincides with the emergence of abilities to solve abstract and complex problems. According to the neurodevelopmental model, patients with schizophrenia may have too many, too few, or unnecessary synaptic connections that are eliminated during adolescence, which results in the onset of psychotic symptomatology. According to one model, schizophrenia would occur due to an abnormally aggressive synaptic pruning process, leading to a reduction in synaptic connectivity beyond a psychosis threshold, resulting in a fragmented or disconnected brain.

This lack of neural connectivity throughout the brain reflects the challenges faced by patients with schizophrenia, with deficits in most areas, including cognitive, social, emotional, and perceptual difficulties. Moreover, this model is supported by postmortem studies that have found reduced neuropil without neuronal loss, in which decreased neuropil represents a loss of connections between neurons.

Early environmental insults, such as OCs, would fit within this neurodevelopmental model by reducing the amount of synaptic pruning necessary to cause psychotic symptomatology. This would lead to an earlier age of onset and possibly portend a worsened clinical outcome. As we have seen, this is precisely what occurs in individuals with a history of hypoxia-associated OCs, who typically have an earlier age of onset and more pronounced neuroanatomical abnormalities.

Viewing schizophrenia as a developmental disorder encourages exploration into possible early intervention and prevention strategies in individuals who are genetically susceptible. The emergence of candidate disease genes, as well as the advances in mapping out molecular pathways involved in schizophrenia, will likely pave the road to understanding and treating an incredibly serious and debilitating disorder.

KEY POINTS

• OCs have been found to be repeatedly associated with schizophrenia outcome, occurring in the histories of 20 - 30% of patients with schizophrenia and 5 - 10% of the overall population.
• Of the prevailing explanatory models, the majority of evidence supports the gene - environment interaction model, which asserts that OCs interact with genes associated with schizophrenia to increase risk for the disorder.
• Many OCs have been associated with schizophrenia, including complications during pregnancy, fetal and infant underdevelopment, and birth complications.
• Lack of oxygen to the fetus, termed fetal hypoxia, likely is involved in many OCs associated with schizophrenia.
• A history of hypoxia-associated OCs differentiates between patients with schzophrenia and their nonschizophrenic siblings, and leads to a form of schizophrenia characterized by earlier age of onset and greater neuroanatomical abnormalities.
• Infection during pregnancy has been repeatedly associated with schizophrenia in offspring. More recent studies using serological confirmation of infection have found an association between HSV-2, influenza, genital and reproductive infection, and T. gondii exposure during pregnancy and schizophrenia spectrum disorders in offspring.
• Most prenatal infections do not cross the placenta; therefore, the damaging effects to the fetus seem to be partially related to the mother's immune response to infection, particularly involving inflammation.
• Genetic polymorphisms that amplify the inflammatory response to infection have been found among patients with schizophrenia, suggesting that genetic factors may confer heightened sensitivity to infection and other prenatal insults.
• Both infection and proinflammatory cytokines have been linked to increased fetal hypoxia, which has been associated with schizophrenia and many of the brain abnormalities linked to the disorder.
• Some theorists propose that schizophrenia arises due excessive reduction in the connections throughout the brain (synaptic pruning), leading to problems in most areas of functioning. OCs fit within this model by further reducing the amount of connections in the brain, leading to an earlier age of onset and worsened clinical outcome.

LAUREN M. ELLMAN
TYRONE D. CANNON

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