Given the foregoing, it is imperative to identify the mechanisms through which OCs interact with the developing brain to increase the likelihood of schizophrenia in late adolescence and early adulthood. One theory is that OCs confer a latent constitutional vulnerability that become evident when interacting with later neuromaturational processes.93–95
Within this framework, we review evidence suggesting that early hippocampal lesions (associated with OCs) can interact with normative adolescent increases in (1) synaptic pruning and (2) stress hormone levels and thereby contribute to the onset of psychosis.
In healthy development, the peak of synaptic density occurs at 2 years of age and is followed by a slow drop during childhood followed by a steep decline in adolescence.96,97
Early in development many synaptic connections are superfluous, and the increase in synaptic pruning occurring during adolescence, particularly in the prefrontal brain regions, is thought to be related to efficiency and adult reasoning capabilities.96
Indeed, abilities to solve abstract and complex problems coincide with the pruning during this period.98
McGlashan and Hoffman99
proposed that an abnormally aggressive synaptic pruning process, which would lead to a reduction in synaptic connectivity, may be a strong contributing factor to psychosis. This idea is supported by postmortem studies, which have shown reduced neuropil, representing a loss of connections between neurons, without neural loss.100
In continuing within the framework of this model, OCs disrupting a particular neural structure(s) (eg, hypoxia affecting the hippocampus) would, in effect, reduce the amount of synaptic pruning necessary to pass a threshold of synaptic loss, resulting in psychosis. This prediction is congruent with research of individuals with a history of OCs, who typically have an earlier age of onset and more pronounced neuroanatomical abnormalities.101
An example through which OCs could fit within this framework also relates to the effects of early hippocampal damage. More specifically, a body of animal literature suggests that particular structures such as the hippocampus, and particular neural systems such as the HPA axis, are particularly susceptible to OCs, as discussed above.102,103
This work is of interest to our understanding of the etiology of psychotic disorders because the hippocampus regulates the HPA axis that governs the release of cortisol.104
Several lines of research suggest that prenatal insult can produce hippocampal damage in the fetus, and this can render the organism hypersensitive to stress postnatally.105
During adolescence, a time period also associated with the synaptic pruning noted above, there is also a well-documented normative increase in cortisol.93,106
Although the mechanisms are not yet clearly understood, it is clear that GC secretion augments dopamine activity in certain brain regions, especially the mesolimbic system.107–109
Because cortisol is known to augment dopamine activity, it is believed that the hippocampus and HPA axis act as a nonspecific moderating system potentiating expression of psychotic disorders as well as mediating the effects of stress on symptom expression.95,110
Within this framework, OCs resulting in hippocampal and/or HPA axis abnormality could result in a constitutional vulnerability or lesion, which may later interact with normative maturational processes leading to psychosis.95
By acting through these distinct pathways, OCs may result in neural changes that place individuals at higher risk for schizophrenia. The brain may be “preprogrammed,” in part via the impact of OCs on genetically susceptible brain regions such as the hippocampus, to be vulnerable to later life (ie, adolescent) stress and/or neurobiological influences (ie, circulating neurohormonal surges during pubertal maturation), which may subsequently trigger psychosis.