The migration of neurons from the ventricular zone to their proper positioning in the cortex is well orchestrated and requires a multitude of neural events including start signals, cell-cell recognition, cell adhesion, motility, and stop signals. Since schizophrenia appears to involve disturbances in cortical migration, researchers have focused their attention on some of the molecules thought to play a role in this process. One such candidate is a protein called reelin. Reelin is thought to help guide newly arriving migrating neurons to their proper destination, though the precise mechanism is presently unknown. A recent study (Impagnatiello et al., 1998) revealed that patients with schizophrenia only have about half of the normal levels of reelin and its transcript in all of the brain areas examined (prefrontal and temporal cortex, hippocampus, caudate nucleus, and cerebellum). Interestingly, while reelin levels are normal in patients with other psychiatric disorders such as unipolar depression, reelin levels are also decreased in patients with bipolar disorder, a psychiatric disease characterized in part by psychotic symptoms (Guidotti et al., 2000).
Neural cell adhesion molecules (N-CAMs), which are important for the motility of neurons during migration, have also been found to be changed in postmortem studies. N-CAM levels are found to be increased in the brain of people with schizophrenia, however, more N-CAMs are found in their polysialylated form, rendering neurons less mobile. Schizophrenia has also been associated with changes in the expression of neurotrophic factors that regulate growth, survival, and plasticity such as brain-derived nerve growth factor (BDNF), which have their maximum expression during early neuronal differentiation and migration. GAP-43, a protein important for axon growth, targeting, and synaptogenesis, is also found to be altered in schizophrenia, although these results are still somewhat controversial (Selemon, 2001).
In summary, the neuropathological evidence clearly supports disturbances in early neurodevelopment. However, neurodevelopment is not limited to perinatal life. In fact, there are many "developmental" changes that occur at different stages of postnatal life, including neurite pruning, neurogenesis, apoptosis, neurite proliferation, axonal myelination, and structural brain changes. Many of the neuropathological abnormalities observed in schizophrenia may therefore be the result of neurodevelopmental lesions or insults that leave the brain more vulnerable to any number of further changes that may coincide with the "clinical onset" of schizophrenia, or acute relapses.
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