Cerebral Housekeeping or Implementing Plan B

The development of the brain is a highly complex coordinated process that can be roughly divided into neurogenesis, neuronal migration, glial proliferation, and neuronal differentiation. These events occur as part of a specific timetable in discrete critical windows of time, which is presumed to be largely under genetic control.168 This unfolding maturational program can be derailed by environmental events; cell proliferation, differentiation, and migration can be slowed or inhibited or cells killed outright. Importandy, because many events only occur at a particular "critical window of time",13 '184 even if the event causing this impairment is acute (transient hypoxia due to placental infarction for example), the impairment is irreparable and this has consequences for subsequent neural development. The architectural plan for brain development started in utero does not, of course, reach completion until early adulthood, when final connections are made in the prefrontal and temporal lobes, and corticolimbic pathways. These are all key regions where aberrant neuronal development may contribute to the behavioural dysfunction of schizophrenia.

As discussed in relation to premature birth, cell loss may continue long after the acute injury has finished. Cells, be they neurons or glia, require other glia and neurons to provide the necessary support and signals cues to survive.185"1 This balance is exquisitely fine. During normal development substantial numbers of initially generated cells do not form appropriate connections or are in excess of requirements. These cell are removed by physiological apoptosis.188 Critically, however, programmed cell death is also triggered when cells lose essential input from other cells, for example due to injury elsewhere in the brain. In such a pathological situation, upregulation of apoptosis is a normal part of the complex 'social' controls that ensure that individual cells behave for the good of the whole.185 The brain will thus develop according to an alternate architectural plan—Plan B. Inevitably this leads to a smaller, less complex brain, but a functional one; in as much as function is defined by the ultimate human prime directive: the ability to reproduce.

A critical part of this process may not be simply abnormal neuronal connections, but loss of white matter cells, consistent with the association of mild ventriculomegaly with later impaired grey matter development and neurodevelopmental delay and behavioural difficulties. The hypothesis that loss of glial support is a major contributor to long-term outcome is consistent with the pathological profile of patients with schizophrenia of variable neuronal loss, but a consistent reduction in soma size and abnormal synaptic connections. Oligodenrocytes enhance the number of functional synapses that form between neurons, and regulate neuronal activity. Glia are also a primary source for the growth factors necessary to inhibit apoptosis.189 Insulin-like growth factor (IGF-I) is a key mediator of normal brain development; regulating neural stem cell proliferation, differentiation, and maturation, as well as promoting myelina-tion, neurite outgrowth and synaptogenesis.190 In recent years it has been proposed that a derangement of the IGF axis may be involved in the aetiology of schizophrenia,191 and that the excessive synaptic pruning which is a feature of the schizophrenic brain, is a function not of late (post-natal) neurodevelopmental events, but rather occur secondary to diminished trophic cues.

Is there clinical evidence for such increased, on-going apoptosis? Recent imaging data shows that children who go onto develop schizophrenia have accelerated loss of cortical grey matter compared to controls during adolescence. 92 This deficit enveloped increasing amounts of cortex throughout adolescence, starting in parietal regions, and then swept forward into sensory and motor regions. By 18 years of age this process had moved into the critical areas of the brain known to be key to schizophrenia; the dorsolateral prefrontal and temporal cortices - areas which initially were not affected. This aberrant development is also seen in MZ twins discordant for schizophrenia.193 It is likely that this is an upregulation of the normal remodelling of the brain is in part mediated by an upregulation of physiological apoptosis.186 Consistent with this there is some evidence that apoptotic processes are upregulated in the brain of schizophrenic patients at postmortem,19 and that alterations in glutamate receptor activity seem to be important.195

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