Schizophrenia as a disorder of brain maturation

There is evidence from clinical research implicating aberrant neurodevelopmental processes in the pathophysiology of schizophrenia, (.33> but there is also a growing literature suggestive of progressive deterioration in the disease for at least some patients. (3i> It should be noted that abnormal neurodevelopmental processes are not mutually exclusive of neurodegenerative mechanisms in the pathogenesis of complex neuropsychiatric disorders. Indeed, while some genetic disorders are purely developmental (e.g. fragile X syndrome) and others purely neurodegenerative (e.g. Huntington's disease), some have both developmental and degenerative pathologies (e.g. Down syndrome). Based on the neuropathological literature of the last 30 years some suggestions can be made concerning the pathophysiology of schizophrenia.

Gliosis

Glial cells, mainly astrocytes (Fig 2 and Fig...3), show changes in response to almost every type of injury or disease in the central nervous system. Therefore in typical degenerative brain disorders such as Alzheimer's disease or Huntington's chorea increased glial cell densities are found. Studies using glial cell counts, neurone-to-glial ratios and glial cell nuclear volumes found no difference between schizophrenics and controls in temporolimbic structures, the thalamus, and cingulate cortex. In our own large-scale study we counted the number of astrocytes in several key regions such as the area surrounding the temporal horn and found no evidence for astrogliosis in schizophrenia (Fig 3)—1 Although the question of fibrous gliosis (i.e. increase in glial cell fibres) remains more controversial, the well-controlled study by Bruton et al.(28) also rejects fibrous gliosis in schizophrenia. Therefore it seems unlikely that the majority of schizophrenic patients show a considerable degree of gliosis.

Fig. 3 Astrocyte counts (cells per field of vision) around the temporal horns.

Neurohistological indications of disturbed brain development

Subtle cytoarchitectural anomalies were described in the hippocampal formation, frontal cortex, cingulate gyrus, and entorhinal cortex in patients suffering from schizophrenia compared with control subjects. For example, a significant cellular disarray in the CA3-CA4 interface was described in the left and replicated in the right hippocampus.'36» This was interpreted as a bilateral migrational abnormality and broadly correlated with the degree of disease severity. One subsequent study was not able to fully replicate this findings, but did confirm a within-case correlation with severity; whereas another examination did not find any significant disarray distinguishing schizophrenics from controls. Another prominent finding was of an abnormal sulcogyral pattern or abnormal gross configuration of the temporal lobe and cytoarchitectonic abnormalities of the rostral entorhinal region as well as of the ventral insular cortex of schizophrenics. (3 38» The cytoarchitectonic abnormalities of the rostral entorhinal region consisted of heterotopic pre-a-cells in the pre-b-layer (layer III), which would normally belong to the pre-a-layer (layer II). This observation stimulated considerable research, with some studies supporting these findings, while others did not.

In conclusion, cytoarchitectonic abnormalities recently described in different limbic structures in schizophrenia are very subtle and can easily be missed using classical neuropathological methods. Quantifying them often needs sophisticated staining methods, for example immunohistochemistry, serial sections and a matched control group and even than replicating original findings seems difficult, as outlined above. These findings can be interpreted as a sign for disturbed late neuronal migration or could mirror disturbed programmed cell death as heterotopias are frequently found in the temporal cortex of autopsied children, which seem to dissapear in adults.

Investigations of connectivity

There is some evidence from postmortem studies for disturbed cerebral asymmetry in schizophrenia, for example the planum temporale (for overview see Falkai and

Bogerts(22>). Changes in the asymmetry pattern of the human brain in closely linked to connectivity. Recently, quantitative studies of axons, dendrites, synapses and synapse-related proteins, and mRNAs have begun to explore the hypothesis of disturbed connectivity in schizophrenia. Although the results reported to date have been somewhat inconsistent, the preliminary data look promising. Benes et al.(39) have focused on the anterior cingulate cortex describing decreased neurone density and abnormally spaced aggregates of neurones in this region. Subsequently they found decreased density of interneurones (49 and increased numbers of vertical axons (glutamatergic in origin) in cortical layers in which the altered cytoarchitecture had been found. (41) Together these findings have been interpreted as representing a miswiring of the anterior cingulate. More specific investigations of connectivity are at an early stage but describe abnormal dendritic spine densities in the cortex, various changes in synaptic vesicle protein expression in limbic, temporal, and frontal cortices, and alterations in glutamatergic, catecholaminergic, and intrinsic innervation in anterior cingulate cortex. These findings suggest a 'miswiring' in the brain of schizophrenic patients.

In summary there is growing evidence for pathomorphological abnormalities in the postmortem brains from patients suffering from schizophrenia. The changes are focused on the frontal lobe and temporolimbic regions. They are subtle, lacking the typical signs of degeneration, and point to problems in prenatal (cell migration) and postnatal (connectivity) periods of brain development. Currently, underlying causes are unclear, but the interaction between genetic and non-genetic factors (e.g. birth complications) has to be discussed.

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