Neuropathological Evidence for Neural Injury before Birth in Schizophrenia

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The key neuropathological data for an in utero origin to schizophrenia centre around neuronal migration, and, increasingly, glial proliferation. The presence of neuronal disarray, heterotopias and malpositioning are very suggestive since cytoarchitecture is largely determined during early fetal life, well before the last trimester.5'35. Among the cellular findings are abnormal cytoarchitecture of the entorhinal cortex characterized by poorly formed layer II neuron clusters and laminar disorganization, a reduction and displacement of hippocampal and cortical pyramidal cells, and abnormal development of the subplate.35,37-41 Such studies suggest disturbances of neuronal migration during the late first or early second trimester. An earlier time is excluded since gross abnormalities in the structure and cellular content of the cerebral cortex would be expected if neurogenesis were affected.5

However, these data are not conclusive, since some studies have not found evidence for abnormal migration in schizophrenia,42"44 and other, more consistent findings such as alterations to neuronal size and synaptic and dendritic organisation may occur later in life, well after birth.5,35 The differences between studies may reflect the methodological difficulties and subde nature of the cytoarchitectural changes.35 Alternatively, it could mean that in many cases the putative in utero insult may occur after mid-gestation, when migration is largely complete.45,46 At this stage there is a marked increase in glial proliferation and if correct this would suggest that we should expect to see a consistent reduction in the amount of white matter.45,46

Imaging data suggests that this is indeed the case, but it has not been fully appreciated until recendy because of technical difficulties,47 although the consistent presence of ventriculomegaly in patients strongly suggests diffuse white matter atrophy.48 Instead the focus has been on whether "lesions" exist. Traditionally, the absence of "gliosis" (i.e., astrocytic activation or scarring) in histopathological and imaging studies of patients with schizophrenia has been taken to mean two things: (1) that this must be a neurodevelopmental process and not a neurodegenerative one (which would leave tell-tale scars), and/or (2) that any changes must have taken place before the third trimester, based on the study by Friede, which supposedly showed that gliosis cannot occur until after the end of the second trimester.5 In fact both conclusions are highly likely to be erroneous. There is evidence that that astrocytic activation can occur as early as 20 weeks of gestation,49 and in any case a few studies have found periventricular white matter lesions in region of patients.50,5

Critically, modern imaging data has confirmed that the most common pathological feature of both schizophrenia and affective disorders is diffuse loss of white matter.10,48,52"58 This loss appears to be region specific. There is, for example, loss of oligodendrocytes (the myelinating cells of the central nervous system) and astrocytes and altered oligodendrocyte ultrastructure in specific layers of the prefrontal cortex.52'58 Consistent with these findings, there is evidence of impaired and reduced myelination in schizophrenia,59,60 and altered expression of myelination related genes.61 Thus there is impairment of the normal age-related development of the frontal and temporal lobes in adulthood.62

Loss of the supporting glia likely contributes to the atrophy of neurons that has been described in the prefrontal cortex.52 Layers III and V of the dorsolateral prefrontal cortex, which give rise to glutamatergic projections to neostriatum, demonstrate the most structural pathology. The fundamental pathophysiology of schizophrenia remains unclear, but evidence suggests that there is excessive stimulation of striatal dopamine D2 receptors, deficient stimulation of prefrontal dopamine D1 receptors, and alterations in prefrontal connectivity involving glutamate transmission at the NMDA subtype of receptor.

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