Incipient neurovulnerability and neuroprotection in early psychosis.

The objective of this study was to review the implications of altered regulatory mechanisms of progenitor cell generation and death for neurodevelopment and adult brain functioning in early intervention in schizophrenia and related disorders. MEDLINE databases were searched from 1966 to 2002 using the following key words: stem cells, progenitor cells, glia, neurogenesis, apoptosis, and combined with brain and schizophrenia. Necropsy evidence suggests alterations in synaptic connectivity and a reduction in glial cell numbers with no substantial signs of neuronal cell loss or necrotic neurodegeneration (gliosis). Neuroimaging data propose dynamic structural changes with some evidence of volume loss of the hippocampus during the transition to psychosis. Central and peripheral tissues of patients with schizophrenia give indirect evidence of reduced neurotrophic and anti-apoptotic factors relevant for generation, and atrophic degeneration of cells of glial and, in some brain areas, even neuronal origin. In vivo brain magnetic resonance spectroscopy data in schizophrenia support the loss of neuropil (reduction in n-acetylaspartate) and increased membrane turnover (decrease in phosphomonoesters [PMEs], increase in phosphodiesterases [PDEs]) at the onset of illness, which potentially corresponds with increased apoptotic activity of progenitor cells. In conclusion, dysfunctional regulation of generation and degeneration of progenitor cells of glial and, in some brain areas, neuronal origin may potentially explain early and late neurodevelopmental abnormalities in early psychosis. A reduced genesis or an increased death of glial cells in the grey matter may provide the cellular substrate for synaptic and dendritic changes resulting in local atrophy and disconnectivity. Neuroprotective strategies counteracting the loss or supporting the generation of progenitor cells may therefore be a potent therapeutic avenue to explore.