Schizophrenia is a severe psychiatric disorder with a world-wide prevalence of 1%. The pathophysiology of the illness is not understood, but is thought to have a strong genetic component with some environmental influences on aetiology. To gain further insight into disease mechanism, we used microarray technology to determine the expression of over 30 000 mRNA transcripts in post-mortem tissue from a brain region associated with the pathophysiology of the disease (Brodmann area 10: anterior prefrontal cortex) in 28 schizophrenic and 23 control patients. We then compared our study (Charing Cross Hospital prospective collection) with that of an independent prefrontal cortex dataset from the Harvard Brain Bank. We report the first direct comparison between two independent studies. A total of 51 gene expression changes have been identified that are common between the schizophrenia cohorts, and 49 show the same direction of disease-associated regulation. In particular, changes were observed in gene sets associated with synaptic vesicle recycling, transmitter release and cytoskeletal dynamics. This strongly suggests multiple, small but synergistic changes in gene expression that affect nerve terminal function.

The 27-kDa heat shock protein (HSP27) has a potent ability to increase cell survival in response to a wide range of cellular challenges. In order to investigate the mode of action of HSP27 in vivo, we have developed transgenic lines, which express human HSP27 at high levels throughout the brain, spinal cord, and other tissues. In view of the particular property of HSP27 compared with other HSPs to protect neurons against apoptosis, we have tested these transgenic lines in a well established in vivo model of neurotoxicity produced by kainic acid, where apoptotic cell death occurs. Our results demonstrate for the first time the marked protective effects of HSP27 overexpression in vivo, which significantly reduces kainate-induced seizure severity and mortality rate (>50%) in two independent lines and markedly reduces neuronal cell death in the CA3 region of hippocampus. This reduced seizure severity in HSP27 transgenic animals was associated with a marked attenuation of caspase 3 induction and apoptotic features. These studies clearly demonstrate that HSP27 has a major neuroprotective effect in the central nervous system in keeping with its properties demonstrated in culture and highlight an early stage in the cell death pathway that is affected by HSP27.The heat shock proteins (HSPs) 1 are a family of proteins originally identified as being up-regulated in response to elevated temperature, but now a wide range of cellular stresses such as hypoxia, ischemia, glutamate, and heavy metals have been shown to induce HSPs (1-6). HSPs consist of a family of highly conserved proteins grouped according to their molecular size: the high molecular mass proteins (110, 90, 70 -72, and 55-60 kDa) and the small HSPs, which include HSP27, ubiquitin, ␣A-and ␣B-crystallin, and related species. Although highly conserved across species, variation in protein size occurs; for example, the 27-kDa human HSP27 has a corresponding isoform of 25 kDa in rodents referred to as HSP25. HSPs are both constitutively expressed and induced in response to stressful stimuli (e.g. HSP27 and HSP70). Rapid induction of HSP expression is mediated by specific heat shock factors (heat shock factors 1-4), which regulate transcription (7).The HSPs play a key role in cellular defense systems, acting as protein chaperones facilitating protein folding and the removal of aberrant proteins. These properties have been shown to contribute to the enhanced cellular survival produced following preconditioning stimuli in which a subthreshold stimulus is used to raise endogenous heat shock protein levels prior to the main stimulus. Primary neuronal cultures are protected by prior exposure to mild heat or ischemic stress before subsequent more severe heat or ischemic stress or exposure to glutamate (8 -10). In cardiac tissue, a mild heat shock also protects against a subsequent thermal or ischemic stress (11).The effects of heat shock can be mimicked by overexpression of HSPs alone. Both the ND7 immortalized neuronal cell line, which is derived from dorsal root ganglia ...

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