CELL DEATH AND PROLIFERATION IN MENTAL DISORDER

Abstract

The aetiology of two groups of psychiatric disorders, schizophrenia and the major depressive disorders, are poorly understood. Unlike neurodegenerative conditions, these two disorders have no obvious neuropathology and clues to their aetiology must be gleaned from other fields of research. The dominant models to date have been neurochemical in nature based on known actions of drugs that improve or mimic these conditions. However, the resulting monoaminergic hypotheses have been found to be over-simplistic and unable to comprehensively account for these complex psychiatric disorders. Based on epidemiological findings concerning perinatal factors and the typical adolescent age-of-onset, as well as the results of neuroimaging and neuropathological studies, research interest is now shifting to the processes involved in neurodevelopment, brain maturation and homeostasis. This thesis explores two such processes apoptosis in relation to schizophrenia, and neurogenesis in relation to depressive disorders. The negative associations between cancer, rheumatoid arthritis, and schizophrenia have led to the hypothesis that patients with schizophrenia have an increased susceptibility to programmed cell death (apoptosis). A study was carried out assessing several apoptotic markers in dermal fibroblast cell lines from groups of patients with schizophrenia, patients with non-schizophrenic psychotic disorder, and healthy comparison subjects. Apoptotic nuclei, caspase-3 activity, and protein levels of Bcl-2, Bax and P53P392Ser were quantified. Apoptosis was studied under basal cell culture conditions and after induction using the protein synthesis inhibitor, cycloheximide. The results suggested significant abnormalities in the regulation of apoptosis in schizophrenia that do not occur in non-schizophrenic psychotic disorder. It has been proposed that the therapeutic action of antidepressants is related to their effect on hippocampal neurogenesis mediated by brain-derived neurotrophic factor (BDNF). This hypothesis arose from the finding that blocking the action of BDNF in rodents leads to decreased neurogenesis and increased depressive behaviour. It has also been demonstrated that the neurotrophin receptor, p75NTR, is required for BDNF-induced differentiation of neural precursor cells in vitro, although no in vivo data have been published confirming this. A study was conducted to investigate the effect of running and treatment with the selective serotonin reuptake inhibitor fluoxetine (both positive modulators of neurogenesis) on the pool of hippocampal progenitor cells from which new neurons are derived. The pool of hippocampal progenitor cells was found to be a dynamic population, which varies in proliferative potential with the duration of antidepressant treatment. This variation may be attributable to changes in the number of progenitor cells occurring with prolonged induction of neurogenesis. Whether p75NTR plays a role in the regulation of neurogenesis was then determined. Neurogenesis was found to be reduced in p75NTR knock-out mice, providing us with a mouse model for the study of the role of neurogenesis in depression. Future work will depend on the identification of an appropriate behavioural model of depression that responds to chronic, and not acute, administration of antidepressant medication. A third stream of work involved application of high-throughput technology to investigate gene expression in psychiatric disorders. Clues to the aetiology of psychiatric disorders have been sought from microarray analysis of post-mortem brain tissue. In preparation for a microarray study of post-mortem tissue from a large sample of patients with schizophrenia and depressive disorder, post-mortem mRNA degradation was investigated in mouse brain tissue. A subgroup of mammalian mRNA transcripts was found to be particularly susceptible to post-mortem-related degradation, and to be more likely to carry the AUUUA motif in the 3 untranslated region. As transcription factors are more likely to carry this motif, this finding brings into question the suitability of post-mortem tissue for the study of apoptosis and cell proliferation. In conclusion, there is epidemiological, neuroimaging and neuropathological evidence that neurodevelopmental and brain maturational processes are involved in schizophrenia and depressive disorders. Supporting this view, the literature review identified a substantial number of laboratory studies implicating apoptosis in schizophrenia, and neurogenesis in depressive disorder. The series of studies conducted for this thesis added to this body of evidence. However, specific pathway abnormalities are yet to be determined. The complex multi-factorial nature of psychiatric disorder suggests that multiple molecular pathways will be implicated, and that future research needs to be conducted on much larger samples using multi-level assays (genotype - gene expression - protein levels - cellular function). Neurobiological studies of schizophrenia and major depression using large sample sizes, convergent experimental approaches, and employing high-throughput technologies will be required to achieve this aim