Thesis (MScMedSc (Biomedical Sciences. Medical Physiology)--Stellenbosch University, 2008. / For many centuries, scientists have engaged in a theoretical debate concerning the etiology
of mood disorders, with very few ancient scholars speculating about the importance of
genetic factors and affective temperaments as factors in the etiology of depression. Mood,
emotion and cognition have been shown to be modulated by the serotonergic midbrain
raphe system; implicated in the pathogenesis of psychiatric disorders like those of the
affective spectrum. Evidence from neuroscience, genetics, and clinical investigation
demonstrate that depression is a disorder of the brain. Brain imaging research is revealing
that in depression, neural circuits responsible for moods, thinking, sleep, appetite, and
behavior fail to function properly, and that the regulation of critical neurotransmitters is
impaired. Genetics research, including studies of twins, indicates that genes play a role in
depression. Vulnerability to depression appears to result from the influence of multiple genes
acting together with environmental factors. Other research has shown that stressful life
events, particularly in the form of loss such as the death of a close family member, may
trigger major depression in susceptible individuals. Depression and anxiety have often been
successfully treated by means of selective serotonin reuptake inhibitors. However, selective
serotonin reuptake inhibitors do not solve all the problems inherent to the treatment of
depression, for approximately 30 % of depressed patients do not respond to treatment and
20 % experience relapses whilst on treatment. Of consideration is the fact that the majority
of drugs today are based on proteins, with 50 % of therapeutics on the market targeting cell
membrane proteins. Up to this day the precise pathophysiology of mood disorders remains
obscure, as does the neurobiology of normal mood regulation. Accordingly, there is a need
for methods to identify the structural and/or signaling components which lead to changes in
the brain, particularly the hippocampus, of subjects having mood disorders such as bipolar
depressive disorder, chronic major depressive disorder and the like. Similarly, there is a
need for the early detection, screening and diagnosis of individuals at risk for a mood
disorder. As the serotonin tranpsorter is the primary target for therapeutic intervention in the
treatment of numerous psychiatric disorders and considering the fact that at the structural
level this protein’s function as transporter in membranes remains incompletely understood,
investigating its function in psychiatric disorders are of importance . The objective of this
study was to determine the role of the serotonin transporter in wild type and serotonin
knockout rats, with regards to the hippocampus. Rat hippocampi were fractionated into
cytosolic and membrane components, which were run and further separated in two
dimensions. Firstly separation occurred by isoelectrical focusing (pI), follwed by gel
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electrophoresis (molecular weight). Gels were compared to see whether protein spots have
changed between animals that have been differentially bred. Differentially expressed protein
spots, as determined by PD Quest software, were excised, digested and analyzed by means
of mass spectrometry. Our results indicated that metabolic, structural and cell signaling
proteins were differentially expressed in both the ventral and dorsal hippocampus of the
serotonin knockout rat. Futhermore, cellular stress proteins were found to be only
differentially expressed in the ventral hippocampus. The majority of proteins identified in
both hippocampal areas as well as both fractions, were assigned to energy metabolism. The
cytosolic protein profile mirrored the pattern of the membrane protein profile. In conclusion,
this proteomic study identified various protein groups that interacted with one another, thus
establishing compensation for disrupted serotonin homeostasis.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/1771 |
| Date | 03 1900 |
| Creators | Fairbairn, Lorren R. |
| Contributors | Daniels, William M. U., Stein, Dan J., Stellenbosch University. Faculty of Health Sciences. Dept. of Biomedical Sciences. Medical Physiology. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 2389865 bytes, application/pdf |
| Rights | Stellenbosch University |
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