D-serine metabolism is implicated in schizophrenia pathophysiology. This is based on reduced D-serine levels in the disorder, its ameliorative effects therapeutically and the potential genetic contributions of its metabolic enzymes, D-amino acid oxidase (DAO) and serine racemase (SRR). D-serine is a gliotransmitter and the N-methyl D-aspartate receptor (NMDAR) co-agonist. Thus, altered D-serine metabolism may contribute to NMDAR hypofunction in schizophrenia. The research in this thesis was designed to investigate D-serine metabolic enzymes further through studying their distribution, their expression in schizophrenia and their effect on NMDARs. The regional and cellular distribution of DAO and SRR in rodent and human brain were investigated using immunohistochemistry. Both enzymes were found within frontal cortex, hippocampus and cerebellum. In rodent frontal cortex, SRR expression was neuronal suggesting D-serine is not always glia-derived. In the human this was not the case, highlighting possible species differences. DAO in the rodent and human cortex was robustly detected, challenging previous views. In rodent cerebellum, both enzymes were neuronal and glial and in human, predominantly glial. In schizophrenia, DAO and SRR expression were investigated using western blotting and real-time PCR. DAO expression was elevated in the cerebellum in the disorder, without an accompanying change in SRR. In the dorso-lateral prefrontal cortex (DPFC), DAO and SRR mRNAs were unchanged in schizophrenia but SRR protein was significantly increased. The elevation in DPFC SRR protein was not replicated however in a second study. To investigate the effects of D-serine metabolic enzymes on NMDARs, an in vitro model of altered SRR expression was developed, but its use hindered through technical complications. The data detailed demonstrate new findings of DAO and SRR’s distributions in the brain and highlight novel potential roles for these enzymes. In addition, the data provide some paradoxical findings including DAO’s cortical expression. The investigations in schizophrenia lend to robust demonstrations of DAO’s elevated cerebellar expression in the disorder. However, its roles therein and that of DAO and SRR on NMDAR function remain unclear.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:492305 |
| Date | January 2008 |
| Creators | Verrall, Louise |
| Contributors | Burnet, P. ; Wood, M. |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:de3d94cc-8734-4c47-b453-fd4b12729441 |
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