Levels of retinoic acid (RA), the active metabolite of vitamin A, are tightly regulated throughout vertebrate CNS development by RA synthesising and catabolising enzymes. However, increasing evidence suggests that similar regulatory mechanisms exist in the adult brain to maintain RA at the optimum level. The hippocampus is one of very few regions where neurons continue to be born. Furthermore, the hippocampus is one of the regions in which RA regulates function. RA is synthesised in the region of the hippocampus by the enzyme, retinaldehyde dehydrogenase 2 (RALDH2), expressed in the adjacent meninges. CYP26B1 has been previously shown to be present by in situ hybridisation in the CA4/3 region between the two blades of the dentate gyrus. We hypothesised that a gradient was set up between the source and sink of RA in the adult hippocampus. To test this, we disrupted the balance using exogenous RA and using inhibitors to its catabolising enzymes. A reporter mouse was used to detect RA signalling and significantly more lacZ expression was detected in the infrapyramidal blade (closest to the meninges) compared to the suprapyramidal blade. Furthermore, administration of RA equalised lacZ expression between the two blades. RA is a potent differentiation agent; however, its effects on cell proliferation are less clear. In order to examine the direct effects RA on cell proliferation, an organotypic hippocampal slice culture technique was optimised and it was found that RA inhibits cell proliferation specifically in the dentate gyrus in a dose dependent manner. Taken together, this thesis provides insight for the first time into a parallel regulatory mechanism in the adult hippocampus to the embryo where RA is tightly regulated by its synthesising and catabolising enzymes and this mechanism is involved in the regulation of cell proliferation in the adult dentate gyrus.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:542630 |
| Date | January 2010 |
| Creators | Godman, Timothy Hugh |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=167035 |
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