The extracellular calcium sensing receptor (CaSR) is a G-protein coupled receptor that monitors extracellular, free ionized-calcium levels ([Ca2+]o) in organs that maintain systemic [Ca2+]o homeostasis. CaSR is also expressed in the nervous system, where this lab recently found that it regulates the axonal growth and branching of sympathetic neurons and the dendritic growth of hippocampal pyramidal neurons during development. Other labs have subsequently shown that CaSR regulates presynaptic physiology in response to activity induced synaptic fluctuations in [Ca2+]o. Although individuals with CaSR mutations may present with seizures from childhood, the developmental significance of synaptic CaSR has not been investigated. This thesis reports the developmental regulation of Casr mRNA expression in multiple brain regions of mice. A previously unreported peak in hippocampal Casr mRNA expression at postnatal day 14 led to the testing of the hypothesis that CaSR may play a role in synapse formation. A novel in vitro culture method was developed to circumvent perinatal lethality in the available in vivo conditional CaSR knockout model. However, this study, using both pharmacological and genetic methods, has been unable to find any evidence to suggest that CaSR regulates synaptogenesis in vitro. This thesis also reports an effect of [Ca2+]o on neurite outgrowth from sympathetic neural cells early in their development. However no deficit in proximal sympathetic axon growth is observed in CaSR knockout embryos in vivo. Novel findings suggest that in 2.3 mM Ca2+o, elevated wild type CaSR expression is necessary and sufficient for CaSR-promoted axonal growth in late embryonic sympathetic neuron cultures. This effect is not seen in low [Ca2+]o medium or cells expressing inactivated CaSR mutants, but is shown to require ERK1/2 activation, a portion of the C-terminal domain of CaSR, and is regulated by a PKC phosphorylation site contained therein.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:585311 |
| Date | January 2013 |
| Creators | Newton, Michael |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/53398/ |
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