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Title: Features of NMDA receptor-dependent LTP and LTD in the CA1 area of P14 and adult rat hippocampal slices
Author: France, Grace
ISNI:       0000 0004 5920 8682
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2014
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N_methyl-O-aspartate receptors (NMOARs) play a pivotal role in synaptic plasticity in the CA1 region of the hippocampus and NMOAR abnormalities have been implicated in many neuropathological diseases and pathophysiologies. Whilst some forms of longterm potentiation (LTP) and long-term depression (LTD) have long been known to have an NMOAR dependence, the involvement of specific NMOAR subunits in LTP and LTD, especially under development, is still a controversial topic. The aim of this study was to clarify the role of the different NMOAR subunits in L TP and L TO, and to investigate the change in kinase activity involved in L TP induction during development. Furthermore, the effects of a newly synthesised phenanthrene derivative and NMOAR potentiator UBP709 were examined on synaptic plasticity at the CA3-CA 1 synapse. In two-week-old animals LTP induction (100 pulses, 100 Hz) was shown to be NMOAR dependent; however, no dominance of a single subunit was discovered. In contrast, LTD was also NMOAR dependent but required activation of GluN2B containing NMOARs in P14 rats. Kinase activity, which is involved in high frequency stimulation induced LTP, was demonstrated to change with age. A multi kinase pathway exists in P14 rats, but this is downregulated and LTP induction becomes CaMKl1 dependent in adult rats. A transient potentiation lasting approximately thirty minutes, known as short-term potentiation (STP), precedes L TP and is also NMOAR-dependent. Induction of STP is dependent on GluN2B- and GluN20-containing NMOARs as STP decays faster in the presence of Ro 25-6981, a GluN2B preferring antagonist, or UBP145, a GluN20 preferring antagonist. NVP, a GluN2A preferring antagonist, had no effect on STP. The novel NMOAR allosteric potentiator, UBP709, enhanced LTO induced by LFS (1 Hz, 900 pulses) and permitted induction of L TO using a 10Hz paradigm that did not induce L TO under control conditions in slices from P14 slices. In adult and aged rats L TO is not readily induced by LFS. However, application of UBP709 permitted induction of a robust L TO in slices from both adult and aged rats. This effect was shown to be NMOARdependent and, in adult rats, required activation of the GluN2B subunit. In summary, results have shown that CaMKl1 appears to dominate LTP in adulthood with the exception of PKA that is involved in STP, induction of which is dependent on GluN2B/20 subunits. Induction of L TP does not depend on a particular NMOAR-subunit whereas induction of L TO is strictly GluN2B dependent, irrespective of the developmental stage of the preparation. UBP709 appears to be a useful tool to investigate synaptic plasticity, which might 'prove beneficial for targeted development of GluN2B selective modulators.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available