Davis, Sabrina

2018-01-31T11:19:41Z

2018-01-31T11:19:41Z

1991

Activation of the N-Methyl-D-aspartate (NMDA) receptor is crucial for the induction of hippocampal Long-term potentiation (LTP), a form of synaptic plasticity that has come to be regarded by many neuroscientists as a neural substrate underlying the processing of information during learning. The hippocampus is also a structure that has long been implicated in spatial reference and/or working memory. The aim of this thesis is to test more rigorously, the hypothesis that hippocampal NMDA receptors are involved in "hippocampal learning" through induction of LTP, by investigation the dose-response effect of the NMDA receptor antagonist, AP5 on (i) induction of LTP and spatial learning, tested in individual animals, and (ii) it's effect on working memory

In the first experiment a range of concentrations (5mM, 13mM, 20mM, 30mM, 40mM) of (D-AP5) were chronically infused (icv) into rats, at a rate of 0. 5^j1 a day for 14 days. Control animals consisted of either sham or unoperated rats, or rats infused with aCSF. During the 14 day experimental period rats were tested on a spatial reference memory task in the open field water maze for 6 days and then an attempt to evoke LTP in each rat was made. At the end of the experiment micro dialysed samples of ecf were taken from the left hippocampus for 2 hours. Finally, tissue samples from 5 brain areas, including the right and left hippocampus were dissected out and the exact content of AP5 in the brain during the experimental period was measured using HPLC. The animals were regrouped according to the whole tissue concentration of AP5 in the hippocampus. The results showed a dose dependent impairment of spatial reference memory that correlated with the dose dependent blockade of LTP. The amount of AP5 recovered from the ecf of the hippocampus was estimated to be compatible with binding studies showing percentage receptor occupancy and electrophysiological studies showing the amount of AP5 required to block LTP in the hippocampal slice.

In the second experiment, a single concentration known to impair spatial reference memory and block LTP (30mM D-AP5) was used to test animals ability to learn a spatial working memory task in the open field water maze. AP5 caused no impairment in working memory when the delay between trials was short (30s). When the delay was extended to 2 hours or 5 hours, however, animals infused with AP5 showed a significant impairment. Also at the 5 hour delay, control animals showed a trend towards an impairment in the task.

The results from this thesis suggest activation of the hippocampal NMDA receptors are necessary for the processing of spatial information. The high correlation between the learning impairment and the induction of LTP strengthens the hypotheses that the physiological activity underlying learning is a form of plasticity similar to that seen with LTP. Furthermore, from the working memory experiments it can be implied that this type of plasticity occurs when information is required over longer periods of time.

http://hdl.handle.net/1842/26433

The University of Edinburgh

Annexe Thesis Digitisation Project 2017 Block 15

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The role of the NMDA receptor in the hippocampus in certain forms of learning

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PhD Doctor of Philosophy