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 memoryIn 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
