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By Mark Yarchoan
First discovered in 1973 by Timothy Bliss and Terje Lomo, long term potentiation (LTP)
is a form of synaptic plasticity that is thought to serve as a cellular basis of memory. LTP is
caused by a prior synaptic activation. Changes in NDMA receptor activity are believed to
underlie LTP. The NMDA receptor is a type of glutamate receptor, and it differs from the AMPA
class of glutamate receptor because it can conduct calcium ions in addition to sodium ions. In
the NMDA receptor, calcium ion channels open in response to glutamate binding if there is
sufficient postsynaptic depolarization to displace a magnesium ion block on the channel. The
influx of calcium is thought to trigger a cascade of events which ultimately lead to an increase in
synaptic efficacy.
NMDA receptors in the hippocampus have been extensively studied because the
importance of the hippocampus in spatial memory is well established, and it is therefore easy to
evaluate the roll of hippocampal NMDA receptors on memory systems. A study by Tonegawa et
al. titled The Essential Role of Hippocampal CA1 NMDA Receptor–Dependent Synaptic
Plasticity in Spatial Memory demonstrates that NMDA receptors in the hippocampus are
necessary for spatial memory function. To discover this, the researchers produced a strain of
NMDA 1 receptor (NMDAR1) knock out mice and compared the performance of these mice to
normal control mice with normal NMDAR1 function in a series of spatial and non-spatial
learning tasks. The NMDAR1 is present only in CA1 pyramidal cells of the hippocampus, and
therefore the researchers hypothesized that only spatial memory would be affected by the gene
knock out. Consistent with their hypothesis, the NMDAR1 knock out mice grew to be adults
without any obvious abnormalities, and yet the mice performed far worse than normal mice in
two water maze tests, indicating that their spatial memory was disrupted. Using the landmark
test, the researchers demonstrated that nonspatial memory was not affected by the gene knock
out. After these behavior measurements were concluded, the NMDAR1 knock out mice were
perfused and LTP in the CA1 region of the hippocampus was assessed. Tetanic stimulation to
this region failed to produce LTP, suggesting that the absence of NMDAR1 receptors inhibited
Another study that supports the conclusion that LTP in the hippocampus is necessary for
spatial memory is called Impaired Spatial Learning after Saturation of Long-Term Potentiation,
by Morris, Richard G. M. et al. This study demonstrates that LTP in the hippocampus can be
hippocampus, the authors unilaterally lesioned the hippocampus in rats in order to reduce total
hippocampal volume, and then stimulated the intact hippocampus with three electrodes. Some
rats received low frequency stimulations which did not saturate LTP and served as the control
specimens, while the experimental rats received high frequency stimulations. The tetanus
stimulations used to saturate LTP were given at 0, 1.5, 3, 4.5, and 6 hours after the previous
stimulation. After LTP was induced, the animals were trained to find a hidden platform in a
water maze, and their performance in this spatial memory task was assessed by measuring the
time the animals spent finding the platform. Finally, after the animals participated in the water
maze, the extent of cumulative LTP saturation in the high frequency stimulation rats was
measured by recording the enhancement in EPSP slope after additional tetanus stimulation in a
new site in the hippocampus. The high frequency stimulation rats were thus divided into animals
that showed < 10% LTP (near complete LTP saturation during the water maze test) and animals
that showed >10% LTP (not complete LTP saturation during the water maze test). The >10%
LTP group performed similarly to the control group in the maze test, while the <10% LTP group
took substantially more time on average to find the platform out of the maze. This strongly
suggests that complete saturation of LTP can severely restrict spatial learning, which supports the
In order to conclusively demonstrate that learning is caused by LTP, three things must be
shown: blockade, saturation, and erasure. Here I discuss two articles which demonstrate that if
LTP in the hippocampus is blocked (by knocking out NMDA receptors) or if LTP in the
disrupted. Although no study to date has clearly demonstrated that the termination of LTP causes
forgetting, the findings of the two studies described here strongly implicate LTP in the function
of memory.