The Role of NMDA Receptors in Learning and Memory in Rats 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 defined as a long lasting enhancement of the effectiveness of synaptic transmission, and it 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 LTP in the region, and consequently disrupted spatial memory. 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 saturated, resulting in a disruption of spatial memory. In order to saturate LTP in the 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 idea that LTP is essential to memory. 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 hippocampus is saturated, spatial learning, a normal function of the hippocampus, is severely 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.

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