The Role of NMDA Receptors in Learning and Memory in Rats

By Mark YarchoanFirst 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 isdefined as a long lasting enhancement of the effectiveness of synaptic transmission, and it iscaused by a prior synaptic activation. Changes in NDMA receptor activity are believed tounderlie LTP. The NMDA receptor is a type of glutamate receptor, and it differs from the AMPAclass of glutamate receptor because it can conduct calcium ions in addition to sodium ions. Inthe NMDA receptor, calcium ion channels open in response to glutamate binding if there issufficient postsynaptic depolarization to displace a magnesium ion block on the channel. Theinflux of calcium is thought to trigger a cascade of events which ultimately lead to an increase insynaptic efficacy. NMDA receptors in the hippocampus have been extensively studied because theimportance of the hippocampus in spatial memory is well established, and it is therefore easy toevaluate the roll of hippocampal NMDA receptors on memory systems. A study by Tonegawa etal. titled The Essential Role of Hippocampal CA1 NMDA Receptor–Dependent SynapticPlasticity in Spatial Memory demonstrates that NMDA receptors in the hippocampus arenecessary 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 tonormal control mice with normal NMDAR1 function in a series of spatial and non-spatiallearning tasks. The NMDAR1 is present only in CA1 pyramidal cells of the hippocampus, andtherefore the researchers hypothesized that only spatial memory would be affected by the geneknock out. Consistent with their hypothesis, the NMDAR1 knock out mice grew to be adultswithout 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 tothis region failed to produce LTP, suggesting that the absence of NMDAR1 receptors inhibitedLTP 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 besaturated, resulting in a disruption of spatial memory. In order to saturate LTP in thehippocampus, the authors unilaterally lesioned the hippocampus in rats in order to reduce totalhippocampal volume, and then stimulated the intact hippocampus with three electrodes. Somerats received low frequency stimulations which did not saturate LTP and served as the controlspecimens, while the experimental rats received high frequency stimulations. The tetanusstimulations used to saturate LTP were given at 0, 1.5, 3, 4.5, and 6 hours after the previousstimulation. After LTP was induced, the animals were trained to find a hidden platform in awater maze, and their performance in this spatial memory task was assessed by measuring thetime 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 wasmeasured by recording the enhancement in EPSP slope after additional tetanus stimulation in anew site in the hippocampus. The high frequency stimulation rats were thus divided into animalsthat showed < 10% LTP (near complete LTP saturation during the water maze test) and animalsthat showed >10% LTP (not complete LTP saturation during the water maze test). The >10%