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The Role of NMDA Receptors in Excitotoxicity
NMDA receptors have been implicated by a number of studies to be strongly involved with excitotoxicity. Because NMDA receptors play an important role in the health and function of neurons, there has been much discussion on how these receptors can affect both cell survival and cell death. Recent evidence supports the hypothesis that overstimulation of extrasynaptic NMDA receptors has more to do with excitotoxicity than stimulation of their synaptic counterparts. In addition, while stimulation of extrasynaptic NMDA receptors appear to contribute to cell death, there is evidence to suggest that stimulation of synaptic NDMA receptors contributes to the health and longevity of the cell. There is ample evidence to support the dual nature of NMDA receptors based on location, and the hypothesis explaining the two differing mechanisms is know as the "Localization Hypothesis".

Differing Cascade Pathways
In order to support the localization hypothesis, it would be necessary to show differing cellular signaling pathways are activated by NMDA receptors based on its location within the cell membrane. Experiments have been designed to stimulate either synaptic or non-synaptic NMDA receptors exclusively. These types of experiments have shown that different pathways are being activated or regulated depending on the location of the signal origin. Many of these pathways use the same protein signals, but are regulated oppositely by NMDARs depending on its location. For example, synaptic NMDA excitation caused a decrease in the intracellular concentration of p38 mitogen-activated protein kinase (p38MAPK). Extrasynaptic stimulation NMDARs regulated p38MAPK in the opposite fashion, causing an increase in intracellular concentration. Experiments of this type have since been repeated with the results indicating these differences stretch across many pathways linked to cell survival and excitotoxicity.

Two specific proteins have been identified as a major pathway responsible for these different cellular responses ERK1/2, and Jacob. ERK1/2 is responsible for phosphorylation of Jacob when excited by synaptic NMDARs. This information is then transported to the nucleus. Phosphorylation of Jacob does not take place with extrasynaptic NMDA stimulation. This allows the transcription factors in the nucleus to respond differently based in the phosphorylation state of Jacob.

Neural Plasticity
NDMA receptors are also associated with synaptic plasticity. The idea that both synaptic and extrasynaptic NMDA receptors can affect long-term potentiation (LTP) and long-term depression (LTD) differently has also been explored. Experimental data suggest that extrasynaptic NMDA receptors inhibit LTP while producing LTD. Inhibition of LTP can be prevented with the introduction of a NMDA antagonist. A theta burst stimulation that usually induces LTP with synaptic NMDARs, when applied selectively to extrasynaptic NMDARs produces a LTD. Experimentation also indicates that extrasynaptic activity is not required for the formation of LTP. In addition, both synaptic and extrasynaptic are involved in expressing a full LTD.

The Role of Differing Subunits
Another factor that seems to affect NMDAR induced toxicity is the observed variation in subunit makeup. NMDA receptors are heterotetramers with two GluN1 subunits and two variable subunits. Two of these variable subunits, GluN2A and GluN2B, have been shown to preferentially lead to cell survival and cell death cascades respectively. Although both subunits are found in synaptic and extrasynaptic NMDARs there is some evidence to suggest that the GluN2B subunit occurs more frequently in extrasynaptic receptors. This observation could help explain the dualistic role that NMDA receptors play in excitotoxicity.

Despite the compelling evidence and the relative simplicity of these two theories working in tandem, there is still disagreement about the significance of these claims. Some problems in proving these theories arise with the difficulty of using pharmacological means to determine the subtypes of specific NMDARs. In addition, the theory of subunit variation does not explain how this effect might predominate, as it is widely held that the most common tetramer, made from two GluN1 subunits and one of each subunit GluN2A and GluN2B, makes up a high percentage of the NMDARs.

Excitotoxicity in a Clinical Setting
Excitotoxicity has been thought to play a role in the degenerative properties of neurodegenerative conditions since the late 1950s. NMDA receptors seem to play an important role in many of these degenerative diseases affecting the brain. Most notably exocytotic events involving NMDA receptors have been linked to Alzheimer's Disease and Huntington's Disease as well as with other medical conditions such as strokes and epilepsy. Treating these conditions with one of the many known NMDA receptor antagonists, however, lead to a variety of unwanted side effects, some of which can be quite severe. These side effects are, in part, observed because the NMDA receptors do not just signal for cell death but also play an important role in its vitality. Treatment for these conditions might be found in blocking NDMA receptors not found at the synapse.