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Glutamate receptors are ionotropic activated. Ionotropic activation in NMDA receptors is the binding of the glutamate ligand-gated channels known for its unique role in a neurotransmission of an excitatory stimulus within the brain. The NMDA receptor differs from the other 2 subtypes of the glutamate receptors in that an NMDA receptor allows calcium to influx into the channel, with its association to the magnesium ion acting as a voltage-dependent sensor that controls the influx of calcium into the cell only during depolarization. Aside from that, the NMDA receptor is a heteromeric receptor composing of different subunits that function as a whole unit, rather than homomeric receptors where they have identical subunits functioning as one.
The NMDA receptor is an acronym for N-methyl-D-Aspartate receptors. It comprises of five main subunits known as NMDAR1, NMDAR2A, NMDAR2B, NMDAR2C, and NMDAR2D. These receptors functions to mediate synaptic transmission, and plasticity: the ability for synapses to change, causing the synaptic transmission to be weak or strong from the central nervous system, in response to an excitatory stimulus. This plays a crucial role "in the formation of spatial memory" (Miyashita, 2004). Aside from playing a key role in being a mediator in the synaptic transmission and synaptic plasticity, the NMDA receptors has been known to also play roles in "the generation of rhythmic motor activity, and the regulation of neuronal development in the embryonic nervous system," (Juntian& Yun 2000). The key importance of this NMDA receptor lies within its function when it comes to the synaptic plasticity being identified as the root source of certain forms of learning. According to the "Aging and NMDA receptors," by K.R. Magnusson (1998) "The NMDA receptors are involved in the performance of spatial, working and passive avoidance, memory tasks and in long term potentiation, a cellular phenomenon that is believed to be involved in at least some types of memory." The NMDA receptors are ligand gated channels which allow calcium, sodium, and potassium to influx into the channel without being picky, during depolarization of the postsynaptic cell, but have a voltage-sensitivity effect when it comes to the magnesium embedded deep inside the channel. There are 3 main binding sites that NMDA receptors composes of outside the channel; one for glutamate binding which is known as the NMDAR2 subunits, and the other one for glycine binding which is the NMDAR1 and one inside the pore for magnesium. There are 5 main components that make up NMDAR and researchers have identified 2 more that play a minor role. The main unit NMDAR1 and NMDAR2 subunits (A, B, C, and D) come together to form "heteromeric assemblies" (Cull-Candy, Brickley & Farrant, 2001), in other words different parts coming together to form one functioning whole. Each of the subunits have their own properties that contribute to the function of NMDA. The NMDAR2 subunits have an affinity for glutamate leaving the NMDAR1 subunit to have an affinity for glycine (Cull-Candy, Brickley & Farrant, 2001). The conductance and block by Mg2+ is dependent on the types of NMDAR2 that make up the structure of our receptor. According to Cull-Candy et al., if NMDAR has NMDAR2A or NMDAR2B subunits it generates 'high-conductance' channel openings and stronger attraction for magnesium blockage (Cull-Candy, Brickley & Farrant, 2001). They also found that the opposite is true for NMDAR2C and NMDAR2D subunits. NMDAR2C and NMDAR2D subunits demonstrate a 'low-conductance' opening and a weaker attraction to magnesium. It is thought that the difference between the sensitivity to magnesium gives antagonists the ability to block long-term potentiation and long-term depression in the hippocampus (Cull-Candy, Brickley & Farrant, 2001).
Throughout different areas of the brain there are different concentrations of each subunit and there are different subunit assemblies during development. During embryonic stages of development there is a significant amount of NMDAR2B subunits composing NMDA receptors throughout different regions in the fetal brain, it was also noted that NMDAR2D was highly concentrated in the diencephalon (Cull-Candy, Brickley & Farrant, 2001). After birth those subunits change, NMDAR2B subunits quickly get replaced by NMDAR2A subunits. The amount of change between subunits differs between regions (Cull-Candy, Brickley & Farrant, 2001). It has been seen that NMDAR2A subunits take over a majority of the regions in the brain while NMDAR2C subunits appear only in the cerebellum (Yun & Juntian, 2000). Also, NMDA2B are restricted to the forebrain and NMDA2D are almost completely whipped out (Yun & Juntian, 2000). The change from NMDAR2B subunits to NMDAR2A subunits is what is thought to cause NMDAR-EPSC decay. NMDAR-EPSC decay, acronym for N-methyl-D-aspartate excitatory postsynaptic current, is an event that causes "neuronal circuits to exhibit experience-dependent synaptic plasticity" (Cull-Candy, Brickley & Farrant, 2001). Experience-dependent synaptic plasticity is the "strengthening or weakening of existing synapses as well as structural plasticity, including synaptic formation and elimination" (Holtmaat & Svodoba, 2009).
As we age memory and cognitive processes start to decline. They attribute this to the decrease of binding between agonist L-glutamate and antagonists CPP, CGS19755, and CGP39653 in the hippocampus and cerebral cortex (Magnusson, 1998). These two areas are related to important memory processes. Tests have shown that there is a noticeable decline in NMDA receptors in the cerebral cortex then in the hippocampus in most cases (Magnusson, 1998). Over time there is a decrease in binding sites that makes it difficult for these agonists and antagonists to bind and it should not be confused with the receptor's affinity for binding (Magnusson, 1998). Only in glutamate and glycine binding sites does affinity decrease due to aging (Magnusson, 1998). The cause for decline in receptor binding and affinity is not clear and opens up an area for further research. Researchers are looking into the decrease in NMDAR1 expression as a possible cause for the declinations (Magnusson, 1998). Rodents are the predominant model organisms to compare to humans and have been used in various NMDA receptor studies. In many of these rodent studies there have been results indicating that lower binding to NMDA receptors in the frontal cortex and or the hippocampus has contributed to the decrease in spatial memory (Magnusson, 1998). There were a few cases where the result of their experiment showed that the opposite was true, lower binding caused better memory, but was not further looked into.
As aforementioned, NMDA receptors are known as an inotropic glutamate receptor because once the glutamate binds to its recognition site a co-agonist is needed to activate the channel allowing the channel to have a cascade effect. Several different molecules and ions have different functions and effects when it comes to the NMDA receptors because of the different ligand binding sites which act to control, the response of the channel. For instance, once the channel is open, calcium ion is able to flow into the channel which functions to intensify the attraction for glycine the co-agonist, in the recognition sites of the NMDAR1subunit, aside from that, calcium functions to deactivate the NMDA receptor, preventing further ionic flux in a non-voltage dependent way. Zinc also acts to prevent the current flow in a noncompetitive and non-voltage dependent way, similar to magnesium's blocker effect, except magnesium is voltage dependent and its binding site is located internally rather than externally within the channel. Lead has also been found to play a role in controlling the response of an NMDA receptor by having a toxic effect, which had been linked to the declining results when it comes to memory and learning function. Another way that an NMDA receptor is controlled is through polyamines, this protein binding sites act to intensify or inhibit the response of the channel to glutamate. Aside from various ways that an activity of the NMDA receptors is controlled through different binding sites, the concentration of protons in the environment plays a huge role in the activity of the NMDA receptors. The change in the pH concentration can suppress the NMDA receptor channel when there is a high concentration of protons binding in the binding sites, therefore causing a restriction to the influx of calcium ions into the channel. Since calcium ions function in neuronal plasticity, the influx of calcium ions might be the key to learning expression, according to Magnusson (1998).
The NMDA receptors are easily activated when both the glutamate and it's co-agonist glycine binds and activates the channel, but a prolonged exposure to either the glycine alone, calcium, or both will cause the channel to be inactive. This process shows just how important the different binding sites are because they contribute to the action of the channel. In normal cases, both the glycine and calcium have the ability to deactivate the channel, but in an abnormal way, when a disorder occurs in one of the multiple binding sites, a neurological disorder can occur disrupting the homeostasis of the glutamate. A prolonged or excessive activation of the excitatory glutamate receptors can lead to a neuronal injury and or neuronal death which increases the chances for disorders such ischemia, trauma, seizures or stroke, and or other neurodegenerative disorders such as dementia or Huntington disease to occur (Hardingham & Bading, 2003).
Provoking NMDA receptors in an ill-suited manner can lead to distress and disease. The inappropriate influx of calcium ions into NMDA receptors contribute to excitotoxic neuronal death which is nerve damage caused by the excessive stimulation of neurotransmitters (Cull-Candy, Brickley & Farrant, 2001). This excitotoxicity is a mechanism for stroke and seizures. By blockading NMDA receptors from excessive influx we can protect against ischemia at the molecular level. But, we must be weary of blockading NMDA receptors using certain agonists or antagonists. Some can have severe psychological drawbacks as seen with ketamine and phencyclidine, these non-competitive antagonists can cause behavioral changes similar to schizophrenia (Cull-Candy, Brickley & Farrant, 2001). An opportunity for further research can be conducted by finding antagonists and agonists that blockade NMDA receptors without psychological drawbacks. The associations between NMDA receptor subunits and ischemia have been found to not all affect neuronal death (Cull-Candy, Brickley & Farrant, 2001). Different subunits have greater impact on ischemia where as others do not. A rodent study found that mice lacking NMDAR2C subunits had less neuronal death after having an episode (Cull-Candy, Brickley & Farrant, 2001).
A new topic of focus has been getting much attention when it comes to excessive stimulation of the NMDA receptors, the association of Huntington's disease with NMDA receptors. There has been a concentration on two proteins, huntingtin (htt) and a mutant form of huntingtin (mhtt), and how overexpression of these two can influence the function and cause excitotoxicity of NMDA receptors (Fernades & Raymond, 2009). Researchers mostly focus on the overexpression of mhtt on NMDA receptors composed of NMDAR1 and NMDAR2B subunits which causes the receptor to become overly active and contribute to excitotoxicity (Fernades & Raymond, 2009). Evaluations of brains from Huntington's patients that have passed away show less NMDA receptor binding sites in the striatum (Fernades & Raymond, 2009).
NMDA receptors have been shown to impact schizophrenia a form of psychosis. Schizophrenic models have been made to observe how NMDA receptors attribute to schizophrenia. It was observed that in these models early administration of antagonists on these receptors increased cellular destruction or changed the function of the NMDA receptor. This all occurs in early development but the psychosis itself does not become apparent until later on in life (BubenÄ±kova -Valesova, Horacek, Vrajova & Hoschl, 2008).
Since we live in a time where people are living longer that they use to, thanks to the medical advancement and medication that has helped prolonged the age of every individual alive today, Alzheimer's disease, a type of dementia has been on the rise. Whether it be HIV associated dementia or its common form through Alzheimer's, this type of disease has shown to have a declining effect in cognitive function, causing individuals to live a life with behavioral disturbances and cognitive failures. A dysfunction in the neurotransmission of the glutamate has been found to have an association with behavioral changes and cognitive failure. The cognitive memory and NMDA receptors are linked together through neuronal plasticity. So a decline in cognitive memory and the rise of behavioral disturbances can be linked to the neuronal plasticity impairment.
According to a study with Aging and NMDA receptor by Magnusson, "a factor that contributes to neurodegenerative disorders occurs through old age, like many other organs, the NMDA receptors declines in its functional ability as one age." The change that occurs within the NMDA receptors have shown to have a correlation with a declining effect in memory and learning function due to some of the subunit changing its expressions as one ages. This was evident after observing a study with old and young rats having different composition of subunit functional expression within the frontal cortex and the hippocampus regions (Magnusson 1998). This could also be a potential answer as to why old age causes the recall of memory performance to be poor or less efficient in older generations. All though more study is needed to truly confirm that this theory is due to old age, having a negative effect on the NMDA receptors has been believed to be the cause of neurodegenerative disorder such as dementia in respect to a decline in the function of the NMDA receptors subunit (Magnusson1998).
The NMDA receptors have shown to play major roles in vertebrate mammalian organism. So having a good functional NMDA receptor is needed for a cell to survive. The cause of an imbalance of the glutamate, and calcium levels in an NMDA receptor has the ability to disrupt a cells life cycle and cause neuronal death because it can result in excitotoxity. A lot of the disorders are really due to a decline in how efficient the NMDA receptors have become when it comes to excitatory stimulus and its tolerance effect.
The most effective innovation created to function as an antagonist as a treatment for the disorders of NMDA receptor has been through memantine. Memantine is known as 1-amino adamantine derivative that binds in an uncompetitive way to the receptor, preventing the common behavioral function of the NMDA receptor, but having no effect when it comes to learning and memory. It has been proven to be efficient when it comes to treating dementia in Alzheimer's disease, but also has been seen to have a good effect in other neurodegenerative disorders such as with stroke, epilepsy, and trauma. (Sonkusare SK, Kaul CL, Ramarao P 2004)
Most research has been concentrated on the excitotoxicity of NMDA receptors but other research has shown that a lower concentration of NMDA receptors can also help in neuroprotection (Ogita, Okuda, Yamamoto, Nishiyama & Yoneda, 2003). Ogita et al. conducted a study to observe whether NMDA receptors protect against the agonist kainate. Kainate was defined by Ogita as an excitotoxin that has the ability to cause epileptic events that lead to irreversible pathological damage to neurons, glia, myelin sheaths and blood vessels in the central nervous system (Ogita, Okuda, Yamamoto, Nishiyama & Yoneda, 2003). In their study they found that treatment of NMDA caused complete protection against the loss of neurons by kainate agonists. With this conclusion this can open up a door for pharmacological research. Drug companies can look into NMDA receptor neuroprotection as a way to help prevent neurodegenative diseases.