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Understanding the Role of NMDA Receptors

By: Sai Srihaas Potu

NMDA receptors have played a dominant role for many years in studies focusing on learning and memory as well as neurotoxicity. N-Methyl-D-aspartate receptors are essential for cellular homeostasis and the neuroplasticity of the brain. Any disruption in this pathway, leading to either enhanced or decreased activity, may result in the manifestation of neuropsychiatric pathologies such as schizophrenia, mood disorders, substance-induced psychosis, Huntington’s disease, and Alzheimer’s disease. Previous research studies have proven the integral role of NMDA receptors in the brain. As the brain ages, the NMDA receptor system becomes progressively hypofunctional which ultimately contributes to decreases in memory and learning performance.


NMDA receptors can be activated by binding with an assortment of neurotransmitters such as glutamate, aspartate, glycine, D-serine. NMDA receptors work with these neurotransmitters to activate areas of the brain that help you learn new information and form memories by stimulating the neurons.


However, if the neurons stay excited for too long, they can become overstimulated and start to function poorly. Eventually, they become so overexcited that they die. That kind of overstimulation is called excitotoxicity. Glutamate and aspartate, in excess, are both classified as excitotoxins. To keep excitotoxicity from killing our brain cells, we also have neurotransmitters that calm the neurons. They're called inhibitors. Glycine, another one of the brain chemicals that bind with NMDA receptors, is an inhibitor in the spinal cord but is believed to be excitatory in the brain.


According to recent research, an NMDA receptor blockade can disrupt a variety of functions associated with neural plasticity, including the acquisition of learned responses and long-term potentiation. Deficits in memory are significantly correlated with deficits in measures of paradoxical sleep in several amnesic populations.


Sleep spindles are generated by the thalamic reticular nucleus. Thalamus is a brain region that redistributes sensory information from sensory organs to other regions, and its reticular nucleus is involved in regulating the nervous system's activity. In particular, the reticular nucleus helps to filter the information exchanged by the thalamus and the cortex. Together thalamus and cortex form the thalamocortical system of the brain. In people with psychosis, the normal activity of the thalamocortical system is disturbed, although not all mechanisms of these disorders have been studied. Individuals with schizophrenia are often characterized by a deficit of sleep spindles. Sleep problems are common to the illness but are often overlooked. Patients with schizophrenia often have a combination of subjective sleep complaints and objective findings on polysomnographic testing.


In the study, researchers looked at how NMDA glutamate receptors of the thalamocortical system contribute to the deficit of sleep spindles. They took sedated rats and injected them various medicines, such as ketamine–a substance that blocks NMDA receptors and causes a condition similar to acute psychosis. The changes in the activity of certain brain neurons under the medications were registered by microelectrodes placed on various levels of the thalamocortical system. A deficit of sleep spindles was observed in rats, similar to the changes in brain activity in people with schizophrenia. The researchers also observed a considerable decrease in delta oscillations, which appear in the brain in the state of deep natural sleep.


These observations confirm the role of NMDA receptors in sleep disorders that accompany psychotic states. The NMDA receptor blockade in rats was accompanied by changes in the strength of the connection between the thalamus and the thalamic reticular nucleus, which led to changes in EEG oscillations. Similar changes in brain activity may also appear in patients with schizophrenia, but this assumption requires further confirmation.


In light of this study, researchers have been able to conclude that overactive NMDA receptors can be detrimental to a human body both physically and psychologically. While more strong evidence being produced, researchers have been able to create many drugs and supplements that can alter the function of NMDA receptors. These substances come in two opposite forms: antagonists and agonists.


In the case of NMDA receptors, antagonists inhibit reception, meaning that they block neurotransmitters from unlocking these receptors. Many neurodegenerative diseases and other central nervous system disorders are sometimes treated with these types of medications. On the other hand, NMDA receptor agonists make it easier for neurotransmitters to access these receptors and increase the flow of information through the brain. These drugs are sometimes used to treat mood and mental disorders, including schizophrenia and suicidal thoughts. With further research being conducted, scientists will be able to understand the physiology and pathology of NMDA receptors which will help them develop new techniques that will prevent neurocognitive impairment.



References:

1. Belforte JE, Zsiros V, Sklar ER. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Natural Neuroscience. 2010.

2. Hughes EG, Peng X, Gleichman AJ. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. Journal of Neuroscience. 2010.

3. McIlhinney R. A. J., Philipps E., Le Bourdelles, Grimwood B. S., Wafford K., Sandhu S. Assembly of N-methyl-d-aspartate (NMDA) receptors. Biochemical Society Transactions. 2003.

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