Scientific Research on NMDA Neurotransmission
NMDA receptors are one of the subsets of glutaminergic receptors, involved in mediating the effects of the main stimulatory neurotransmitter glutamate. NMDA receptors are also responsive to D-Aspartic Acid and its methylated form, which is N-methyl-D-Aspartic Acid (NMDA for short).
It is one of the more well researched glutaminergic receptors, alongside AMPA receptors and Kainate receptors. Beyond those three, there are a series of eight metabotropic glutamate receptors (mGluR1-8) which are G-protein coupled receptors.
When activated, NMDA receptors cause calcium influx into a neuron and increase its excitability.
The NMDA receptor is one of the receptors that mediates the effects of the main excitatory amino acid, glutamate. It is also selectively responsive to D-aspartic acid and named after it'e methylated form (N-methyl-D-aspartic acid or NMDA)
The NMDA receptor is known to have a glycine-binding site, which responds to glycinergic compounds with high affinity and subsequently alters the affinity of the NMDA receptor towards agonists. Due to this, activity at the glycine binding site is seen as supportive of NMDA neurotransmission and ligands that bind here are known as co-agonists.
Although the binding site is named after Glycine, which was the first agonist to be discovered to affect this site (hence the name), it was later discovered that D-serine is more biologically relevant at this site.
The glycine binding site positively modulates NMDA receptor activity, and glycincergic compounds can support NMDA neurotransmission
1.3Synaptic v. Extrasynaptic
Synaptic receptors induce primarily nuclear Ca2+ signaling and are seen as neuroprotective, and are classically defined as functional receptors activated by glutmate during low frequency synaptic events.
Extrasynaptic receptors are those that mediate excitotoxic cell death. These consist of approximately one third of receptors in immature cells and increase with maturation. Approximately a quarter of extrasynaptic receptors are known as perisynaptic (within 100nM of the post-synaptic density).
NMDA receptors can be located on the synapse, or they can be located off the synapse (perisynaptic or extrasynaptic). Depending on the location of the receptor, they appear to have differential effects on the neuron
In general, COX2 appears to be involved in NMDA excitotoxicity and its pharmacological inhibition is able to reduce NMDA-mediated cell death in neurons. This neuroprotection can be reversed by the arachidonic acid prostaglandins PGE2 and since activation of the NMDA receptors has elsewhere been linked to an increase in COX2 mRNA and arachidonic acid metabolism which correlates with neurotoxicity it seems that excessive COX2 activity (from excessive NMDA activation) can cause prostaglandin-dependent neurotoxicity.
Mice completely lacking COX2, however, appear to have enhanced seizure threshold.
COX2 expression has differential effects on NMDA induced excitotoxicity, and while it is inhernetly protective it can mediate excitotoxic cell death when it is overexpressed
- Hardingham GE, Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci. (2010)
- Harris AZ, Pettit DL. Extrasynaptic and synaptic NMDA receptors form stable and uniform pools in rat hippocampal slices. J Physiol. (2007)
- Scimemi A, et al. NR2B-containing receptors mediate cross talk among hippocampal synapses. J Neurosci. (2004)
- Tovar KR, Westbrook GL. The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J Neurosci. (1999)
- Petralia RS, et al. Organization of NMDA receptors at extrasynaptic locations. Neuroscience. (2010)
- Cottrell JR, et al. Distribution, density, and clustering of functional glutamate receptors before and after synaptogenesis in hippocampal neurons. J Neurophysiol. (2000)
- Groc L, Bard L, Choquet D. Surface trafficking of N-methyl-D-aspartate receptors: physiological and pathological perspectives. Neuroscience. (2009)
- Tovar KR, Westbrook GL. Mobile NMDA receptors at hippocampal synapses. Neuron. (2002)
- Groc L, et al. NMDA receptor surface mobility depends on NR2A-2B subunits. Proc Natl Acad Sci U S A. (2006)
- Yamagata K, et al. Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron. (1993)
- Stark DT, Bazan NG. Synaptic and extrasynaptic NMDA receptors differentially modulate neuronal cyclooxygenase-2 function, lipid peroxidation, and neuroprotection. J Neurosci. (2011)
- Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. (1993)
- Aamodt SM, Constantine-Paton M. The role of neural activity in synaptic development and its implications for adult brain function. Adv Neurol. (1999)
- Hewett SJ, et al. Cyclooxygenase-2 contributes to N-methyl-D-aspartate-mediated neuronal cell death in primary cortical cell culture. J Pharmacol Exp Ther. (2000)
- Strauss KI, Marini AM. Cyclooxygenase-2 inhibition protects cultured cerebellar granule neurons from glutamate-mediated cell death. J Neurotrauma. (2002)
- Carlson NG. Neuroprotection of cultured cortical neurons mediated by the cyclooxygenase-2 inhibitor APHS can be reversed by a prostanoid. J Neurosci Res. (2003)
- Li SQ, et al. Activation of NMDA receptor is associated with up-regulation of COX-2 expression in the spinal dorsal horn during nociceptive inputs in rats. Neurochem Res. (2009)
- Bosetti F. Arachidonic acid metabolism in brain physiology and pathology: lessons from genetically altered mouse models. J Neurochem. (2007)
- Toscano CD, et al. NMDA-induced seizure intensity is enhanced in COX-2 deficient mice. Neurotoxicology. (2008)