The Connection between Magnesium and NMDA Receptor
Why You Need to Supplement Magnesium for the Good of your Brain
After a long hiatus, I’ve decided to begin publishing here again. So long as this is free, there will be a lot of crossover between the content on here and on twitter (I mean X). With that in mind, the contents of this post are pulled from a recent twitter post of mine that I wrote about the interaction between magnesium and the NMDA glutamate receptor. This is one of the favorite things I have written, and it is an important interaction that you should be aware of if you want to learn more about neuroscience and the brain.
The pictures used in this post are from a paper looking at the physiological properties of the NMDA receptor, “NMDA Receptor Function and Physiological Modulation” (Zito and Scheuss, 2009) (Link to the Article). All of them are part of figure 3, looking at the relationship between this receptor and magnesium. I’ll include the full figure below.
With that, onto the content of this post.
The NMDA glutamate receptor is the most unique receptor in the brain. Its a ligand gated ion channel like many others but it contains a physical blocker, a magnesium ion.
Why does it matter?
This channel is permeable to calcium as well as sodium. Calcium is an important signaling molecule, but too much of it drives cell disfunction and death. More on that later. The structure of this channel allows a magnesium ion to sit in it and block ion flow even if glutamate (and glycine a co-agonist) are bound. At rest, the inside of neurons are more negative than the outside of the neuron (about -70 mV), and this attracts the very positive magnesium ion (Mg2+) to sit inside the channel with hopes of entering the very negative space, though it won't. It will just block the action of this receptor when the inside of the neuron is more negative than the outside, or has a negative membrane potential.
When the neuron is just as positive or more positive than its outside, the magnesium ion leaves the channel and ions can flow freely when glutamate is bound. An image of this phenomena is shown below.
What does this look like in practice though? This graph shows the total current flow through an NMDA channel at different membrane potentials with or without magnesium present (dotted = magnesium, filled = no magnesium). When magnesium is present the channel allows nothing through until a positive membrane potential, when there is no negative charge to attract it anymore.
Without magnesium present ions can flow through freely at any membrane potential. The same is shown in the next image, the "spikes" show current and the flatter the line the less ions moving through the channel. With no magnesium, the channel is active at negative membrane potentials, whereas only positive with magnesium.
But if the channels are blocked what causes the neuron to become more positive? Activation of AMPA receptors, the other ionotropic glutamate receptor. These are a simple receptor, letting sodium (Na+) into the neuron when activated, making its inside more positive. Therefore, sufficient AMPA activity is needed to allow NMDA receptors to activate. At least when there's sufficient magnesium present. Lack of magnesium allows NMDA receptors to be activated when they normally wouldn't be able to under the correct physiological condition.
Today, most are magnesium deficient. Lack of magnesium means a lower concentration in the brain, and therefore more NMDA activity (which isn't a good thing). This receptors activity is supposed to be gated until the neuron receives enough input elsewhere. Then when it finally activates is allows calcium (Ca2+) into the cell. Calcium, being an important signaling molecule, triggers signaling cascades and drives synaptic plasticity, generally to make the connection of the two neurons stronger in some way (like inserting more receptors into the membrane). This mechanism is heavily implicated in learning and memory, but it's thrown out of whack with a lack of magnesium.
Excess calcium is also neurotoxic, and can kill neurons if too much is allowed in. This is a driving force of cell death in ischemic stroke.
No blood flow means lack of oxygen and glucose, leads to lack of ATP, this causes membrane potential to not be upheld and glutamate to not be reuptaken out of synapses, action potentials fire like crazy activating receptors, and a huge influx of calcium leads to cell death.
Supplementing magnesium helps make sure there is a high enough concentration in your brain to actively block NMDA receptors when it should, protecting you against glutamate excitotoxicity, and overall decreasing glutamate activity. This is one of the primary ways magnesium has anti-anxiety effects when taken.
In short; take your magnesium, your brain will thank you.
Moving forward, I’m planning to post more long post style content here. Like I said above, for now there will be a lot of overlap between here and twitter so long as this newsletter remains free. If you have any topics you would like to see posts on in the future please let me know with a comment here.