NMDA Receptor - STDP mechanism

I've talked a lot about STDP and also calcium spikes - Larkum calls them NMDA spikes. I thought I'd dive into a little more detail about NMDA receptors - how they work, how they may be signaling, and how they are involved in learning.

The peculiar thing about STDP is that it almost completely reverses in a manner of milliseconds. If the action-potential is not precisely timed relative to the release of glutamate at the synapse, then STDP can completely reverse. People think that the mechanism of this is the NMDA receptor. What makes the NMDA receptor uniquely suitable as a mechanism for STDP is that it can be blocked by Magnesium. NMDA is primarily a Ca+2 transmitter, and Mg+2 - with the same charge, is pretty similar to Ca. However, Mg cannot fit through the NMDA receptor and can get stuck. If it gets stuck in the receptor it blocks any Calcium from getting through.

There is a special circumstance where the Mg block is removed. It all has to do with driving forces and electro-chemical gradients. The simplest way of understanding how ions will move across the cell membrane is to consider the voltage of the cell and the charges of the ions - if the cell is negatively charged it will attract positively charged ions. But there is another aspect: the concentration gradient. Ions will move to also equilibrate their relative concentrations. Calcium is a very special ion. The neuron has channels and calcium stores that pump out or suck up all the calcium floating in the intracellular space. There is basically no calcium in the cell. Terry Sejnowski said that they've calculated that there probably is only a single free calcium atom floating in a synaptic bouton. So calcium has a strong chemical gradient, and will still move into the cell, even if the cell is positively charged. Magnesium, however, is not pumped out, and its movement across the membrane is dominated by the electrical gradient - Mg mainly follows the electrical gradient. 

So there is a range where the cell can be at the right voltage such that Calcium is being driven into the cell, while magnesium is driven out of the cell. This period is when the NMDA receptor will flux calcium into the cell. The NMDA receptor is also a glutamate receptor. For it to conduct calcium the pre-synaptic cell must release glutamate just before the post-synaptic cell depolarizes - like from an action-potential. This sets up a precise temporal window where NMDA receptors can flux calcium, and it is thought that this triggers the cascade leading to potentiation of the synapse.