LTP induction

The AMPA receptor (AMPAR) is the engine that drives excitatory postsynaptic potentials (EPSPs). While some forms of the AMPAR can conduct calcium, most AMPARs found in the neocortex do not. The AMPAR, upon binding two glutamate molecules, undergoes a conformational change that resembles the opening of a clam shell. This conformational change opens an ion channel within the AMPAR protein structure that allows sodium ions to flow into the cell and potassium ions to flow out (i.e. it is a mixed cation-conducting channel). The Na⁺ and K⁺ permeabilities of the AMPAR channel are roughly equal, so when this channel is open the resulting change in membrane potential tends towards zero (a bit more than halfway between the equilibrium potentials E_K and E_Na). This balance point is reached at around 0 mV (i.e. the reversal potential of the EPSP current is roughly 0 mV). However, the postsynaptic membrane potential will not change by more than a few millivolts from resting potential with a single presynaptic release of glutamate, because not many AMPAR channels open. The lifetime of the glutamate in the synaptic cleft is too short to allow more than a brief opening of the AMPAR channel, thus causing only a small depolarization. The open AMPAR channel is often considered to be non-calcium permeable, but this is only an approximation as AMPARs with certain subunit compositions will allow calcium through, albeit at different levels and frequency to NMDARs.

Historically, the most widely used experimental means of inducing LTP has been to deliver a tetanic stimulation to the presynaptic axon of a synapse or group of synapses. The frequency of this tetanus is typically 100 Hz, and the duration typically 1 s. A single AMPAR-mediated EPSP has a rise time-to-peak of approximately 2–5 ms and a duration of approximately 30 ms. If a synapse is being stimulated at 100 Hz, the presynaptic neuron will be attempting to release glutamate once every 10 ms. An EPSP occurring only 10 ms after a previous EPSP will arrive at a time when that previous EPSP is at its peak amplitude. Thus, during a 100 Hz stimulus train, each EPSP will add to the membrane depolarization caused by the previous EPSPs. This synaptic summation drives the membrane potential toward values that could not be reached with single synaptic stimuli. As the EPSPs summate, they will exceed the spike threshold.

The NMDA receptor (NMDAR) does not, in resting or near-resting membrane potential conditions, contribute significant current to the EPSP. Following the presynaptic release of the glutamate that binds to and opens the AMPAR, the NMDAR also binds this glutamate and opens. However, current does not flow through the NMDAR ion channel because it is instantaneously blocked by a magnesium ion (Mg²⁺) that binds to a site "inside" the open pore of the NMDAR channel. Magnesium has access to this binding site only when the NMDAR channel is opened by glutamate binding, a so-called open channel block.