Retrograde signaling in LTP

As it pertains to long-term potentiation (LTP), retrograde signaling is a hypothesis describing how events underlying LTP may begin in the postsynaptic neuron but be propagated to the presynaptic neuron, even though normal communication across a chemical synapse occurs in a presynaptic to postsynaptic direction. It is used most commonly by those who argue that presynaptic neurons contribute significantly to the expression of LTP.

Background
Long-term potentiation is the persistent increase in the strength of a chemical synapse that lasts from hours to days. It is thought to occur via two temporally separated events, with induction occurring first, followed by expression. Most LTP investigators agree that induction is entirely postsynaptic, whereas there is disagreement as to whether expression is principally a presynaptic or postsynaptic event. Some researchers believe that both presynaptic and postsynaptic mechanisms play a role in LTP expression.

Were LTP entirely induced and expressed postsynaptically, there would be no need for the postsynaptic cell to communicate with the presynaptic cell following LTP induction. However, postsynaptic induction combined with presynaptic expression requires that, following induction, the postsynaptic cell must communicate with the presynaptic cell. Because normal synaptic transmission occurs in a presynaptic to postsynaptic direction, postsynaptic to presynaptic communication is considered a form of retrograde transmission.

Mechanism
The retrograde signaling hypothesis proposes that during the early stages of LTP expression, the postsynaptic cell "sends a message" to the presynaptic cell to notify it that an LTP-inducing stimulus has been received postsynaptically. The general hypothesis of retrograde signaling does not propose a precise mechanism by which this message is sent and received. One mechanism may be that the postsynaptic cell synthesizes and releases a retrograde messenger upon receipt of LTP-inducing stimulation. Another is that it releases a preformed retrograde messenger upon such activation. Yet another mechanism is that synapse-spanning proteins may be altered by LTP-inducing stimuli in the postsynaptic cell, and that changes in conformation of these proteins propagates this information across the synapse and to the presynaptic cell.

Identity of the messenger
Of these mechanisms, the retrograde messenger hypothesis has received the most attention. Among proponents of the model, there is disagreement over the identity of the retrograde messenger. A flurry of work in the early 1990s to demonstrate the existence of a retrograde messenger and to determine its identity generated a list of candidates including carbon monoxide, platelet-activating factor, arachidonic acid, and nitric oxide. Nitric oxide has received a great deal of attention in the past, but has recently been superseded by adhesion proteins that span the synaptic cleft to join the presynaptic and postsynaptic cells. In recent years it has been generally accepted that the endocannabinoids anandamide and/or 2-AG, acting through G-protein coupled cannabinoid receptors, are the primary retrograde messangers in the brain.