Retrograde signaling in biology is a process whereby the function of one part of a cell is controlled by feedback from another part of the cell, or where one cell sends reciprocal messages back to another cell that regulates it.
In neuroscience, retrograde signaling (or retrograde neurotransmission) refers more specifically to the process by which a retrograde messenger, such as anandamide or nitric oxide, is released by a postsynaptic dendrite or cell body, and travels "backwards" across a chemical synapse to bind to the axon terminal of a presynaptic neuron.
In cell biology
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The primary purpose of retrograde neurotransmission is regulation of chemical neurotransmission. For this reason, retrograde neurotransmission allows neural circuits to create feedback loops. In the sense that retrograde neurotransmission mainly serves to regulate typical, anterograde neurotransmission, rather than to actually distribute any information, it is similar to electrical neurotransmission.
In contrast to conventional (anterograde) neurotransmitters, retrograde neurotransmitters are synthesized in the postsynaptic neuron, and bind to receptors on the axon terminal of the presynaptic neuron.
Retrograde signaling may also play a role in long-term potentiation, a proposed mechanism of learning and memory, although this is controversial.
Formal definition of a retrograde neurotransmitter
In 2009, Regehr et al. proposed criteria for defining retrograde neurotransmitters. According to their work, a signaling molecule can be considered a retrograde neurotransmitter if it satisfies all of the following criteria:
- The appropriate machinery for synthesizing and releasing the retrograde messenger must be located in the postsynaptic neuron
- Disrupting the synthesis and/or release of the messenger from the postsynaptic neuron must prevent retrograde signaling
- The appropriate targets for the retrograde messenger must be located in the presynaptic bouton
- Disrupting the targets for the retrograde messenger in the presynaptic boutons must eliminate retrograde signaling
- Exposing the presynaptic bouton to the messenger should mimic retrograde signaling provided the presence of the retrograde messenger is sufficient for retrograde signaling to occur
- In cases where the retrograde messenger is not sufficient, pairing the other factor(s) with the retrograde signal should mimic the phenomenon
Types of retrograde neurotransmitters
Retrograde signaling in long-term potentiation
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.
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.
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. The endocannabinoids anandamide and/or 2-AG, acting through G-protein coupled cannabinoid receptors, may play an important role in retrograde signaling in LTP.
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