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In neuroscience, retrograde signaling (retrograde neurotransmission) is 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.[1] The primary purpose of retrograde neurotransmission is regulation of chemical neurotransmission.[1] For this reason, retrograde neurotransmission allows neural circuits to create feedback loops. In the sense that retrograde neurotransmission mainly to regulate typical, anterograde neurotransmission, rather than to actually distribute any information, it is similar to electrical neurotransmission. In contrast with conventional (anterograde) neurotransmitters, retrograde neurotransmitters are synthesized in the postsynaptic neuron, and bind to receptors on the axon terminal of the presynaptic neuron.

Endocannabinoids like anandamide are known to act as retrograde messengers,[2][3][4] as is nitric oxide.

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:[1]

  • 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

The most prevalent endogenous retrograde neurotransmitters are nitric oxide and various cannabinoids.

Retrograde signaling in long-term potentiation

Main article: 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,[5] platelet-activating factor,[6][7] 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.[8] The endocannabinoids anandamide and/or 2-AG, acting through G-protein coupled cannabinoid receptors, are the primary retrograde messengers in the brain, and may also play an important role in retrograde signaling in LTP.[2][3]

Nitric oxide is the molecule that signals from post synaptic neurons to presynaptic neurons. This causes glutamate release which upregulates presynaptic AMPA receptors thus sustaining long term potentiation


  1. 1.0 1.1 1.2 Regehr, Wade G., Carey, Megan R.; Best, Aaron R. (30 July 2009). Activity-Dependent Regulation of Synapses by Retrograde Messengers. Neuron 63 (2): 154–170.
  2. 2.0 2.1 Alger BE (2002). Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog. Neurobiol. 68 (4): 247–86.
  3. 3.0 3.1 Wilson RI, Nicoll RA (2001). Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410 (6828): 588–92.
  4. DOI:10.1016/S0959-4388(02)00328-8
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  5. Alkadhi K, Al-Hijailan R, Malik K, Hogan Y (2001). Retrograde carbon monoxide is required for induction of long-term potentiation in rat superior cervical ganglion. J Neurosci 21 (10): 3515–20.
  6. Kato K, Zorumski C (1996). Platelet-activating factor as a potential retrograde messenger. J Lipid Mediat Cell Signal 14 (1–3): 341–8.
  7. Kato K, Clark G, Bazan N, Zorumski C (1994). Platelet-activating factor as a potential retrograde messenger in CA1 hippocampal long-term potentiation. Nature 367 (6459): 175–9.
  8. Malenka R, Bear M (2004). LTP and LTD: an embarrassment of riches. Neuron 44 (1): 5–21.
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