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 factors with the retrograde signal should mimic the phenomenon Types of retrograde neurotransmitters The most prevalent endogenous retrograde neurotransmitters are nitric oxide and various endocannabinoids, which are lipophilic ligands. The retrograde neurotransmitter, nitric oxide (NO) is a soluble gas that can readily diffuse through various cell membranes. Nitric oxide synthase is the enzyme responsible for the synthesis of NO in various presynaptic cells. Specifically, NO is known to play a critical role in LTP, which plays an important role in memory storage within the hippocampus. Additionally, literature suggests that NO can act as intracellular messengers in the brain and can also have an effect on the presynaptic glutamatergic and GABAergic synapses. Utilizing retrograde signaling, endocannabinoids, a type of retrograde neurotransmitter, are activated when they bind to G-protein coupled receptors on the presynaptic terminals of neurons. The activation of endocannabinoids results in the release of particular neurotransmitters at the excitatory and inhibitory synapses of a neuron, ultimately impacting various forms of plasticity. Retrograde signaling in long-term potentiation As it pertains to 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