Synaptic tagging

Synaptic tagging, or the synaptic tagging hypothesis, was first proposed in 1997 by Uwe Frey and Richard G. Morris; it seeks to explain how neural signaling at a particular synapse creates a target for subsequent plasticity-related product (PRP) trafficking essential for sustained LTP and LTD. Although the molecular identity of the tags remains unknown, it has been established that they form as a result of high or low frequency stimulation, interact with incoming PRPs, and have a limited lifespan.'We propose that LTP initiates the creation of a short-lasting protein-synthesis-independent 'synaptic tag' at the potentiated synapse which sequesters the relevant protein(s) to establish late LTP. In support of this idea, we now show that weak tetanic stimulation, which ordinarily leads only to early LTP, or repeated tetanization in the presence of protein-synthesis inhibitors, each results in protein-synthesis-dependent late LTP, provided repeated tetanization has already been applied at another input to the same population of neurons. The synaptic tag decays in less than three hours. These findings indicate that the persistence of LTP depends not only on local events during its induction, but also on the prior activity of the neuron.' Synaptic tagging, or the synaptic tagging hypothesis, was first proposed in 1997 by Uwe Frey and Richard G. Morris; it seeks to explain how neural signaling at a particular synapse creates a target for subsequent plasticity-related product (PRP) trafficking essential for sustained LTP and LTD. Although the molecular identity of the tags remains unknown, it has been established that they form as a result of high or low frequency stimulation, interact with incoming PRPs, and have a limited lifespan. Further investigations have suggested that plasticity-related products include mRNA and proteins from both the soma and dendritic shaft that must be captured by molecules within the dendritic spine to achieve persistent LTP and LTD. This idea was articulated in the synaptic tag-and-capture hypothesis. Overall, synaptic tagging elaborates on the molecular underpinnings of how L-LTP is generated and leads to memory formation. Frey, a researcher at the Leibniz Institute for Neurobiology, and Morris, a researcher at the University of Edinburgh, laid the groundwork for the synaptic tagging hypothesis, stating: L-LTP inducing stimulus induces two independent processes including a dendritic biological tag that identifies the synapse as having been stimulated, and a genomic cascade that produces new mRNAs and proteins (plasticity products). While weak stimulation also tags synapses, it does not produce the cascade. Proteins produced in the cascade are characteristically promiscuous, in that they will attach to any recently tagged synapse. However, as Frey and Morris discovered, the tag is temporary and will disappear if no protein presents itself for capture. Therefore, the tag and protein production must overlap if L-LTP is to be induced by the high-frequency stimulation. The experiment performed by Frey and Morris involved the stimulation of two different sets of Schaffer collateral fibers that synapsed on same population of CA1 cells. They then recorded field EPSP associated with each stimulus on either S1 or S2 pathways to produce E-LTP and L-LTP on different synapses within the same neuron, based on the intensity of the stimulus. Results showed 1) that E-LTP produced by weak stimulation could be turned into L-LTP if a strong S2 stimulus was delivered before or after and 2)that the ability to convert E-LTP to L-LTP decreased as the interval between the two stimulations increased, creating temporal dependence. When they blocked protein synthesis prior to the delivery of strong S2 stimulation, the conversion to L-LTP was prevented, showing importance of translating the mRNAs produced by the genomic cascade. Subsequent research has identified an additional property of synaptic tagging that involves associations between late LTP and LTD. This phenomenon was first identified by Sajikumar and Frey in 2004 and is now referred to as 'cross-tagging'. It involves late-associative interactions between LTP and LTD induced in sets of independent synaptic inputs: late-LTP induced in one set of synaptic inputs can transform early-LTD into late-LTD in another set of inputs. The opposite effect also occurs: early LTP induced in the first synapse can be transformed into late LTP if followed by a late LTD-inducing stimulus in an independent synapse. This phenomenon is seen because the synthesis of nonspecific plasticity related proteins (PRPs) by late-LTP or -LTD in the first synapse is sufficient to transform early-LTD/LTP to late-LTD/LTP in the second synapse after synaptic tags have been set. Blitzer and his research team proposed a modification to the theory in 2005, stating that the proteins captured by the synaptic tag are actually local proteins that are translated from mRNAs located in the dendrites. This means that mRNAs are not a product of genomic cascade initiated by strong stimulus, but rather, is delivered as a result of continual basal transcription. They proposed that even weakly stimulated synapses that were tagged, yet lack the genomic cascade, can accept proteins that were produced nearby from a strong stimulation. Synaptic tagging/ tag-and-capture theory potentially addresses the significant problem of explaining how mRNA, proteins, and other molecules may be specifically trafficked to certain dendritic spines during late phase LTP. It has long been known that the late phase of LTP depends on protein synthesis within the particular dendritic spine, as proven by injecting anisomycin into a dendritic spine and observing the resulting absence of late LTP. To achieve translation within the dendritic spine, neurons must synthesize the mRNA in the nucleus, package it within a ribonucleoprotein complex, initiate transport, prevent translation during transport, and ultimately deliver the RNP complex to the appropriate dendritic spine. These processes span a number of disciplines and synaptic tagging/tag-and-capture cannot explain them all; nevertheless, synaptic tagging likely plays an important role in directing mRNA trafficking to the appropriate dendritic spine and signaling the mRNA-RNP complex to dissociate and enter the dendritic spine.